Petition for Inter Partes Review of USP 7,297,703
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`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
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`
`
`In re Inter Partes Review of:
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`U.S. Patent No. 7,297,703
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`Issued: Nov. 20, 2007
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`Application No.: 11/020,860
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`Filing Date: Dec. 23, 2004
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`For: Macrolides
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`FILED VIA PRPS
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`
`PETITION FOR INTER PARTES REVIEW
`OF U.S. PATENT NO. 7,297,703
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`Table of Contents
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`Petition for Inter Partes Review of USP 7,297,703
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`I.
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`II.
`
`Introduction ...................................................................................................... 1
`
`Requirements for Petition for Inter Partes Review ......................................... 1
`
`A. Grounds for Standing (37 C.F.R. § 42.104(a)) ..................................... 1
`B.
`Notice of Lead and Backup Counsel and Service Information ............. 1
`C.
`Notice of Real-Parties-in-Interest (37 C.F.R. § 42.8(b)(1)) .................. 2
`D. Notice of Related Matters (37 C.F.R. § 42.8(b)(2)) .............................. 3
`Fee for Inter Partes Review .................................................................. 3
`E.
`F.
`Proof of Service ..................................................................................... 3
`
`III.
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`Identification of Claims Being Challenged (§ 42.104(B)) .............................. 3
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`IV. Description of The Purported Invention .......................................................... 4
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`V.
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`Background Knowledge of a POSA of the ’703 Patent .................................. 5
`
`A.
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`D.
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`Solid Mixtures, Including Solid Dispersions, Were Well-
`Known in the Art ................................................................................... 5
`B. Microemulsions Were Well-Known in the Art ..................................... 7
`C.
`Poly-ene Macrolides, Including Rapamycin and its Derivative
`40-O-(2-hydroxy)ethyl-rapamycin, Were Well-Known in the
`Art .......................................................................................................... 7
`Poly-ene Macrolides, Including Rapamycin and the Rapamycin
`Derivative 40-O-(2-hydroxy)ethyl Rapamycin, Were Well-
`Known to be Unstable under Normal Conditions and Were
`Routinely Stabilized by Mixing with Antioxidants, Including
`Vitamin E, Vitamin C, and 2,6-di-tert-butyl-4-methylphenol
`(BHT) .................................................................................................... 8
`Solid Mixtures of Poly-ene Macrolides, Including Rapamycin
`and its Derivative 40-0-(2-hydroxy)ethyl-rapamycin, Were
`Routine and Included Pharmaceutical Compositions Containing
`Pharmaceutically Acceptable Carriers or Diluents ............................. 11
`
`E.
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`VI. The Person of Ordinary Skill in the Art ........................................................ 11
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`VII. The Invalidating Prior Art Relied Upon ........................................................ 12
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`A. Guitard (Ex. 1004) ............................................................................... 12
`B.
`Fricker (Ex. 1005) ............................................................................... 14
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`Petition for Inter Partes Review of USP 7,297,703
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`C.
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`Eastlick (Ex. 1006) .............................................................................. 16
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`VIII. Motivation to Combine the Prior Art References.......................................... 18
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`A. Motivation to Combine Fricker with Eastlick ..................................... 19
`B.
`Reasonable Expectation of Success in Combining Fricker with
`Eastlick ................................................................................................ 23
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`IX. Claim Construction ........................................................................................ 24
`
`A.
`B.
`C.
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`“solid mixture” .................................................................................... 25
`“catalytic amount” ............................................................................... 26
`“admixed with” .................................................................................... 27
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`X.
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`Precise Reasons For The Relief Requested ................................................... 29
`
`F.
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`Ground 1: Claims 1-3, 6-9, and 11 are Invalid under 35 U.S.C.
`§ 102 on the Ground That They are Anticipated by Guitard .............. 31
`G. Ground 2: Claims 1-3, 6-9, and 11 are invalid under 35 U.S.C.
`§ 103 on the Ground That They are Rendered Obvious by
`Eastlick in view of Fricker .................................................................. 42
`
`XI. Conclusion ..................................................................................................... 60
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`Petition for Inter Partes Review of USP 7,297,703
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`
`Exhibit List
`
`1001 U.S. Patent No. 7,297,703 (“the ’703 Patent”)
`
`1002 Declaration of Eric J. Benjamin, Ph.D. in Support of Petition for Inter
`Partes Review of U.S. Patent No. 7,297,703
`
`1003 Curriculum Vitae of Eric J. Benjamin, Ph.D.
`
`1004 International Publication No. WO 97/03654, “Pharmaceutical Composi-
`tions,” filed July 12, 1996, published Feb. 6, 1997 (“Guitard”)
`
`1005 Canadian Application No. 2,124,259, “Galenical Formulations,” filed May
`25, 1994, published Nov. 28, 1994 (“Fricker”)
`
`1006 European Publication No. 0329460, “Stabilised macrolide compositions,”
`filed Feb. 17, 1989, published Aug. 23, 1989 (“Eastlick”)
`
`1007 Tamio Mizutani et al., Isotope Effects on the Metabolism and Pulmonary
`Toxicity of Butylated Hydroxytoluene in Mice by Deuteration of the 4-
`Methyl Group, 69 TOXICOLOGY & APPLIED PHARMACOLOGY 283 (1983)
`
`1008 Anjni Koul et al., Chapter III: Extraction of Membrane Lipids, in MANUAL
`ON MEMBRANE LIPIDS 37 (1996)
`
`1009 J.S. Hogan et al., Bovine Neutrophil Responses to Parenteral Vitamin E, 75
`J. DAIRY SCI. 399 (2001)
`
`1010 Rita Carini et al., Comparative evaluation of the antioxidant activity of α-
`tocopherol, α-tocopherol polyethylene glycol 1000 succinate and α-
`tocopherol succinate in isolated hepatocytes and liver microsomal suspen-
`sions, 39 BIOCHEMICAL PHARMACOLOGY 1597 (1990)
`
`1011 Helmut Sapper et al., The thermotropic phase behavior of ascorbyl palmi-
`tate: an infrared spectroscopic study, 59 CAN. J. CHEMISTRY 2543 (1981)
`
`1012 Excerpts from Grant & Hackh’s Chemical Dictionary (5th ed. 1987)
`
`1013 Excerpt from A Dictionary of Pharmaceutical Science (1882)
`
`1014 Excerpts from Webster’s New Collegiate Dictionary (9th ed. 1984)
`
`iii
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`Petition for Inter Partes Review of USP 7,297,703
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`1015 Dictionary.com, accessed May 26, 2015, available at
`http://dictionary.reference.com/browse/admix?s=t
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`iv
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`I.
`
`INTRODUCTION
`
`Petition for Inter Partes Review of USP 7,297,703
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`Par Pharmaceutical, Inc. (“Petitioner”), in accordance with 35 U.S.C. § 311
`
`and 37 C.F.R. § 42.100, hereby requests inter partes review of claims 1-3, 6-9, and
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`11 of United States Patent No. 7,297,703, titled “Macrolides” (the “’703 Patent”).
`
`According to USPTO records, the ’703 Patent is assigned to Novartis Ag (“Novar-
`
`tis”). A copy of the ’703 Patent is provided as Ex. 1001.
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`II. REQUIREMENTS FOR PETITION FOR INTER PARTES REVIEW
`A. Grounds for Standing (37 C.F.R. § 42.104(a))
`Petitioner certifies that the ’703 Patent is available for inter partes review
`
`and that Petitioner is not barred or estopped from requesting inter partes review of
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`the challenged claims of the ’703 Patent on the grounds identified herein.
`
`B. Notice of Lead and Backup Counsel and Service Information
`Pursuant to 37 C.F.R. §§ 42.8(b)(3), 42.8(b)(4), and 42.10(a), Petitioner pro-
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`vides the following designation of Lead and Back-Up counsel.
`
`LEAD COUNSEL
`Daniel G. Brown (Reg. No. 54,005)
`(dan.brown@lw.com)
`Postal & Hand-Delivery Address:
`Latham & Watkins LLP
`885 Third Avenue
`New York, NY 10022-4834
`T: 212-906-1200; F: 212-751-4864
`
`
`BACKUP COUNSEL
`Robert Steinberg (Reg. No. 33,144)
`(bob.steinberg@lw.com)
`Latham & Watkins LLP
`355 South Grand Avenue
`Los Angeles, CA 90071-1560
`T: 213-485-1234; F: 213-891-8763
`
`1
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`

`
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`Pursuant to 37 C.F.R. § 42.10(b), a Power of Attorney for Petitioner is attached.
`
`Petition for Inter Partes Review of USP 7,297,703
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`C. Notice of Real-Parties-in-Interest (37 C.F.R. § 42.8(b)(1))
`Petitioner Par Pharmaceutical, Inc. (“Par”) is a real-party-in-interest for this
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`proceeding. Out of an abundance of caution, and as a result of ongoing integration
`
`and reorganization activities, Petitioner identifies the following additional entities
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`as real-parties-in-interest who, going forward, may have control over this proceed-
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`ing: Endo International PLC; Endo DAC; Endo Management Limited; Endo Lux-
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`embourg Holding Company S.a.r.l.; Endo Luxembourg Finance Company I S.a.r.l.;
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`Endo U.S. Inc.; Endo US Holdings Luxembourg I S.a.r.l.; Endo US Holdings Lux-
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`embourg II S.a.r.l.; Endo Health Solutions Inc.; Hawk Acquisition Ireland Limited;
`
`and Par Pharmaceutical Companies, Inc.1 No other parties exercised or could have
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`exercised control over this petition; no other parties funded or directed this peti-
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`tion. See Office Patent Trial Practice Guide, 77 Fed. Reg. 48759-60.
`
`1 As a result of Endo International PLC’s acquisition of Par Pharmaceutical, Inc.,
`
`Petitioner states that: Sky Growth Intermediate Holdings Corporation I, Sky
`
`Growth Intermediate Holdings Corporation II and Par Pharmaceutical Companies,
`
`Inc. were merged into and reorganized with Par Pharmaceutical Holdings, Inc.,
`
`which was immediately thereafter re-named Par Pharmaceutical Companies, Inc.
`
`For clarity, the newly reorganized Par Pharmaceutical Companies, Inc. is not iden-
`
`tical to the entity previously known by the same name.
`
`2
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`Petition for Inter Partes Review of USP 7,297,703
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`D. Notice of Related Matters (37 C.F.R. § 42.8(b)(2))
`Novartis Pharm. Corp. et al. v. Par Pharm., Inc., No. 1:14-cv-1289-RGA
`
`(D. Del.). Novartis Pharm. Corp. et al. v. Par Pharm., Inc., No. 1:14-cv-1494-
`
`RGA (D. Del.). Novartis Pharm. Corp. et al. v. Par Pharm., Inc., No. 1:15-cv-78-
`
`RGA (D. Del.). Novartis Pharm. Corp. et al. v. Par Pharm., Inc., No. 1:15-cv-
`
`475-RGA (D. Del.). Petition for Inter Partes Review of U.S. Patent No.
`
`5,665,772, No. IPR2016-00084 (to be filed concurrently). Petition for Inter Partes
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`Review of U.S. Patent No. 6,455,518, No. IPR2016-00078 (to be filed concurrent-
`
`ly). Petition for Inter Partes Review of U.S. Patent No. 7,741,338, No. IPR2016-
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`00074 (to be filed concurrently). According to USPTO records, no patent claims
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`priority to the ’703 Patent .
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`Fee for Inter Partes Review
`
`E.
`The Director is authorized to charge the fee specified by 37 C.F.R.
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`§ 42.15(a) to Deposit Account No. 506269.
`
`Proof of Service
`
`F.
`Proof of service of this petition on the patent owner at the correspondence
`
`address of record for the ’703 Patent is attached.
`
`III.
`IDENTIFICATION OF CLAIMS BEING CHALLENGED
`(§ 42.104(B))
`
`Claims 1-3, 6-9, and 11 of the ’703 Patent (the “challenged claims”) are un-
`
`patentable in view of the following prior art:
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`3
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`Petition for Inter Partes Review of USP 7,297,703
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`• International Publication No. WO 97/03654, to Guitard, Haeberlin, Link,
`
`and Richter, entitled “Pharmaceutical Compositions,” filed with WIPO on
`
`July 12, 1996, published February 6, 1997 (“Guitard,” attached as Ex. 1004);
`
`• Canadian Application No. 2,124,259, to Fricker, Haeberlin, Meinzer, and
`
`Vonderscher, entitled “Galenical Formulations,” filed with the Canadian In-
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`tellectual Property Office on May 25, 1994, published November 28, 1994
`
`(“Fricker,” attached as Ex. 1005);
`
`• European Publication No. 0329460, to Eastlick, entitled “Stabilised macro-
`
`lide compositions,” filed with the EPO on February 17, 1989, published Au-
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`gust 23, 1989 (“Eastlick,” attached as Ex. 1006).
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`Specifically, the challenged claims are invalid under 35 U.S.C. §§ 102 and
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`103 on the following grounds:
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`• Ground 1: Claims 1-3, 6-9, and 11 are invalid under 35 U.S.C. § 102 on
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`the ground that they are anticipated by Guitard.
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`• Ground 2: Claims 1-3, 6-9, and 11 are invalid under 35 U.S.C. § 103 on
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`the ground that they are rendered obvious by Eastlick in view of Fricker.
`
`IV. DESCRIPTION OF THE PURPORTED INVENTION
`The ’703 Patent relates to mixtures comprising a poly-ene macrolide and an
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`antioxidant, as well as processes for stabilizing a poly-ene macrolide. Ex. 1001,
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`’703 Patent at Abstract, 1:11-15. The ’703 Patent states that the handling and
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`storage of oxidation-sensitive poly-ene macrolides is difficult. Id. at 1:16-22.
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`Petition for Inter Partes Review of USP 7,297,703
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`Thus, the ’703 Patent discloses a process for stabilizing a poly-ene macrolide
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`comprising adding a “catalytic amount” of an antioxidant to the purified macrolide.
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`Id. at 1:27-36. According to the ’703 Patent, particularly preferred poly-ene
`
`macrolides are rapamycin and 40-O-(2-hydroxy)ethyl-rapamycin. Id. at 2:25-26.
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`Preferred antioxidants include 2,6-di-tert-butyl-4-methylphenol (BHT), vitamin E,
`
`and vitamin C. Id. at 2:27-29. The ’703 Patent also states that stabilized
`
`macrolides are easier to handle and store in bulk form and may be used to produce
`
`desired pharmaceutical formulations. Id. at 2:43-50. Thus, the ’703 Patent
`
`provides for pharmaceutical compositions comprising a stabilized mixture and one
`
`or more pharmaceutically acceptable diluents or carriers. Id. at 2:55-58.
`
`V. BACKGROUND KNOWLEDGE OF A POSA OF THE ’703 PATENT
`The ’703 Patent involves several common concepts in pharmaceutical
`
`formulation that were well known to those working with poly-ene macrolides in
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`the late-1990s. Ex. 1002, Declaration of Eric J. Benjamin, Ph.D. in Support of
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`Petition for Inter Partes Review of U.S. Patent No. 7,297,703 (“Benjamin Decl.”)
`
`at ¶ 28.
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`A.
`
`Solid Mixtures, Including Solid Dispersions, Were Well-Known in
`the Art
`
`By December 1998, solid mixtures, including solid dispersions, were well-
`
`known in the art. Id. at ¶ 29. As discussed below in Section IX.A, the term “solid
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`5
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`mixture,” as recited in the ’703 Patent claims, is a broad term indicating a solid
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`Petition for Inter Partes Review of USP 7,297,703
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`combination of two or more solid substances that are mixed, but not chemically
`
`combined. Id. Solid mixtures are used in most routes of drug administration, par-
`
`ticularly oral administration because they provide a number of benefits over liquid
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`solutions, including extended shelf life and ease of packaging. Id. Common
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`methods for creating solid mixtures from active pharmaceutical ingredients and
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`one or more solid substances include physical mixing, dissolving in a solvent and
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`subsequently removing the solvent, or mixing in melted carriers or diluents. Id. A
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`POSA at the time would immediately understand that the “admixing” and “inti-
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`mate mixing” disclosed in Eastlick (Ex. 1006 discussed in Section VII.C infra) are
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`well-known methods for forming solid mixtures. Id.
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`A “solid dispersion” is a specific, well-known type of solid mixture in which
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`one finely divided solid component is dispersed throughout a continuous solid
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`component but not chemically combined. Solid dispersions generally result in in-
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`creased oral bioavailability and are, therefore, advantageous for oral compositions.
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`Id. at ¶ 30. A POSA at the time would understand the solid dispersions disclosed
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`by Guitard (Ex. 1004 discussed in Section VII.A infra) and Eastlick to be types of
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`well-known solid mixtures. Id. Co-precipitation – dissolving two or more solid
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`substances in a solvent and subsequently removing the solvent – is a common
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`method for creating solid dispersions. Id. A POSA at the time would immediately
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`6
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`understand the “precipitat[ion]” described in Eastlick to mean co-precipitation – a
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`Petition for Inter Partes Review of USP 7,297,703
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`well-known method for producing solid dispersions. Id.
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`B. Microemulsions Were Well-Known in the Art
`By December 1998, microemulsions were well-known in the art. Micro-
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`emulsions are liquid mixtures generally comprised of a lipophilic phase, hydro-
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`philic phase, and a surfactant. Id. at ¶ 31. Microemulsions are generally formed
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`through mixing of the components. Id. As discussed above, microemulsions are
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`not generally considered ideal for oral administration because they have generally
`
`shorter shelf life and are more difficult to manufacture and package compared to
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`solid mixtures, including solid dispersions. Id.
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`C.
`
`Poly-ene Macrolides, Including Rapamycin and its Derivative 40-
`O-(2-hydroxy)ethyl-rapamycin, Were Well-Known in the Art
`
`By December 1998, poly-ene macrolides, including rapamycin and its deriv-
`
`ative 40-O-(2-hydroxy)ethyl-rapamycin, were well-known in the art. Id. at ¶ 32.
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`Poly-ene macrolides are a group of chemicals, typically antibiotics, produced by
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`some species of Streptomyces bacteria, for example Streptomyces hygroscopicus or
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`Streptomyces tsukubaensis. Id. Poly-ene macrolides are defined by their chemical
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`structure, which features a large ring of atoms containing multiple double bonds,
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`hence “poly-ene,” on one side of the ring and multiple hydroxyl groups bonded to
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`the other side of the ring. Id. In addition, poly-ene macrolides also contain a lac-
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`tone group, hence “macrolides.” Id. Numerous poly-ene macrolides were known
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`7
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`at the time, including both rapamycin and its derivative 40-O-(2-hydroxy)ethyl-
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`Petition for Inter Partes Review of USP 7,297,703
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`rapamycin, as disclosed in Guitard and Fricker (Ex. 1005 discussed in Section
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`VII.B infra), as well as the S541 antibiotic, as disclosed in Eastlick, and FK506, as
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`disclosed in the ’703 Patent specification. Id. A POSA at the time would under-
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`stand immediately that all of those compounds are poly-ene macrolides. Id.
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`Rapamycin and
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`its derivative 40-O-(2-hydroxy)ethyl-rapamycin were
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`known to be useful for treating and/or preventing tissue transplant rejection and au-
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`toimmune disease, among others. Id. at ¶ 33. 40-O-(2-hydroxy)ethyl-rapamycin in
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`particular was known at the time to be highly immunosuppressive and useful for
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`treating and/or preventing tissue transplant rejection, graft-versus-host disease, and
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`autoimmune and inflammatory conditions. Id.
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`D.
`
`Poly-ene Macrolides, Including Rapamycin and the Rapamycin
`Derivative 40-O-(2-hydroxy)ethyl Rapamycin, Were Well-Known
`to be Unstable under Normal Conditions and Were Routinely
`Stabilized by Mixing with Antioxidants, Including Vitamin E,
`Vitamin C, and 2,6-di-tert-butyl-4-methylphenol (BHT)
`
`By December 1998, solid mixtures and microemulsions containing poly-ene
`
`macrolides,
`
`including rapamycin and
`
`its derivative 40-O-(2-hydroxy)ethyl-
`
`rapamycin, were known to be unstable under normal conditions of preparation,
`
`use, and storage. See, e.g., Ex. 1004, Guitard at 2:1-6; Ex. 1006, Eastlick at 1:10-
`
`11; see also Ex. 1002, Benjamin Decl. at ¶ 34. Those of ordinary skill in the art at
`
`the time understood that antioxidants could be used to stabilize solid mixtures as
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`8
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`well as microemulsions and regularly did so. See, e.g., Ex. 1004, Guitard at 6:9-
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`Petition for Inter Partes Review of USP 7,297,703
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`12; Ex. 1006, Eastlick at 1:10-12; see also Ex. 1002, Benjamin Decl. at ¶ 34.
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`Antioxidants commonly used to stabilize poly-ene macrolide solid mixtures
`
`included 2,6-di-tert-butyl-4-methylphenol (BHT), ascorbyl palmitate (a vitamin C
`
`derivative), and tocopherols such as α-tocopherol (vitamin E) and tocopherol poly-
`
`ethylene glycol succinate (TPGS). Id. at ¶ 35. Of those antioxidants, 2,6-di-tert-
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`butyl-4-methylphenol (BHT) was known to be particularly useful. See, e.g., Ex.
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`1006, Eastlick at 2:48-53; see also Ex. 1002, Benjamin Decl. at ¶ 35.
`
`A POSA at the time would understand that 2,6-di-tert-butyl-methylphenol
`
`(BHT) is commonly referred to as “butylated hydroxytoluene,” as in Guitard, “bu-
`
`tyl hydroxyl toluene,” as in Fricker, and “butylated hydroxytoluene,” as in East-
`
`lick. See, e.g., Ex. 1007, Tomio Mizutani et al., Isotope Effects on the Metabolism
`
`and Pulmonary Toxicity of Butylated Hydroxytoluene in Mice by Deuteration of
`
`the 4-Methyl Group, 69 TOXICOLOGY & APPLIED PHARMACOLOGY 283, Abstract
`
`(1983) (using “butylated hydroxytoluene,” “2,6-di-tert.-butyl-4-methylphenol,”
`
`“BHT” interchangeably); Ex. 1008, Anjni Koul et al., Chapter III: Extraction of
`
`Membrane Lipids, in MANUAL ON MEMBRANE LIPIDS 37, 49 (1996) (using “butyl
`
`hydroxy toluene” and “BHT” interchangeably);2 Ex. 1002, Benjamin Decl. at ¶ 36.
`
`2 These references are provided for background purposes only and are not relied
`
`upon as a part of any ground for invalidity.
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`9
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`Petition for Inter Partes Review of USP 7,297,703
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`A POSA at the time would immediately understand that vitamin E is com-
`
`monly referred to as “DL-α-tocopherol,” as in Guitard, or “α-tocopherol,” as in
`
`Fricker and Eastlick. See, e.g., Ex. 1009, J.S. Hogan et al., Bovine Neutrophil Re-
`
`sponses to Parenteral Vitamin E, 75 J. DAIRY SCI. 399 (2001) (using “vitamin E,”
`
`“DL-α-tocopherol,” and “α-tocopherol” interchangeably);3 Ex. 1002, Benjamin
`
`Decl. at ¶ 37. Moreover, a POSA at the time would understand that tocopherol
`
`polyethylene glycol succinate (TPGS), a well-known vitamin E derivative, can act
`
`as a surfactant as well as an antioxidant in pharmaceutical compositions. See, e.g.,
`
`Ex. 1010, Rita Carini et al., Comparative evaluation of the antioxidant activity of
`
`α-tocopherol, α-tocopherol polyethylene glycol 1000 succinate and α-tocopherol
`
`succinate in isolated hepatocytes and liver microsomal suspensions, 39 BIOCHEMI-
`
`CAL PHARMACOLOGY 1597, 1597 (1990) (identifying TPGS as a form of vitamin E
`
`found in the body);4 Ex. 1002, Benjamin Decl. at ¶ 37.
`
`A POSA at the time would understand that “ascorbyl palmitate,” as in Gui-
`
`tard and Fricker, is a well-known vitamin C derivative. See, e.g., Ex. 1011,
`
`Helmut Sapper et al., The thermotropic phase behavior of ascorbyl palmitate: an
`
`
`3 Same.
`
`4 Same.
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`10
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`infrared spectroscopic study, 59 CAN. J. CHEMISTRY 2543, 2543 (1981) (ascorbyl
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`Petition for Inter Partes Review of USP 7,297,703
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`palmitate is an analogue of vitamin C);5 Ex. 1002, Benjamin Decl. at ¶ 38.
`
`E.
`
`Solid Mixtures of Poly-ene Macrolides, Including Rapamycin and
`its Derivative 40-0-(2-hydroxy)ethyl-rapamycin, Were Routine
`and Included Pharmaceutical Compositions Containing Pharma-
`ceutically Acceptable Carriers or Diluents
`
`By December 1998, solid mixtures containing poly-ene macrolides,
`
`including rapamycin and 40-O-(2-hydroxy)ethyl-rapamycin, were commonly
`
`formulated with pharmaceutically acceptable diluents and carriers and
`
`administered by conventional routes, in particular orally. Ex. 1002, Benjamin
`
`Decl. at ¶ 39. Pharmaceutically acceptable diluents or carriers improve drug
`
`delivery and effectiveness, for example, by increasing bioavailability, controlling
`
`release, decreasing metabolism, or reducing toxicity. Id. A POSA at the time
`
`would understand that the term “pharmaceutically acceptable carrier” is commonly
`
`referred to as “carrier medium,” as disclosed in Guitard and Fricker, and a “carrier
`
`or excipient,” as disclosed in Eastlick. Id.
`
`VI. THE PERSON OF ORDINARY SKILL IN THE ART
`The purported inventions of the ’703 Patent involve an understanding of the
`
`preparation of pharmaceutical compositions and solid mixtures comprising a poly-
`
`ene macrolide and an antioxidant, as well as knowledge of industry practices in the
`
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`5 Same.
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`11
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`late-1990s. Ex. 1002, Benjamin Decl. at ¶ 40. A “person of ordinary skill in the
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`Petition for Inter Partes Review of USP 7,297,703
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`art” (“POSA”) with this knowledge and understanding thus has: a Ph.D. in phar-
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`maceutical chemistry; or a Masters-level degree in pharmaceutics and at least 7
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`years of experience formulating pharmaceutical compositions comprising active
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`pharmaceutical ingredients, including poly-ene macrolides, antioxidants, and
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`pharmaceutically acceptable carriers or diluents. Id. at ¶ 41.
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`VII. THE INVALIDATING PRIOR ART RELIED UPON
`A. Guitard (Ex. 1004)
`Guitard is prior art to the ’703 Patent under at least 35 U.S.C. § 102(b) be-
`
`cause it published on February 6, 1997 – more than one year prior to the earliest
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`claimed filing date of the ’703 Patent of December 7, 1998. Guitard discloses
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`pharmaceutical compositions comprising a solid dispersion of a poly-ene macro-
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`lide, including 40-O-(2-hydroxy)ethyl-rapamycin, and an antioxidant, including
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`2,6-di-tert-butyl-4-methylphenol (BHT), vitamin E, or a vitamin C derivative, with
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`pharmaceutically acceptable carriers. Ex. 1002, Benjamin Decl. at ¶ 46.
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`Guitard discloses “a pharmaceutical composition in the form of a solid dis-
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`persion comprising a rapamycin and a carrier medium.” Ex. 1004, Guitard at 2:7-
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`8; Ex. 1002, Benjamin Decl. at ¶ 47. “The term solid dispersion as used [in Gui-
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`tard] is understood to mean a co-precipitate of the rapamycin, e.g. 40-O-(2-
`
`hydroxy)ethyl rapamycin or rapamycin, with the carrier medium.” Ex. 1004, Gui-
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`12
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`tard at 3:3-6; Ex. 1002, Benjamin Decl. at ¶ 47. As discussed in Section V.A
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`Petition for Inter Partes Review of USP 7,297,703
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`above, a POSA at the time would understand the “solid dispersion” in Guitard to
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`be a well-known type of solid mixture. Ex. 1002, Benjamin Decl. at ¶ 47.
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`Guitard states that such rapamycins include 16-O-substituted rapamycins
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`and 40-O-substituted rapamycins. Ex. 1004, Guitard at 1:12-3:6; Ex. 1002, Ben-
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`jamin Decl. at ¶ 48. Guitard identifies rapamycin and its derivative 40-O-(2-
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`hydroxy)ethyl rapamycin as “[p]referred rapamycins for use in the solid dispersion
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`compositions.” Ex. 1004, Guitard at 2:21-24; Ex. 1002, Benjamin Decl. at ¶ 48.
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`“Antioxidants . . . may be included in the compositions . . . in an amount of
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`up to about 1 % by weight, for example between 0.05 and 0.5 % by weight.” Ex.
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`1004, Guitard at 6:9-12; Ex. 1002, Benjamin Decl. at ¶ 49. Antioxidants for use in
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`stabilizing poly-ene macrolide solid dispersions include 2,6-di-tert-butyl-4-
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`methylphenol (BHT), vitamin E, and a vitamin C derivative. Ex. 1004, Guitard at
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`6:9-12; Ex. 1002, Benjamin Decl. at ¶ 49. As discussed in Section V.D above, a
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`POSA at the time would understand the “butylated hydroxytoluene” disclosed in
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`Guitard to be 2,6-di-tert-butyl-4-methylphenol (BHT). Ex. 1002, Benjamin Decl.
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`at ¶ 49. As discussed in Section V.D above, a POSA at the time would understand
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`the “DL-α-tocopherol” disclosed by Guitard to be vitamin E. Ex. 1002, Benjamin
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`Decl. at ¶ 49. Finally, as discussed in Section V.D above, a POSA at the time
`
`would immediately understand the “ascorbyl palmitate” disclosed by Guitard to be
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`13
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`a well-known vitamin C derivative. Ex. 1002, Benjamin Decl. at ¶ 49.
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`Petition for Inter Partes Review of USP 7,297,703
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`Guitard teaches that such solid dispersions are useful as oral compositions
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`with known pharmaceutical applications, such as the treatment and prevention of
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`organ or tissue transplant rejection, autoimmune disease and inflammatory condi-
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`tions. Ex. 1004, Guitard at 7:22-9:1; Ex. 1002, Benjamin Decl. at ¶ 50. Guitard
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`also discloses four examples of pharmaceutical compositions comprising solid dis-
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`persions of poly-ene macrolides, including rapamycin and 40-O-(2-hydroxy)ethyl-
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`rapamycin, together with a carrier medium. Ex. 1004, Guitard at 12:17-13:24; Ex.
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`1002, Benjamin Decl. at ¶ 51. As discussed in Section V.E above, a POSA would
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`immediately understand the “carrier medium” disclosed by Guitard to be a phar-
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`maceutically acceptable carrier or diluent. Ex. 1002, Benjamin Decl. at ¶ 51.
`
`Fricker (Ex. 1005)
`
`B.
`Fricker was not before the USPTO during prosecution of the ’703 Patent.
`
`Fricker is prior art to the ’703 Patent under at least 35 U.S.C. § 102(b) because it
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`published on November 28, 1994 – more than one year prior to the earliest claimed
`
`filing date of the ’703 Patent of December 7, 1998. Fricker discloses pharmaceuti-
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`cal compositions comprising a microemulsion of a poly-ene macrolide, including
`
`rapamycin or 40-O-(2-hydroxy)ethyl-rapamycin, and an antioxidant, including 2,6-
`
`di-tert-butyl-4-methylphenol (BHT), vitamin E, or vitamin C derivatives, together
`
`with a pharmaceutically acceptable carrier. Ex. 1002, Benjamin Decl. at ¶ 53.
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`Petition for Inter Partes Review of USP 7,297,703
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`Fricker discloses “[a] pharmaceutical composition containing macrolide, e.g.
`
`a rapamycin compound in an emulsion preconcentrate or microemulsion.” Ex.
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`1002, Fricker at Abstract; Ex. 1002, Benjamin Decl. at ¶ 54. “In one particular
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`embodiment there is provided a pharmaceutical composition in the form of a mi-
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`croemulsion preconcentrate comprising rapamycin or 40-O-(2-hydroxy)ethyl ra-
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`pamycin as an active ingredient in a carrier medium.” Ex. 1005, Fricker at 3a:1-3;
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`Ex. 1002, Benjamin Decl. at ¶ 54. “The pharmaceutical composition may also in-
`
`clude further additives or ingredients, for example antioxidants (such as ascorbyl
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`palmitate [a vitamin C derivative], . . . butyl hydroxy toluene (BHT) and tocopher-
`
`ols) [that] may comprise about 0.05 to 1% by weight of the total weight of the
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`composition . . . . Preferably the antioxidant is α-tocopherol (vitamin E).” Ex.
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`1005, Fricker at 14:21-15:3; Ex. 1002, Benjamin Decl. at ¶ 54. As discussed in
`
`Section V.D above, a POSA would understand the “ascorbyl palmitate” disclosed
`
`by Guitard to be a well-known vitamin C derivative. Ex. 1002, Benjamin Decl. at
`
`¶ 54. Similarly, as discussed in Section V.D above, a POSA would immediately
`
`understand the “butyl hydroxy toluene (BHT)” disclosed by Guitard to be 2,6-di-
`
`tert-butyl-4-methylphenol (BHT). Id. at ¶ 54. Fricker also discloses an example of
`
`a pharmaceutical composition for oral administration. Ex. 1005, Fricker at 21:1-
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`13; Ex. 1002, Benjamin Decl. at ¶ 56.
`
`Fricker differs from the challenged claims of the ’703 Patent only in that
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`15
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`
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`Fricker discloses microemulsions, i.e. liquid mixtures, as opposed to solid mix-
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`Petition for Inter Partes Review of USP 7,297,703
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`tures. Ex. 1002, Benjamin Decl. at ¶ 57. Regardless, solid mixtures were well-
`
`known at the time, and Fricker discloses every other element of the challenged
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`claims of the ’703 Patent. Id.
`
`C. Eastlick (Ex. 1006)
`Eastlick is prior art to the ’703 Patent under at least 35 U.S.C. § 102(b) be-
`
`cause it published on August 23, 1989 – more than one year prior to the earliest
`
`claimed filing date of December 7, 1998. Eastlick relates to improvements in the
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`stability of antibiotic S541 and its derivatives, which have the following structure:
`
`
`
`The disclosed S541 antibiotics contain a conjugated double bond and are, there-
`
`fore, classified as poly-ene. Ex. 1002, Benjamin Decl. at ¶ 59. The molecules also
`
`contain a lactone group and are, therefore, considered macrolides. Id. Thus, as
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`discussed in Section V.C above, a POSA at the time would understand the com-
`
`pounds disclosed in Eastlick to be poly-ene macrolides similar to rapamycin and its
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`16
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`derivative 40-O-(2-hydroxy)ethyl-rapamycin. Id.
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`Petition for Inter Partes Review of USP 7,297,703
`
`Eastlick discloses pharmaceutical compositions comprising a solid mixture
`
`of a poly-ene macrolide and an antioxidant, including 2,6-di-tert-butyl-4-
`
`methylphenol (BHT), together with a pharmaceutically acceptable diluent or carri-
`
`er. Id. at ¶ 60. Eastlick states that these compounds “tend to be unstable under
`
`normal conditions of preparation, use and storage” and teaches that “the stability of
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`the compounds can be considerably enhanced when they are in the presence of an
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`antioxidant.” Ex. 1006, Eastlick at 2:10-12; Ex. 1002, Benjamin Decl. at ¶ 60.
`
`“[A]ny loss due to instability of the compounds during preparation can be mini-
`
`mized by addition of an antioxidant.” Ex. 1006, Eastlick at 2:12-14; Ex. 1002,
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`Benjamin Decl. at ¶ 60. Eastlick states, “we have found butylated hydroxyltoluene
`
`to be particularly useful,” and teaches that the “antioxidant may be present in the
`
`compositions . . . in amounts ranging from 0.005 to 1%, especially 0.02 to 0.3%
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`with respect to antibiotic compounds.” Ex. 1006, Eastlick at 2:52-56; Ex. 1002,
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`Benjamin