Inter Partes Review of USP 7,297,703
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`
`In re Inter Partes Review of:
`U.S. Patent No. 7,297,703
`Issued: Nov. 20, 2007
`Application No.: 11/020,860
`Filing Date: Dec. 23, 2004
`
`For: Macrolides
`
`FILED VIA PRPS
`
`
`)
`)
`)
`)
`)
`
`
`
`
`
`
`
`
`
`
`DECLARATION OF ERIC J. BENJAMIN, PH.D. IN SUPPORT OF
`PETITION FOR INTER PARTES REVIEW
`OF U.S. PATENT NO. 7,297,703
`
`
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 001
`
`

`
`Declaration of Eric J. Benjamin, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 7,297,703
`
`
`TABLE OF CONTENTS
`
`Page
`
`I.
`
`Introduction and Qualifications ....................................................................... 1
`
`II. My Experience with Solid Mixtures Comprising a Poly-ene Macrolide
`and an Antioxidant as Well as Processes for Stabilizing Such Mixtures
`in the Late-1990s ............................................................................................. 3
`
`III. Understanding Of The Governing Law ........................................................... 5
`
`Invalidity by Anticipation or Obviousness ........................................... 5
`A.
`Interpreting Claims Before the Patent Office ........................................ 7
`B.
`C. Materials Relied on in Forming My Opinions ...................................... 8
`
`IV. Overview Of The ’703 Patent .......................................................................... 8
`
`V.
`
`Summary Of Opinions ................................................................................... 10
`
`VI. Common General Knowledge Of a POSA Of The ’703 Patent .................... 11
`
`A.
`
`D.
`
`Solid Mixtures, Including Solid Dispersions, Were Well-
`Known in the Art ................................................................................. 11
`B. Microemulsions Were Well-Known in the Art ................................... 13
`C.
`Poly-ene Macrolides, Including Rapamycin and its Derivative
`40-O-(2-hydroxy)ethyl-rapamycin, Were Well-Known in the
`Art ........................................................................................................ 13
`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) .................................................................................................. 15
`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 ............................. 17
`
`E.
`
`VII. The Person Of Ordinary Skill In The Art ...................................................... 18
`
`i
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 002
`
`

`
`Declaration of Eric J. Benjamin, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 7,297,703
`
`VIII. The Invalidating Prior Art Relied Upon ........................................................ 19
`
`A. Guitard (Ex. 1004) ............................................................................... 19
`B.
`Fricker (Ex. 1005) ............................................................................... 24
`C.
`Eastlick (Ex. 1006) .............................................................................. 27
`
`IX. Motivations To Combine The Prior Art ........................................................ 33
`
`A. Motivation to Combine Fricker with Eastlick ..................................... 33
`A.
`Reasonable Expectation of Success in Combining Fricker with
`Eastlick ................................................................................................ 37
`
`X.
`
`Claim Constructions ...................................................................................... 38
`
`A.
`B.
`C.
`D.
`
`Legal Standard ..................................................................................... 38
`“solid mixture” .................................................................................... 39
`“catalytic amount” ............................................................................... 41
`“admixed with” .................................................................................... 42
`
`XI. Grounds Of Invalidity .................................................................................... 44
`
`A. 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 .............. 44
`1.
`Claim 1 ...................................................................................... 44
`2.
`Claim 2 ...................................................................................... 54
`3.
`Claim 3 ...................................................................................... 55
`4.
`Claim 6 ...................................................................................... 56
`5.
`Claim 7 ...................................................................................... 59
`6.
`Claim 8 ...................................................................................... 60
`7.
`Claim 9 ...................................................................................... 65
`8.
`Claim 11 .................................................................................... 67
`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 ................................................................. 68
`1.
`Claim 1 ...................................................................................... 68
`2.
`Claim 2 ...................................................................................... 91
`3.
`Claim 3 ...................................................................................... 91
`4.
`Claim 6 ...................................................................................... 93
`5.
`Claim 7 ...................................................................................... 99
`6.
`Claim 8 .................................................................................... 101
`7.
`Claim 9 .................................................................................... 112
`
`B.
`
`ii
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 003
`
`

`
`Declaration of Eric J. Benjamin, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 7,297,703
`
`
`
`
`8.
`
`Claim 11 .................................................................................. 114
`
`iii
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 004
`
`

`
`Declaration of Eric J. Benjamin, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 7,297,703
`
`
`I, Eric J. Benjamin, resident of Jamestown, North Carolina, hereby declare
`
`as follows:
`
`I.
`
`INTRODUCTION AND QUALIFICATIONS
`1.
`
`I have been retained by Par Pharmaceutical, Inc. (“Par”) to provide
`
`my opinions concerning the invalidity of claims 1-3, 6-9, and 11 (the “challenged
`
`claims”) of U.S. Patent No. 7,297,703 (Ex. 1001, the “’703 Patent”) in support of
`
`Par’s Petition for Inter Partes Review of U.S. Patent No. 7,297,703 (the “’703
`
`Petition”). I have not previously been employed or retained by Par in any capacity.
`
`2.
`
`I have worked in the pharmaceutical industry for forty years and
`
`retired in 2011 as the Vice President of Pharmaceutical Development at TransTech
`
`Pharma in High Point, North Carolina. At TransTech, I was responsible for all
`
`chemistry and manufacturing control activities related to drug substance and drug
`
`products being conducted
`
`in-house and at contract organizations.
`
` My
`
`responsibilities included discovery support, manufacturing and testing of drug
`
`substances, pre-formulation and formulation studies, the development of analytical
`
`methods and testing of drug products, preparation and packaging of clinical trial
`
`materials, and preparation of chemistry and manufacturing control regulatory
`
`submissions. Since beginning at TransTech in 2003, I have also served as the
`
`Director and Senior Director of Pharmaceutical Development.
`
`1
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 005
`
`

`
`Declaration of Eric J. Benjamin, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 7,297,703
`
`
`3.
`
`From 1996 to 2003, I was employed by Wyeth Research in Pearl Riv-
`
`er, New York. I started as the Section Head and was promoted to Associate Direc-
`
`tor of the Solids Formulation Development department and was responsible for the
`
`development of formulations and processes of oral solid conventional and sus-
`
`tained-release dosage forms for new chemical entities.
`
`4.
`
`Prior to joining Wyeth, from 1986 to 1996, I served as the Director of
`
`Pharmaceutical Research and Development or Pharmaceutical Sciences at a num-
`
`ber of pharmaceutical companies, including Schein Pharmaceutical Inc., So-
`
`la/Barnes-Hind, and Adria Laboratories. From 1978 to 1986 I worked at the Syn-
`
`tex Research Institute of Pharmaceutical Sciences in Palo Alto, California and was
`
`initially responsible for the development of stability-specific analytical methods for
`
`new drug substances in various dosage forms and stability studies. Later, I was
`
`promoted to Group Leader for the Solid and Liquid Formulation Development
`
`Group. From 1967 to 1971 I supervised the Sterile Products Division at Pfizer La-
`
`boratories in Karachi, Pakistan and was responsible for manufacturing both liquid
`
`and solid sterile products.
`
`5.
`
`Over the last forty years, I have authored or co-authored fifteen peer-
`
`reviewed publications related to API synthesis, formulations, drug delivery and an-
`
`alytical methods. I am also a named inventor on twenty four U.S. patents and pa-
`
`2
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 006
`
`

`
`Declaration of Eric J. Benjamin, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 7,297,703
`
`tent applications related to active pharmaceutical ingredients, formulations, and
`
`drug delivery.
`
`6.
`
`I received my Ph.D. in Pharmaceutical Chemistry from the University
`
`of Kansas in 1978. I received my M.S. in Medicinal Chemistry from the Universi-
`
`ty of Oklahoma in 1974. I received my B.S. in Pharmacy from Punjab University
`
`in 1966.
`
`7.
`
`In summary, I have extensive technical experience relating to all
`
`aspects of formulating solid mixtures containing active ingredients, including poly-
`
`ene macrolides, antioxidants, and pharmaceutically acceptable carriers or diluents.
`
`8. My curriculum vitae is attached as Exhibit 1004. My work in this
`
`matter is being billed at my standard consulting rate of $350 per hour. My
`
`compensation is not in any way contingent upon the outcome of the ’703 Petition.
`
`I have no financial or personal interest in the outcome of this proceeding or any
`
`related proceeding or litigation.
`
`II. MY EXPERIENCE WITH SOLID MIXTURES COMPRISING A
`POLY-ENE MACROLIDE AND AN ANTIOXIDANT AS WELL AS
`PROCESSES FOR STABILIZING SUCH MIXTURES IN THE LATE-
`1990S
`9.
`
`At Wyeth, I was in charge of the solid dosage form development de-
`
`partment. During that time, my group worked on various formulations of the poly-
`
`3
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 007
`
`

`
`Declaration of Eric J. Benjamin, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 7,297,703
`
`ene macrolide rapamycin 42-[3-Hydroxy-2-(hydroxymethyl)-2-methylpropanoate
`
`– commonly referred to as CCI-779 or temsirolimus.
`
`10.
`
`I am named as an inventor on the following four related U.S. patent
`
`applications resulting from this work:
`
`•
`
`•
`
`•
`
`•
`
`U.S. Patent Application No. 10/663,506, “Oral Formulations,” filed
`
`September 15, 2003, published April 22, 2004;
`
`U.S. Patent Application No. 11/030,685, “Directly compressible
`
`pharmaceutical composition for the oral administration of CCI-779,”
`
`filed January 6, 2005, published July 14, 2005;
`
`U.S. Patent Application No. 12/075,520, “Orally bioavailable CCI-
`
`779 formulations,” filed March 12, 2008, published July 3, 2008; and
`
`U.S. Patent No. 7,446,111, “Amorphous rapamycin 42-ester with 3-
`
`hydroxy-2- (hydroxymethyl)-2-methylpropionic acid and its pharma-
`
`ceutical compositions,” filed August 10, 2007, published March 20,
`
`2008, and issued November 4, 2008.
`
`11. Much like rapamycin and 40-O-(2-hydroxy)ethyl-rapamycin, CCI-779
`
`exhibited poor aqueous solubility and was subject to degradation by oxidation,
`
`which resulted in low bioavailability and initially made CCI-779 unsuitable for
`
`oral formulation. I supervised development of a formulation and process to in-
`
`crease the solubility of CCI-779 by wet granulating CCI-779 with a water-soluble
`
`4
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 008
`
`

`
`Declaration of Eric J. Benjamin, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 7,297,703
`
`polymer such as povidone. We also added one or more antioxidants to the phar-
`
`maceutical compositions, including 2,6-di-tert-butyl-methylphenol (BHT), to pre-
`
`vent oxidation of the CCI-779.
`
`12. We also prepared solid dispersions containing the poly-ene macrolide
`
`CCI-779 and antioxidants, including 2,6-di-tert-butyl-methylphenol (BHT), by dis-
`
`solving CCI-779 in a dehydrated ethanol solvent along with antioxidants, evaporat-
`
`ing the solvent, and collecting the co-precipitated CCI-779/antioxidant solid dis-
`
`persion. The resulting pharmaceutical compositions were stable and displayed in-
`
`creased solubility, which made them suitable for oral administration.
`
`III. UNDERSTANDING OF THE GOVERNING LAW
`A.
`Invalidity by Anticipation or Obviousness
`13.
`
`I have been informed by counsel for Par that a patent claim is invalid
`
`if it is anticipated or obvious in view of the prior art. I have further been informed
`
`by counsel for Par that a finding of invalidity requires that a claim be anticipated or
`
`obvious from the perspective of a person of ordinary skill in the relevant art
`
`(“POSA”), at the time the invention was made.
`
`14.
`
`I have been informed by counsel for Par that anticipation of a claim
`
`requires that every element of the claim be disclosed expressly or inherently in a
`
`single prior art reference, arranged as in the claim. I have also been informed by
`
`5
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 009
`
`

`
`Declaration of Eric J. Benjamin, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 7,297,703
`
`counsel for Par that a prior art reference disclosing a species falling within a
`
`claimed genus will anticipate that claim.
`
`15.
`
`I have been informed by counsel for Par that 35 U.S.C. § 103 governs
`
`the determination of obviousness. According to 35 U.S.C. § 103:
`
`A patent for a claimed invention may not be obtained, notwithstand-
`ing that the claimed invention is not identically disclosed as set forth
`in section 102, if the differences between the claimed invention and
`the prior art are such that the claimed invention as a whole would
`have been obvious before the effective filing date of the claimed in-
`vention to a person having ordinary skill in the art to which the
`claimed invention pertains. Patentability shall not be negated by the
`manner in which the invention was made.
`
`16.
`
`I have also been informed by counsel for Par that the first three factors
`
`to be considered in an obviousness inquiry are: (1) the scope and content of the
`
`prior art; (2) the differences between the prior art and the claims; and (3) the level
`
`of ordinary skill in the pertinent art. I have also been informed by counsel for Par
`
`that when a patent claims a genus, that claim is obvious if a single embodiment
`
`falling within the scope of the claims is obvious.
`
`17.
`
`I have also been informed by counsel for Par that when there is some
`
`recognized reason to solve a problem, and there are a finite number of identified,
`
`predictable solutions, a person of ordinary skill in the art has good reason to pursue
`
`the known options within his or her technical grasp. If such an approach leads to
`
`6
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 010
`
`

`
`Declaration of Eric J. Benjamin, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 7,297,703
`
`the anticipated success, it is likely the product not of innovation but of ordinary
`
`skill and common sense. In such a circumstance, when a patent simply arranges
`
`old elements with each performing the same function it had been known to perform
`
`and yields no more than one would expect from such an arrangement, the combina-
`
`tion is obvious.
`
`18.
`
`I have also been informed by counsel for Par that certain factors,
`
`sometimes known as “secondary considerations,” must be considered, if present,
`
`when in an obviousness determination. These secondary considerations include:
`
`(i) long-felt need, (ii) unexpected results, (iii) skepticism of the invention, (iv)
`
`teaching away from the invention, (v) commercial success, (vi) praise by others for
`
`the invention, and (vii) copying by other companies.
`
`19.
`
`I have also been informed by counsel for Par that the earliest patent
`
`application leading to the ’703 Patent was filed on December 7, 1998. I have
`
`therefore analyzed obviousness as of that day or somewhat before, understanding
`
`that as time passes, the knowledge of a person of ordinary skill in the art will in-
`
`crease.
`
`B.
`20.
`
`Interpreting Claims Before the Patent Office
`
`I have been informed by counsel for Par Pharmaceutical, Inc. that
`
`Inter Partes Review is a proceeding before the United States Patent & Trademark
`
`Office (“PTO”) for evaluating the validity of issued patent claims. I have been
`
`7
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 011
`
`

`
`Declaration of Eric J. Benjamin, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 7,297,703
`
`informed that in an Inter Partes Review claims are given their broadest reasonable
`
`interpretation that is consistent with the patent’s specification. I have been
`
`informed that a patent’s “specification” includes all the figures, discussion, and
`
`claims within the patent document. I have been informed that the PTO will look to
`
`the specification to see if there is a definition for a given claim term, and if not,
`
`will apply the broadest reasonable interpretation from the perspective of a POSA at
`
`the time the invention was made. I present a more detailed explanation of the
`
`interpretation of certain terms in the ’703 Patent in the section titled “Claim
`
`Construction” below.
`
`C. Materials Relied on in Forming My Opinions
`In forming my opinions herein, I have relied on the ’703 Patent’s
`21.
`
`claims, disclosure, and file history, on the prior art exhibits to the ’703 Petition,
`
`any other materials cited in this declaration, the knowledge of the POSA in the
`
`relevant timeframe, and my own experience and expertise.
`
`IV. OVERVIEW OF THE ’703 PATENT
`22. According to its specification, the ’703 Patent relates to mixtures
`
`comprising a poly-ene macrolide and an antioxidant in which the poly-ene macro-
`
`lide preferably
`
`is rapamycin and
`
`the antioxidant
`
`is 2, 6-di-tert-butyl-4-
`
`methylphenol, as well as processes for stabilizing a poly-ene macrolide selected
`
`8
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 012
`
`

`
`Declaration of Eric J. Benjamin, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 7,297,703
`
`from the group consisting of rapamycin, a 16-O-substituted rapamycin, and a 40-
`
`O-substituted rapamycin. Ex. 1001, ’703 Patent at Abstract, 1:11-15.
`
`23. The ’703 Patent states that the handling and storage of oxidation-
`
`sensitive poly-ene macrolides is difficult (particularly in bulk form) and requires
`
`special handling such as air-tight packaging under protective gas and the addition
`
`of substantial amounts of stabilizers. Id. at 1:16-22. Thus, the ’703 Patent disclos-
`
`es a process for stabilizing a poly-ene macrolide comprising adding an antioxidant
`
`to the purified macrolide. Id. at 1:27-30. Further, the ’703 Patent discloses adding
`
`a “catalytic amount” of this antioxidant, which it defines as up to 1% (based on the
`
`weight of the macrolide) with a preferred amount of 0.01 to 0.5%. Id. at 1:33-36.
`
`24. According to the ’703 Patent, particularly preferred poly-ene macro-
`
`lides are rapamycin and 40-O-(2-hydroxy)ethyl-rapamycin. Id. at 2:25-26. Pre-
`
`ferred antioxidants include 2,6-di-tert-butyl-4-methylphenol (BHT), vitamin E, and
`
`vitamin C. Of those, 2,6-di-tert-butyl-methylphenol (BHT) is “particularly pre-
`
`ferred.” Id. at 2:26-29. A POSA at the time would understand that vitamin E is
`
`often also referred to by its chemical name, α-tocopherol. The ’703 Patent disclos-
`
`es producing solid mixtures comprising a poly-ene macrolide and an antioxidant by
`
`dissolving in an inert solvent and co-precipitating the stabilized macrolide mixture.
`
`Id. at 2:34-42.
`
`9
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 013
`
`

`
`Declaration of Eric J. Benjamin, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 7,297,703
`
`
`25. 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 as an active ingredient and one or
`
`more pharmaceutically acceptable diluents or carriers. Id. at 2:55-58. This com-
`
`position may be adapted for parenteral, topical, ocular, nasal, inhalation, or, most
`
`preferably, oral administration. Id. at 2:59-62. The ’703 Patent further states that
`
`compositions of the invention are useful for known macrolide properties. Id. at
`
`3:22-24. For example, the ’703 Patent states that when the macrolide has immune
`
`suppressant properties, e.g., rapamycin or a rapamycin derivative, the composition
`
`may be useful in the treatment or prevention of transplant rejections. Id. at 3:24-
`
`31.
`
`V.
`
`SUMMARY OF OPINIONS
`26.
`
`In my opinion, the challenged claims of the ’703 Patent would have
`
`been anticipated or obvious to a person of ordinary skill in the art as of December
`
`7, 1998, the earliest claimed priority date for the ’703 Patent. The prior art
`
`specifically discloses:
`
`•
`
`Solid mixtures of rapamycin (or 40-O-substituted rapamycin deriva-
`
`tives) and antioxidants in a catalytic amount and admixed with phar-
`
`maceutically acceptable carriers or diluents for oral administration;
`
`10
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 014
`
`

`
`Declaration of Eric J. Benjamin, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 7,297,703
`
`
`•
`
`Processes for stabilizing rapamycin (or 40-O-substituted rapamycin
`
`derivatives) by: (1) dissolving pure rapamycin (or pure 40-O-
`
`substituted rapamycins) in an inert solvent like ethanol, (2) adding an
`
`antioxidant, including vitamin E, vitamin C derivatives, or 2,6-di-tert-
`
`butyl-methylphenol (BHT), in a catalytic amount, and (3) isolating the
`
`resulting mixture by co-precipitation.
`
`27. Therefore, it is my opinion that the challenged claims of the ’703
`
`Patent would have been anticipated or obvious to a person of ordinary skill in the
`
`art as of December 7, 1998.
`
`VI. COMMON GENERAL KNOWLEDGE OF A POSA OF THE ’703
`PATENT
`28. The ’703 Patent involves several common concepts in pharmaceutical
`
`product formulation that were well known to those working with poly-ene
`
`macrolides in the late-1990s, including the preparation of pharmaceutical
`
`compositions and solid mixtures comprising a poly-ene macrolide and an
`
`antioxidant.
`
`A.
`
`Solid Mixtures, Including Solid Dispersions, Were Well-Known in
`the Art
`29. By December 1998, solid mixtures, including solid dispersions, were
`
`well-known in the art. As discussed below in Section X.B, the term “solid mix-
`
`ture,” as recited in the ’703 Patent claims, is a broad term indicating a solid combi-
`
`11
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 015
`
`

`
`Declaration of Eric J. Benjamin, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 7,297,703
`
`nation of two or more solid substances that are mixed, but not chemically com-
`
`bined. Solid mixtures are used in most routes of drug administration, particularly
`
`oral administration because they provide a number of benefits over liquid solu-
`
`tions. Benefits of solid mixtures include extended shelf life and ease of packaging.
`
`Common methods for creating solid mixtures from active pharmaceutical ingredi-
`
`ents and one or more solid substances include physical mixing, dissolving in a sol-
`
`vent and subsequently removing the solvent, or mixing in melted carriers or dilu-
`
`ents. A POSA at the time would immediately understand that the “admixing” and
`
`“intimate mixing” disclosed in Eastlick (Ex. 1006 discussed in Section VIII.C in-
`
`fra) are well-known methods for forming solid mixtures.
`
`30. A “solid dispersion” is a specific, well-known type of solid mixture in
`
`which one finely divided solid component is dispersed throughout a continuous
`
`solid component but not chemically combined. Solid dispersions generally result
`
`in increased oral bioavailability after oral administration and are, therefore, advan-
`
`tageous for oral pharmaceutical compositions. A POSA at the time would under-
`
`stand the solid dispersions disclosed by Guitard (Ex. 1004 discussed in Section
`
`VIII.A infra) and Eastlick to be types of well-known solid mixtures. Common
`
`methods for creating solid dispersions from active pharmaceutical ingredients and
`
`one or more solid substances include dissolving in a solvent and subsequently re-
`
`moving the solvent, commonly referred to as co-precipitation. A POSA at the time
`
`12
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 016
`
`

`
`Declaration of Eric J. Benjamin, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 7,297,703
`
`would immediately understand the “precipitat[ion]” described in Eastlick to mean
`
`co-precipitation – a well-known method for producing solid dispersions.
`
`B. Microemulsions Were Well-Known in the Art
`31. By December 1998, microemulsions were well-known in the art. Mi-
`
`croemulsions are liquid mixtures generally comprised of a lipophilic phase, hydro-
`
`philic phase, and a surfactant. Microemulsions are generally formed through mix-
`
`ing of the components. As discussed above, microemulsions are not generally
`
`considered ideal for oral administration because they have generally shorter shelf
`
`life and are more difficult to manufacture and package compared to solid mixtures,
`
`including solid dispersions.
`
`C.
`
`Poly-ene Macrolides, Including Rapamycin and its Derivative 40-
`O-(2-hydroxy)ethyl-rapamycin, Were Well-Known in the Art
`32. By December 1998, poly-ene macrolides, including rapamycin and its
`
`derivative 40-O-(2-hydroxy)ethyl-rapamycin, were well-known in the art. Poly-
`
`ene macrolides are a group of chemicals, typically antibiotics, produced by some
`
`species of Streptomyces bacteria, for example Streptomyces hygroscopicus or
`
`Streptomyces tsukubaensis. Poly-ene macrolides are defined by their chemical
`
`structure, which features a large ring of atoms containing multiple double bonds,
`
`hence “poly-ene,” on one side of the ring and multiple hydroxyl groups bonded to
`
`the other side of the ring. In addition, poly-ene macrolides also contain a lactone
`
`13
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 017
`
`

`
`Declaration of Eric J. Benjamin, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 7,297,703
`
`group, hence “macrolides.” Poly-ene macrolide research progressed rapidly during
`
`the 1990s, and numerous poly-ene macrolides were known at the time, including
`
`both rapamycin and its derivative 40-O-(2-hydroxy)ethyl-rapamycin, as disclosed
`
`in Guitard and Fricker (Ex. 1005 discussed in Section VIII.B infra), as well as the
`
`S541 antibiotic, as disclosed in Eastlick, and FK506, as disclosed in the ’703 Pa-
`
`tent specification. A POSA at the time would understand immediately that 40-O-
`
`(2-hydroxy)ethyl-rapamycin is a poly-ene macrolide.
`
`33. Rapamycin and its derivative 40-O-(2-hydroxy)ethyl-rapamycin were
`
`known to be useful for treating and/or preventing organ or tissue transplant rejec-
`
`tion, autoimmune disease and inflammatory conditions, asthma, multi-drug re-
`
`sistance, proliferative disorders like tumor proliferation, fungal infections, and in-
`
`fection. Rapamycin and its derivatives were particularly interesting to researchers
`
`in the 1990s because they were known to inhibit the activation of immune cells by
`
`unique, relatively selective, extremely potent, and highly effective mechanisms. In
`
`addition, rapamycin and its derivatives had demonstrated efficacy in experimental
`
`models for multiple sclerosis and rheumatoid reacarthritis. 40-O-(2-hydroxy)ethyl-
`
`rapamycin in particular was known at the time to be highly immunosuppressive
`
`and particularly useful for the treatment and prevention of organ or tissue trans-
`
`plant rejection, graft-versus-host disease, autoimmune disease, and inflammatory
`
`conditions.
`
`14
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 018
`
`

`
`Declaration of Eric J. Benjamin, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 7,297,703
`
`
`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)
`34. 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, East-
`
`lick at 1:10-11. Those of ordinary skill in the art at the time regularly added anti-
`
`oxidants to such mixtures to enhance their stability and understood that antioxi-
`
`dants could be used to stabilize solid mixtures as well as microemulsions. See,
`
`e.g., Ex. 1004, Guitard at 6:9-12; Ex. 1006, Eastlick at 1:10-12.
`
`35. 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 to-
`
`copherol polyethylene glycol succinate (TPGS). Of those antioxidants, 2,6-di-tert-
`
`butyl-4-methylphenol (BHT) was known to be particularly useful in stabilizing
`
`poly-ene macrolide mixtures. See, e.g., Ex. 1006, Eastlick at 2:48-53.
`
`36. A POSA at the time would understand that 2,6-di-tert-butyl-
`
`methylphenol (BHT) is commonly and interchangeably referred to as “butylated
`
`hydroxytoluene,” as disclosed in Guitard, “butyl hydroxy toluene,” as disclosed in
`
`15
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 019
`
`

`
`Declaration of Eric J. Benjamin, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 7,297,703
`
`Fricker, and “butylated hydroxytoluene,” as disclosed in Eastlick. 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,” and “BHT” inter-
`
`changeably); Ex. 1008, Anjni Koul et al., Chapter III: Extraction of Membrane
`
`Lipids, in MANUAL ON MEMBRANE LIPIDS 37, 49 (1996) (using “butyl hydroxy tol-
`
`uene” and “BHT” interchangeably”).
`
`37. A POSA at the time would understand that vitamin E is commonly
`
`and interchangeably referred to as “DL-α-tocopherol,” as disclosed in Guitard, or
`
`“α-tocopherol,” as disclosed in Fricker and Eastlick. See, e.g., Ex. 1009, J.S. Ho-
`
`gan et al., Bovine Neutrophil Responses to Parenteral Vitamin E, 75 J. DAIRY SCI.
`
`399 (2001) (using “vitamin E,” “DL-α-tocopherol,” and “α-tocopherol” inter-
`
`changeably). 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 antio