Inter Partes Review of USP 5,665,772
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re Inter Partes Review of:
`U.S. Patent No. 5,665,772
`Issued: Sept. 9, 1997
`Application No.: 08/416,673
`U.S. Filing Date: April 7, 1995
`
`)
`)
`)
`)
`)
`
`For: O-Alkylated Rapamycin Derivatives and Their Use, Particularly As
`Immunosuppressants
`
`FILED VIA PRPS
`
`DECLARATION OF WILLIAM L. JORGENSEN PH.D. IN SUPPORT OF
`PETITION FOR INTER PARTES REVIEW
`OF U.S. PATENT NO. 5,665,772
`
`Roxane Labs., Inc.
`Exhibit 1003
`Page 001
`
`

`
`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`
`TABLE OF CONTENTS
`
`Page
`
`I.
`
`
`Introduction And Qualifications ...................................................................... 1
`
` My Relevant Experience With Rapamycin And Other II.
`
`
`Immunosuppressants In The Early-1990s ....................................................... 3
`
`
`
` Understanding Of The Governing Law ........................................................... 4 III.
`
`Invalidity by Obviousness ..................................................................... 4
`A.
`B. Materials Relied on in Forming My Opinion ........................................ 6
`
`IV.
`
` Overview Of The ’772 Patent .......................................................................... 6
`
`A. Disclosure of the ’772 Patent ................................................................ 6
`
`V.
`
`
`
`Prosecution History ....................................................................................... 14
`
`VI.
`
` Level Of Skill In The Art .............................................................................. 15
`
`
`
` Claim Construction ........................................................................................ 17 VII.
`
`
`
` Summary Of Opinions ................................................................................... 17 VIII.
`
`IX.
`
` TECHNICAL BACKGROUND AND SCOPE OF THE PRIOR ART ....... 25
`
`A.
`
`2.
`
`3.
`
`Background and State of the Prior Art ................................................ 26
`1.
`Rapamycin And Its Immunosuppressant Activity Were
`Extremely Well-Known to Those of Ordinary Skill in the
`Art ............................................................................................. 26
`Rapamycin’s Poor Solubility Was Extremely Well-
`Known to Those of Ordinary Skill in the Art ........................... 27
`Routine Molecular Modifications To Improve Solubility
`Were Well-Known to Those of Ordinary Skill in the Art ........ 28
`Those of Ordinary Skill in the Art Made Routine
`Modifications to Rapamycin ..................................................... 34
`The Discovery and Disclosure of the Rapamycin/FKBP-
`12 Binding Structure Taught Those of Ordinary Skill in
`the Art the Optimum Position and Types of Substitutions
`to Make to Rapamycin .............................................................. 40
`
`4.
`
`5.
`
`i
`
`Roxane Labs., Inc.
`Exhibit 1003
`Page 002
`
`

`
`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`
`6.
`
`Standard Assays to Test Immunosuppressive Activities
`and Properties of Rapamycin Derivatives Were Well-
`Known to Those of Ordinary Skill in the Art ........................... 56
`Prior Art Relevant to Obviousness Grounds 3 and 4 .......................... 57
`1.
`Computer Based Modeling Allowed for Rapid Screening
`of Possible Modifications ......................................................... 57
`
`B.
`
`X.
`
`
`
`Claims 1-3 & 8-10 Of The ’772 Patent Would Have Been Obvious To
`A Person Of Ordinary Skill In The Art ......................................................... 59
`
`2.
`
`3.
`
`4.
`
`A. Ground 1: Claims 1-3 and 10 of the ’772 Patent Would Have
`Been Obvious In View of Morris, Lemke, Yalkowsky, and Van
`Duyne and Rossmann .......................................................................... 60
`1.
`A Person of Ordinary Skill in the Art Would Have
`Selected Rapamycin as a Lead Compound ............................... 60
`A Person of Ordinary Skill in the Art Would Have Been
`Motivated to Modify Rapamycin to Improve Its
`Solubility As Taught in the Prior Art ........................................ 63
`A Person of Ordinary Skill in the Art Would Have Been
`Motivated to Select C40 of Rapamycin for Modification
`to Avoid Disrupting Its Activity ............................................... 64
`A Person of Ordinary Skill in the Art Would Have
`Modified Rapamycin to Add Short, Flexible Side Chains
`with Solubilizing Substituents at C40 ....................................... 67
`Ground 2: Claims 8 and 9 of the ’772 Patent Would Have Been
`Obvious In View of Morris, Lemke, Yalkowsky, and Van
`Duyne and Rossmann, in further view of Hughes .............................. 75
`1.
`A Person of Ordinary Skill in the Art Would Reasonably
`Expect that Small Solubilizing Modifications to
`Rapamycin at C40 Would Retain Immunosuppressive
`Activity ...................................................................................... 76
`Ground 3: Claims 1-3 and 10 of the ’772 Patent Would Have
`Been Obvious Over Routine Use of Computer-Aided Drug
`Design Software In View of Morris, Van Duyne, Lemke, and
`Yalkowsky ........................................................................................... 78
`D. Ground 4: Claims 8 and 9 Would Have Been Obvious to a
`Person of Ordinary Skill in the Art in October 1992 .......................... 86
`
`B.
`
`C.
`
`
`
`
`
`ii
`
`Roxane Labs., Inc.
`Exhibit 1003
`Page 003
`
`

`
`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`
`1.
`
`A Person of Ordinary Skill in the Art Would Reasonably
`Expect that Solubilizing Modifications to Rapamycin at
`C40 Would Retain Immunosuppressive Activity ..................... 87
`
`XI.
`
` Secondary Considerations Fail To Overcome The Strong Evidence Of
`Obviousness ................................................................................................... 89
`
`
`
`
`
`
`
`iii
`
`Roxane Labs., Inc.
`Exhibit 1003
`Page 004
`
`

`
`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`
`I, William L. Jorgensen, Ph.D. resident of Deep River, Connecticut, hereby
`
`declare as follows:
`
`I.
`
`
`INTRODUCTION AND QUALIFICATIONS
`1.
`
`I have been retained by Par Pharmaceutical, Inc. (“Par”) to provide
`
`my opinions concerning certain claims of U.S. Patent No. 5,665,772 (Ex. 1001,
`
`“the ’772 Patent”) in support of Par’s Petition for Inter Partes Review of the ’772
`
`Patent. I have not previously been employed or retained by Par in any capacity.
`
`2.
`
`From 1967 to 1970, I attended Princeton University, where I received
`
`an A.B. in Chemistry. I then attended Harvard University from 1970 to 1975,
`
`where I received a Ph.D. in Chemical Physics. My Ph.D. supervisor was Prof. E. J.
`
`Corey, a well-known synthetic organic chemist and Nobel Laureate.
`
`3.
`
`From 1975 to 1979, I served as an Assistant Professor in the
`
`Department of Chemistry at Purdue University. While at Purdue, I was promoted
`
`to Associate Professor in 1979 and Professor in 1982. From 1984 to 1987, I served
`
`as the Head of the Organic Chemistry Division at Purdue.
`
`4.
`
`In 1990, I joined the Department of Chemistry at Yale University as
`
`the Whitehead Professor of Chemistry. In 2009, I became the Sterling Professor of
`
`Chemistry, the position I hold today. I additionally served as the Director of the
`
`Division of Physical Sciences and Engineering at Yale from 2009 to 2012.
`
`
`
`1
`
`Roxane Labs., Inc.
`Exhibit 1003
`Page 005
`
`

`
`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`
`5.
`
`I have received numerous awards and honors in the course of my
`
`career, including being elected to the American Academy of Arts and Sciences in
`
`2007 and the National Academy of Sciences in 2011, and receiving an award for
`
`Computers in Chemical and Pharmaceutical Research from the American
`
`Chemical Society in 1998 and the 2015 Tetrahedron Prize for Creativity in Organic
`
`Chemistry.
`
`6.
`
`I have served as an editor for numerous journals, including the Journal
`
`of Chemical Theory and Computation (2005-present), the Journal of Chemical
`
`Information and Modeling (2005-2013), the Encyclopedia of Computational
`
`Chemistry (2001-2005), and the Journal of Computational Chemistry (2002-2003).
`
`7.
`
`I have presented over 600 invited lectures and published more than
`
`400 articles in peer-reviewed journals. I am additionally a named inventor on 7
`
`United States patents and patent applications.
`
`8.
`
`I have extensive expertise in computational chemistry and molecular
`
`design and have been working actively in that field since the 1970s. My research
`
`interests include organic, medicinal, and computational chemistry including
`
`simulations of organic and enzymatic reactions, computer-aided drug design, and
`
`synthesis and development of
`
`therapeutic agents
`
`targeting
`
`infectious,
`
`inflammatory, and hyperproliferative diseases (e.g., cancers).
`
`
`
`2
`
`Roxane Labs., Inc.
`Exhibit 1003
`Page 006
`
`

`
`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`
`9. My curriculum vitae is attached as Exhibit 1004. My work in this
`
`matter is being billed at my standard consulting rate of $600 per hour. My
`
`compensation is not in any way contingent upon the outcome of any inter partes
`
`review. I have no financial or personal interest in the outcome of this proceeding
`
`or any related litigation.
`
` MY RELEVANT EXPERIENCE WITH RAPAMYCIN AND OTHER
`II.
`IMMUNOSUPPRESSANTS IN THE EARLY-1990S
`10.
`
`I am very familiar with rapamycin, including its structure and
`
`activities. In 1991, I published a paper describing molecular modeling performed
`
`to simulate the conformational characteristics of the immunosuppressant FK506, a
`
`compound that binds to the same receptor (known as FKBP) as rapamycin. (Ex.
`
`1016, Julianto Pranata & William L. Jorgensen, Computational Studies on FK506:
`
`Conformational Search and Molecular Dynamics Simulation in Water, 113 J. AM.
`
`CHEMICAL SOC’Y 9483 (1991).) That same year, I published a comment in the
`
`journal Science discussing, among other things, the binding of rapamycin and
`
`FK506 to FKBP. (Ex. 1017, William L. Jorgensen, Rusting of the Lock and Key
`
`Model for Protein-Ligand Binding, 254 SCI. 954 (1991).)
`
`11.
`
`In the early 1990s, my co-workers and I were working on FKBP,
`
`which resulted in several publications on the mechanism of the enzymatic activity
`
`of FKBP and on the binding of inhibitors to FKBP. (Ex. 1018, Modesto Orozco et
`
`
`
`3
`
`Roxane Labs., Inc.
`Exhibit 1003
`Page 007
`
`

`
`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`al., Mechanism for the Rotamase Activity of FK506 Binding Protein from
`
`Molecular Dynamics Simulations, 32 BIOCHEMISTRY 12864 (1993); Ex. 1019,
`
`Michelle L. Lamb & William L. Jorgensen, Investigations of Neurotrophic
`
`Inhibitors of FK506 Binding Protein via Monte Carlo Simulations, 41 J. MED.
`
`CHEMISTRY 3928 (1998); Ex. 1020, Michelle L. Lamb et al., Estimation of Binding
`
`Affinities of FKBP12 Inhibitors Using a Linear Response Method, 7 BIOORGANIC
`
`& MEDICINAL CHEMISTRY 851 (1999).)
`
` UNDERSTANDING OF THE GOVERNING LAW
`III.
`Invalidity by Obviousness
`A.
`12.
`
`I am informed by counsel for Par that obviousness is analyzed from
`
`the perspective of a hypothetical person of ordinary skill in the art at the time of
`
`the alleged invention. I am also informed by counsel for Par that a person of
`
`ordinary skill in the art is presumed to have been aware of all the pertinent prior art
`
`at the time of the alleged invention.
`
`13.
`
`I am 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 . . . 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
`
`
`
`4
`
`Roxane Labs., Inc.
`Exhibit 1003
`Page 008
`
`

`
`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`
`the effective filing date of the claimed invention to a person having
`
`ordinary skill in the art to which the claimed invention pertains.
`
`14.
`
`I am also 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 am further information by counsel that in the
`
`context of evaluating the obviousness of a chemical compound one must analyze
`
`the selection of a lead compound, the motivation to modify the lead compound,
`
`and whether a person of ordinary skill in the art would have a reasonable
`
`expectation of obtaining a compound with the desired properties.
`
`15.
`
`I am also 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
`
`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
`
`combination is obvious.
`
`
`
`5
`
`Roxane Labs., Inc.
`Exhibit 1003
`Page 009
`
`

`
`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`
`16.
`
`I am also 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.
`
`17.
`
`I am also informed by counsel for Par that the earliest patent
`
`application leading to the ’772 Patent was filed on October 9, 1992. 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
`
`increase.
`
`B. Materials Relied on in Forming My Opinion
`In forming my opinion, I have relied on the ’772 Patent’s claims,
`18.
`
`disclosure, and file history, on the prior art exhibits to the Petition for Inter Partes
`
`Review of the ’772 Patent, any other materials cited in this declaration, and my
`
`own experience, expertise, and knowledge of the person of ordinary skill in the art
`
`in the relevant timeframe.
`
`IV.
`
` OVERVIEW OF THE ’772 PATENT
`A. Disclosure of the ’772 Patent
`
`
`
`6
`
`Roxane Labs., Inc.
`Exhibit 1003
`Page 010
`
`

`
`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`
`19. The ’772 Patent (Ex. 1001), describes and claims certain derivatives
`
`of the compound rapamycin, compositions including those derivatives, and their
`
`use as immunosuppressants. Rapamycin, which is shown in the figure below, was
`
`long known to those of ordinary skill in the art prior to October 1992.
`
`HO
`
`40
`
`O
`
`O
`
`O
`
`28
`
`OH
`
`O
`
`N
`
`O
`
`10
`
`O
`OH
`O
`
`O
`
`O
`
`O
`
`
`
`According to the ’772 Patent, the claimed rapamycin derivatives improve on
`
`rapamycin’s properties. (Ex. 1001, ’772 Patent at 1:33-36.)
`
`20. The figure shown above identifies three carbon atoms at rapamycin’s
`
`“10,” “28,” and “40” positions. Those of ordinary skill in the art routinely number
`
`the carbon atoms in illustrations of molecules for ease of identification and refer to
`
`the carbon atoms by their position number—i.e., those three carbons would be
`
`referred to as “C10,” “C28,” and “C40.” Attached to C10, C28, and C40 are
`
`hydroxyl groups (also known as alcohol groups), made up of an oxygen atom
`
`bound to a hydrogen atom and represented in the figure shown above as “-OH.”
`
`
`
`7
`
`Roxane Labs., Inc.
`Exhibit 1003
`Page 011
`
`

`
`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`
`21. As was well known to those of ordinary skill in the art by October
`
`1992, the ’772 Patent acknowledges that rapamycin was known to be “insoluble,”
`
`making it difficult to use in pharmaceutical compositions. (Id. at 1:36-40.)
`
`22. Although the ’772 Patent discloses many rapamycin derivatives, it
`
`only claims rapamycin derivatives that are substituted at the C40 position on the
`
`rapamycin molecule. (Id. at 1:45-2:19.)
`
`23. The ’772 Patent contains 10 claims. I have been asked by counsel for
`
`Par to offer my opinions regarding claims 1-3, and 10, which are directed to
`
`compounds, and claims 8 and 9, which are directed to methods of using those
`
`compounds.
`
`24. Claim 1 of the ’772 Patent claims a compound of the formula1:
`
`
`
`
`1 I note that the structural formula shown in claim 1 of the ’772 Patent depicts a
`
`bond between C3 and C35. I understand from counsel for Par that Novartis has
`
`filed a Request for Certificate of Correction with the Patent Office, and that the
`
`Patent Office has not yet issued a response. I have been asked by counsel for Par
`
`to offer my opinions as if the bond depicted between C3 and C35 did not exist, and
`
`rather a methyl group was bound to the C35 position, consistent with Novartis’s
`
`Request for Certificate of Correction.
`
`
`
`8
`
`Roxane Labs., Inc.
`Exhibit 1003
`Page 012
`
`

`
`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`
`R1O
`
`40
`
`O
`
`O
`
`O
`
`28
`
`OH
`
`O
`
`O
`
`N
`
`O
`
`10
`
`O
`OH
`O
`
`O
`
`O
`
`
`wherein R1 is hydroxyl(C1-6)alkyl or hydroxyl(C1-3)alkoxy(C1-3)alkyl.
`25. The figure shown above identifies three carbon atoms: at the “10,”
`
`
`
`“28,” and “40” positions following the standard numbering scheme used for
`
`rapamycin above. As with rapamycin, hydroxyl groups (represented as “-OH”) are
`
`attached to C10 and C28.
`
`26. The “R1” attached to the C40 (shown in red in the figure above) is a
`
`standard nomenclature used by those of ordinary skill in the art to represent a
`
`number of possible different substitutions at that position.
`
`27. A person of ordinary skill in the art would understand that claim 1
`
`thus covers rapamycin derivatives with alkyloxy groups substituted at the C40
`
`position.
`
`
`
`9
`
`Roxane Labs., Inc.
`Exhibit 1003
`Page 013
`
`

`
`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`
`28. Alkyl groups are obtained by removing a hydrogen atom from an
`
`alkane. Alkanes are saturated hydrocarbons with the general formula CnH2n+2. For
`
`example, removing a hydrogen atom from ethane molecule yields an ethyl group,
`
`which can then bond to a larger molecule.
`
`29. A hydroxy(C1-6)alkyl substituent, as claimed in claim 1, is a saturated
`
`hydrocarbon with a hydrogen atom removed, containing between one and six
`
`carbon atoms and a hydroxyl group. For example, claim 1 includes rapamycin
`
`substituted at the C40 position with a 2-hydroxyethyl group to yield the compound
`
`40-O-(2-hydroxyethyl)-rapamycin, shown below.
`
`40-O-(2-hydroxyethyl)-rapamycin
`
`40
`
`O O
`
`HO
`
`O
`
`O
`
`28
`
`OH
`
`O
`
`N
`
`O
`
`10
`
`O
`OH
`O
`
`O
`
`O
`
`O
`
`
`
`30. Alkoxy substituents are alkyl groups bonded to an oxygen atom, e.g.,
`
`ethoxy, which can be drawn as CH3CH2O-.
`
`
`
`10
`
`Roxane Labs., Inc.
`Exhibit 1003
`Page 014
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`

`
`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`
`31. A hydroxy(C1-3)alkoxy(C1-3)alkyl substituent, as claimed in claim 1, is
`
`a hydroxyl group bound to an alkoxy group containing between one and three
`
`carbon atoms which is further bound to an alkyl group containing between one and
`
`three carbon atoms. For example, claim 1 also includes rapamycin substituted at
`
`the C40 position with a 2-(2-hydroxyethoxy)ethyl group (shown in red in the
`
`figure below) to yield the compound 40-O-[2-(2-hydroxyethoxy)ethyl]-rapamycin,
`
`shown below.
`
`40-O-[2-(2-hydroxyethoxy)ethyl]-rapamycin
`
`40
`
`O O
`
`HO
`
`O
`
`O
`
`O
`
`28
`
`OH
`
`O
`
`N
`
`O
`
`10
`
`O
`OH
`O
`
`O
`
`O
`
`O
`
`
`
`32. Claim 2 depends from claim 1 and recites a compound according to
`
`claim 1 in which R1 is hydroxy(C1-3)alkyl or hydroxy(C1-3)alkoxy(C1-3)alkyl, shown
`
`respectively in the figures below.
`
`
`
`11
`
`Roxane Labs., Inc.
`Exhibit 1003
`Page 015
`
`

`
`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`
`40
`
`O O
`
`O
`
`O
`
`28
`
`OH
`
`O
`
`N
`
`O
`
`10
`
`O
`OH
`O
`
`O
`
`O
`
`O
`
`
`
`HO
`
`(CH2)1-3
`
`40
`
`O O
`
`(CH2)1-3
`
`HO
`
`O
`(CH2)1-3
`
`O
`
`O
`
`28
`
`OH
`
`O
`
`N
`
`O
`
`10
`
`O
`OH
`O
`
`O
`
`O
`
`O
`
`
`
`33. The compounds covered by claim 2 are a subset of the compounds
`
`claimed in claim 1, where the alkyl group must contain between one and three
`
`carbon atoms.
`
`34. Claim 3 depends from claim 1 and recites a compound according to
`
`claim 1 in which R1 is hydroxy(C1-3)alkyl.
`
`
`
`12
`
`Roxane Labs., Inc.
`Exhibit 1003
`Page 016
`
`

`
`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`
`35. The compounds covered by claim 3 are a subset of the compounds
`
`claimed in claim 1, where the rapamycin derivative must contain a hydroxyalkyl
`
`group at C40 containing between one and three carbon atoms.
`
`36. Claim 8 recites a method of inducing an immunosuppressant effect in
`
`a subject in need of immunosuppression, which comprises administering to said
`
`subject an immunosuppressant effective amount of a compound according to claim
`
`1.
`
`37. Claim 9 recites a method of preventing allograft rejection in a subject
`
`in need of such treatment, which comprises administering to said subject a
`
`compound according to claim 1 in an amount effective to prevent allograft
`
`rejection.
`
`38. Claim 10 depends from claim 1 and, as corrected by the Certificate of
`
`Correction attached to the ’772 Patent, recites the compound according to claim 1
`
`which is 40-O-(2-hydroxyethyl)-rapamycin, the compound shown below.
`
`
`
`13
`
`Roxane Labs., Inc.
`Exhibit 1003
`Page 017
`
`

`
`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`
`40-O-(2-hydroxyethyl)-rapamycin
`
`40
`
`O O
`
`HO
`
`O
`
`O
`
`28
`
`OH
`
`O
`
`O
`
`N
`
`O
`
`10
`
`O
`OH
`O
`
`O
`
`O
`
`
`39. Given the definitions of R1 in claims 2 and 3, the compound identified
`
`in claim 10 also falls within the scope of the compounds included in claims 2 and
`
`3.
`
`V.
`
`
`
`PROSECUTION HISTORY
`40.
`
`I have reviewed the prosecution history of the ’772 Patent. (Ex.
`
`1002.)
`
`41. All pending claims in the application for the ’772 Patent were initially
`
`rejected during prosecution on the basis of obviousness over Goulet et al., U.S.
`
`Patent No. 5,258,389, which disclosed rapamycin analogues that either broadly
`
`
`
`14
`
`Roxane Labs., Inc.
`Exhibit 1003
`Page 018
`
`

`
`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`included the claimed compounds or compounds with structural similarity to the
`
`claimed compounds. 2
`
`42. Applicants responded by arguing that the only compound disclosed in
`
`Goulet was very different than the claimed compounds, and one would have to
`
`pick and choose from Goulet’s broad disclosures to arrive at the claimed
`
`compounds. Applicants also included a declaration showing the activity of three of
`
`the claimed compounds against the Goulet compound. Finally, Applicants claimed
`
`priority to a British Application, which predated the date of the Goulet
`
`Application.
`
`43. The Examiner issued a Notice of Allowance on December 16, 1996,
`
`and the ’772 Patent issued on September 9, 1997.
`
`VI.
`
` LEVEL OF SKILL IN THE ART
`44. The purported inventions of the ’772 Patent reflect an understanding
`
`of several fundamental principles of drug design, including knowledge of the prior
`
`
`2 As often occurs with large molecules, different chemists utilized different
`
`numbering schemes for the carbon atoms in rapamycin and rapamycin derivatives
`
`in the 1980s and 1990s. A person of ordinary skill in the art would have
`
`recognized such variation in numbering conventions and have been able to identify
`
`the atoms on rapamycin that were modified.
`
`
`
`15
`
`Roxane Labs., Inc.
`Exhibit 1003
`Page 019
`
`

`
`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`art compounds and their activities and binding domains.
`
`45. Based on those factors, in my opinion a person of ordinary skill in the
`
`art in October 1992 would have had, at a minimum:
`
`a.
`
`a Ph.D. in organic chemistry or medicinal chemistry or physical
`chemistry, or a related field; or
`
`b.
`
`a masters or bachelor’s degree in chemistry or a related field
`and at least three years’ experience in drug discovery and
`design.
`46. This description is approximate, and a higher level of education or
`
`skill might make up for less experience, and vice-versa. In addition, in October
`
`1992, those of ordinary skill in the art had access to technicians with experience in
`
`computer-aided drug design, crystallography, as well as in testing a compound’s
`
`activity in standard chemical and biological assays.
`
`47.
`
`I believe that I would qualify as a person of at least ordinary skill in
`
`the art in October 1992, and that I have a sufficient level of knowledge, experience,
`
`and education to provide an opinion in the field of the ’772 Patent at that time.
`
`48. Furthermore, in my role as a Professor and head of my own research
`
`group, I manage approximately twenty individuals at a given time and, around
`
`October 1992, worked with and supervised individuals who were persons of
`
`ordinary skill in the art as defined above. My job responsibilities include
`
`managing these individuals, assigning tasks and deadlines to them based on their
`
`
`
`16
`
`Roxane Labs., Inc.
`Exhibit 1003
`Page 020
`
`

`
`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`capabilities, and reviewing their work product. I also remain an active practitioner
`
`of computer-aided drug design and developer of
`
`facilitating software.
`
`Accordingly, I am well acquainted with the actual performance of a person of
`
`ordinary skill in the art as defined above in October 1992, and can approach
`
`technical issues from the perspective of such a person.
`
` CLAIM CONSTRUCTION
`VII.
`I understand from counsel for Par that the claim terms of the ’772
`49.
`
`Patent are presumed to take on their ordinary and customary meaning based on the
`
`broadest reasonable interpretation of the claim language. I have interpreted the
`
`’772 Patent claims in this way and do not believe that any special meanings apply
`
`to the claim terms of the ’772 Patent.
`
`50.
`
`I understand from the Certificate of Correction submitted by Novartis
`
`that Novartis maintains that the structure drawn in claim 1 does not have a bond
`
`between C3 and C35, but rather that there is a methyl group on C35. I have been
`
`asked by counsel for Par to assume that this structure is the broadest reasonable
`
`construction for the claim.
`
` SUMMARY OF OPINIONS
`VIII.
`In my opinion, a person of ordinary skill in the art in October 1992
`51.
`
`would have found the subject matter of claims 1-3 & 8-10 of the ’772 Patent
`
`obvious in view of the prior art.
`
`
`
`17
`
`Roxane Labs., Inc.
`Exhibit 1003
`Page 021
`
`

`
`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`
`52.
`
`In short, by October 1992, a person of ordinary skill in the art would
`
`have selected rapamycin as a lead compound, knowing of its relatively poor
`
`solubility. A person of ordinary skill in the art would have been motivated to
`
`modify rapamycin to improve its solubility without disrupting its biological
`
`activity. A person of ordinary skill in the art would have modified rapamycin’s
`
`C40 hydroxyl group because the structure showing rapamycin’s binding to one of
`
`its biological targets, FKBP-12, showed that the C40 hydroxyl was the best
`
`position for modification. Finally, a person of ordinary skill in the art would have
`
`systematically attached solubilizing groups at the C40 and would have made
`
`rapamycin derivatives within the scope of the claims of the ’772 Patent. And
`
`having made these rapamycin derivatives, a person of ordinary skill in the art
`
`would have reasonably expected them to retain their immunosuppressant activities
`
`and administered them as immunosuppressants. For these reasons, it is my opinion
`
`that the claims of the ’772 Patent are obvious in view of the prior art. I expand on
`
`this further below.
`
`53. First, by October 1992, those of ordinary skill in the art were well
`
`aware of rapamycin, and had been for years. Since its discovery in a soil sample
`
`from Easter Island (also known as Rapa Nui, for which rapamycin was named),
`
`rapamycin and its properties had been extensively studied and highly publicized by
`
`those of ordinary skill in the art. Among rapamycin’s best known, most studied,
`
`
`
`18
`
`Roxane Labs., Inc.
`Exhibit 1003
`Page 022
`
`

`
`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`and most promising properties was its potent immunosuppressive activity—i.e., its
`
`potential to prevent organ transplant and allograft rejection. (Ex. 1005, Randall
`
`Ellis Morris, Rapamycins:
`
` Antifungal, Antitumor, Antiproliferative, and
`
`Immunosuppressive Macrolides, 6 TRANSPLANTATION REVIEWS 39, 39-42, 52-64
`
`(1992) (“Morris”).) Scientists and drug companies were intrigued by the
`
`possibilities rapamycin might offer as a potent drug and identified it as a lead
`
`compound for study and analysis. (See § IX.A.1, below.)
`
`54. Second, by October 1992, it was widely reported in the literature that
`
`rapamycin’s utility as a pharmaceutical was limited by its poor solubility. (See,
`
`e.g., Ex. 1005, Morris at 46.) Indeed, this limitation of rapamycin is expressly
`
`acknowledged in the ’772 Patent. (Ex. 1001, ’772 Patent at 1:36-40.) Solubility is
`
`crucial for a pharmaceutical because it is directly linked to bioavailability.
`
`Rapamycin’s relative inability to dissolve therefore limited its ability to enter the
`
`bloodstream and eventually reach the tissue where it would have its intended
`
`immunosuppressive effect. (See § IX.A.2, below.)
`
`55. Well before October 1992, those of ordinary skill in the art understood
`
`that a compound’s solubility could be improved by making routine modifications
`
`to the compound’s molecular structure. Indeed, by 1992, improving solubility was
`
`a common purpose for making modifications to existing molecules. Thus, a person
`
`of ordinary skill in the art would have been motivated to look and combine the
`
`
`
`19
`
`Roxane Labs., Inc.
`Exhibit 1003
`Page 023
`
`

`
`Declaration of William L. Jorgensen, Ph.D., in Support of
`Par Petition for Inter Partes Review of U.S. Patent No. 5,665,772
`
`prior art teachings about rapamycin, including its relatively poor solubility, with
`
`the prior art teachings regarding solubility-enhancing substituents. (See § IX.A.3,
`
`below.)
`
`56. Such publications
`
`listing
`
`the solubilizing effects of various
`
`substituents were available by October 1992, including the following references.
`
`(Ex. 1007, Samuel H. Yalkowsky, Estimation of Entropies of Fusion of Organic
`
`Compounds, 18 INDUS. & ENG’G CHEMISTRY FUNDAMENTALS 108 (1979)
`
`(“Yalkowsky”); Ex. 1021, Thomas W. Bell, Construction of a Soluble Heptacyclic
`
`Terpyridine, 51 J. ORGANIC CHEMISTRY 764, 764 (1986) (“Bell”); Ex. 1008,
`
`Thomas L. Lemke,