UNITED STATES PATENT AND TRADEMARK OFFICE
`________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________________
`
`AGILA SPECIALTIES INC. AND
`MYLAN PHARMACEUTICALS INC.,
`Petitioners
`
`v.
`
`CUBIST PHARMACEUTICALS, INC.
`Patent Owner
`
`U.S. Patent No. 8,058,238
`
`________________________
`
`Case IPR2015: Unassigned
`________________________
`
`EXPERT DECLARATION OF CATHERINE MULLIGAN, PH.D
`
`PETITIONERS
`
`EXHIBIT NO. 1005 Page 1 of 259
`
`
`________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________________
`
`AGILA SPECIALTIES INC. AND
`MYLAN PHARMACEUTICALS INC.,
`Petitioners
`
`v.
`
`CUBIST PHARMACEUTICALS, INC.
`Patent Owner
`
`U.S. Patent No. 8,058,238
`
`________________________
`
`Case IPR2015: Unassigned
`________________________
`
`EXPERT DECLARATION OF CATHERINE MULLIGAN, PH.D
`
`PETITIONERS
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`EXHIBIT NO. 1005 Page 1 of 259
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`
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`TABLE OF CONTENTS
`
`I.
`
`Qualifications and Background ............................................................................1
`
`A.
`B.
`C.
`
`Education and Experience; Prior Testimony..............................................1
`Bases for Opinions and Materials Considered...........................................5
`Scope of Work ............................................................................................5
`
`Summary of Opinions...........................................................................................5
`
`Legal Standards ....................................................................................................9
`
`Person of Ordinary Skill in the Art.....................................................................10
`
`The ‘238 Patent...................................................................................................12
`
`II.
`
`III.
`
`IV.
`
`V.
`
`VI. Background.........................................................................................................19
`
`A.
`B.
`
`Use of Surfactants and Biosurfactants .....................................................19
`Biosurfactant Purification and State of the Art in 2000...........................24
`
`VII. Scope and Content of the Prior Art References..................................................34
`
`A.
`B.
`C.
`D.
`
`U.S. Patent No. 4,874,843 (‘843 Patent) [Ex.1007].................................34
`U.S. Patent No. 4,331,594 (‘594 Paten) [Ex.1009]..................................35
`U.S. Patent No. 5,912,226 (“the ‘226 Patent”) [Ex.1010].......................36
`Baltz “Lipopeptide Antibiotics Produced by Streptomyces
`roseosporus and Streptomyces fradiae,” in BIOTECHNOLOGY OF
`ANTIBIOTICS ed. W.R. Strohl (Marcel Dekker 1997) (“Baltz”)
`[Ex.1008]..................................................................................................38
`E. Mulligan and Gibbs, “Recovery of Biosurfactants by
`Ultrafiltration,” Journal of Chemical Technology & Biotechnology,
`
`PETITIONERS
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`EXHIBIT NO. 1005 Page 2 of 259
`
`
`
`F.
`
`G.
`
`H.
`I.
`
`J.
`
`47:23-9 (1990) (“Mulligan”) [Ex. 1013]..................................................39
`Lin and Jiang, “Recovery and Purification of the Lipopeptide
`Biosurfactant Bacillus subtilis by Ultrafiltration,” Biotechnology
`Techniques, 11:413-6 (June 1997) (“Lin I”) [Ex. 1014]..........................42
`Lin et al., “General Approach for the Development of High-
`Performance Liquid Chromatography Methods for Biosurfactant
`Analysis and Purification,” Journal of Chromatography, 825:149-
`59 (1998) (Lin II) [Ex. 1015] ...................................................................44
`U.S. Patent No. 5,227,294 (‘294 Patent) [Ex. 1016]................................46
`Osman et al., “Tuning micelles of a bioactive heptapeptide
`biosurfactant via extrinsically induced conformational transition of
`surfactin assembly” J. Peptide Sci., 4:449-458 (1998) (“Osman”)
`[Ex. 1017].................................................................................................47
`Tally et al., “Daptomycin: A Novel Agent for Gram-positive
`Infections,” Expert Opin. Invest. Drugs 8:1223-38 (1999) [Ex.
`1018].........................................................................................................49
`
`VIII. INVALIDITY OF THE ‘238 PATENT .............................................................50
`
`A.
`
`B.
`
`C.
`
`All Claims of the ‘238 Patent are Anticipated and/or Obvious Over
`the ‘226 Patent..........................................................................................50
`Claims 1 and 2 of the ‘238 Patent are Obvious Over the ‘843
`Patent or ‘594 Patent In View Of Mulligan, Lin II, and/or the ‘226
`Patent and the ‘294 Patent........................................................................90
`Claims 1-2 of the ‘238 Patent are Obvious Over the ‘594 Patent in
`View of Mulligan, Lin II, and/or the ‘226 Patent and the ‘294
`
`EXPERT DECLARATION OF CATHERINE N. MULLIGAN, PH.D.
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`PETITIONERS
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`EXHIBIT NO. 1005 Page 3 of 259
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`D.
`
`Patent ........................................................................................................97
`Claims 3, 6, 7, 21-36, 49-51, 85-92, 105-107, 113-124, 144-146,
`151-162, 164, 165, 175, 176, 183, 186-190 of the ‘238 Patent are
`Obvious Over the ‘843 Patent or the ‘594 Patent In View of
`Mulligan, Lin II and/or the ‘226 Patent .................................................101
`(a)
`Claims 3 and 6-7 of the ‘238 Patent Are Obvious ..........................101
`(b)
`Claims 21-36 of the ‘238 Patent are Obvious .................................106
`(c)
`Independent Claims 49 and 50 and Dependent Claims 51, 85-92,
`105-107, 113-124, 144-146, 151-162, 164, 165, 175 of the ‘238 Patent Are
`Invalid as Obvious Over the ‘843 Patent or ‘594 Patent in View of Mulligan, Lin
`II and/or the ‘226 Patent.......................................................................................111
`(d)
`Claim 176 of the ‘238 Patent is Invalid as Obvious Over the ‘843
`Patent or ‘594 Patent in View of Mulligan, Lin II and/or the ‘226 Patent ..........121
`(e)
`Claims 183 and 186-190 of the ‘238 Patent are Invalid as Obvious
`Over the ‘843 Patent or ‘594 Patent in View of Mulligan, Lin II and/or the ‘226
`Patent.
`123
`E.
`Claims 4-5, 8-19, 93, 125-138, 166-167, 171, 173-174, 177-179 of
`the ‘238 Patent are Obvious Over the ‘843 Patent or ‘594 Patent In
`View of Mulligan, Lin I and/or Lin II and/or the ‘226 Patent ...............126
`(a)
`Claims 4-5 of the ‘238 Patent are Invalid as Obvious ....................126
`(b)
`Claims 8-9 of the ‘238 Patent is Invalid as Obvious Over the ‘843
`Patent in View of Mulligan, Lin I, Lin II and/or the ‘226 Patent ........................130
`(c)
`Claims 10-19 of the ‘238 Patent are Invalid as Obvious Over the
`‘843 Patent or ‘594 Patent in View of Mulligan, Lin I, Lin II and/or the ‘226
`Patent
`133
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`EXPERT DECLARATION OF CATHERINE N. MULLIGAN, PH.D.
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`PETITIONERS
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`EXHIBIT NO. 1005 Page 4 of 259
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`Claims 93, 125-138, 166-167, 171, 173-174 and 177-179 of the ‘238
`(d)
`Patent are Invalid as Obvious Over the ‘843 Patent or the ‘594 Patent in View of
`Mulligan, Lin I, Lin II and/or the ‘226 Patent .....................................................138
`F.
`Claims 37-42, 48, 66-84, 94-99, 100-104, 112, 139-143, 163 and
`182 of the ‘238 Patent are Obvious Over the ‘843 Patent In View
`of Mulligan, Lin II, and/or the ‘226 Patent and the ‘594 Patent............145
`(a)
`Claims 37-42 of the ‘238 Patent are Invalid as Obvious Over the
`‘843 Patent in View of Mulligan, Lin II, and/or the ‘226 Patent, Lin I and the ‘594
`Patent
`146
`Claims 48, 94-99, 100-104, 112, 139-143 and 163 of the ‘238 Patent
`(b)
`are Invalid as Obvious Over the ‘843 Patent in View of Mulligan, Lin II and/or
`the ‘226 Patent and the ‘594 Patent .....................................................................151
`(c)
`Claims 66-84 and 182 of the ‘238 Patent are Invalid as Obvious Over
`the ‘843 Patent In View of Mulligan, Lin II and/or the ‘226 Patent and Further In
`View of Baltz and the ‘594 Patent .......................................................................160
`G.
`Claims 20, 43-47, 108-111, 147-150, 168-170, 172, 180-181, 184-
`185 and 191-192 of the ‘238 Patent are Obvious Over the ‘843
`Patent or ‘594 Patent In View of Mulligan, Lin II and/or the ‘226
`Patent and Further In View of Osman....................................................170
`(a)
`Claim 20 of the ‘238 Patent is Invalid as Obvious Over the ‘843
`Patent or the ‘594 Patent In View of Mulligan, Lin II and/or the ‘226 Patent and
`Further in View of Osman....................................................................................170
`(b)
`Claims 43-47 of the ‘238 Patent are Invalid as Obvious Over the
`‘843 Patent in View of Mulligan, Lin II and/or the ‘226 Patent and Further in
`View of Osman.....................................................................................................173
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`EXPERT DECLARATION OF CATHERINE N. MULLIGAN, PH.D.
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`PETITIONERS
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`EXHIBIT NO. 1005 Page 5 of 259
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`Claims 108-111, 147-150, 168-170 and 172 of the ‘238 Patent are
`(c)
`Invalid as Obvious Over the ‘843 of the ‘594 Patent in View of Mulligan, Lin II,
`and/or the ‘226 Patent and Osman .......................................................................177
`(d)
`Claims 180-181 and 184-185 of the ‘238 Patent are Invalid as
`Obvious Over the ‘843 Patent or the ‘594 Patent in View of Mulligan, Lin II
`and/or the ‘226 Patent, and Further in View of Osman .......................................183
`(e)
`Claims 191-192 of the ‘238 Patent are Invalid as Obvious Over the
`‘843 Patent of the ‘594 Patent in View of Mulligan, Lin II, and/or the ‘226 Patent
`and Osman 187
`H.
`Claims 52-65 of the ‘238 Patent are Obvious Over the ‘843 Patent
`In View of Mulligan, Lin II, and/or the ‘226 Patent and Tally..............190
`
`IX. CONCLUSION.................................................................................................196
`
`EXPERT DECLARATION OF CATHERINE N. MULLIGAN, PH.D.
`
`PETITIONERS
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`EXHIBIT NO. 1005 Page 6 of 259
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`1
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`1.
`
`My name is Catherine N. Mulligan, Ph.D. I have been retained by
`
`counsel for Mylan Inc. (Mylan). I understand that Mylan intends to petition for
`
`inter partes review of U.S. Patent No. 8,058,238 (the ‘238 patent), which is
`
`assigned to Cubist Pharmaceuticals, Inc. I also understand that Mylan intends to
`
`petition for inter partes review of U.S. Patent No. 8,129,342 (the ‘342 patent),
`
`which is also assigned to Cubist Pharmaceuticals, Inc. I further understand that
`
`Mylan will request that the United States Patent and Trademark Office cancel
`
`certain claims of the ‘238 patent and the ‘342 patent as unpatentable in an Inter
`
`Partes Review petition. I submit this expert declaration, which addresses and
`
`supports Mylan’s Inter Partes Review petition for the ‘238 patent. I have prepared
`
`and submitted a separate declaration which addresses and supports Mylan’s Inter
`
`Partes Review petition for the ‘342 patent.
`
`I.
`
`Qualifications and Background
`
`A.
`
`2.
`
`Education and Experience; Prior Testimony
`
`I received my Bachelors of Engineering and Masters of Engineering
`
`in Chemical Engineering in 1983 and 1985, respectively, from McGill University.
`
`My Masters thesis was under the supervision of Professor David Cooper, an expert
`
`in biosurfactants. I went on to obtain my Ph.D in Geoenvironmental Engineering
`
`from McGill University in 1998 with Professor Raymond N. Yong. My thesis
`
`EXPERT DECLARATION OF CATHERINE N. MULLIGAN, PH.D.
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`PETITIONERS
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`EXHIBIT NO. 1005 Page 7 of 259
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`2
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`project centered around the purification and use of biosurfactants, including
`
`surfactin, a cyclic lipopetide produced as a secondary metabolite during
`
`fermentation of Bacillus subtilis, for the removal of heavy metals from soils and
`
`sediments.
`
`3.
`
`Between obtaining my Masters in Chemical Engineering and entering
`
`the doctoral program at McGill University, I worked at several industrial biological
`
`and chemical engineering facilities, including as a Research Associate in
`
`Fermentation Engineering from 1985-1989 at the Biotechnology Research Institute
`
`(NRCC) in Montreal, Canada, and a Research Engineer from 1989-1999 at SNC
`
`Research Corporation, also in Montreal, Canada. At the Biotechnology Research
`
`Institute, I studied factors that influenced the production of biosurfactants by
`
`Bacillus and Pseudomonas species during fermentation. My work resulted in the
`
`publication of a research article in the Journal of Chemical Technology and
`
`Biotechnology in 1990 related to the use of ultrafiltration technology to purify
`
`biosurfactants, including surfactin and rhamnolipids, from culture supernatant
`
`fluids. See Mulligan, C.N. and Gibbs, B.F., “Recovery of biosurfactants by
`
`ultrafiltration,” J. Chem. Technol. Biotechnol. 47:23-9 (1990) [Ex. 1013]. My
`
`1990 research article took advantage of the ability of biosurfactant molecules to
`
`EXPERT DECLARATION OF CATHERINE N. MULLIGAN, PH.D.
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`PETITIONERS
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`EXHIBIT NO. 1005 Page 8 of 259
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`3
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`form micelles at concentrations above the critical micelle concentration. This
`
`allowed the surfactant aggregates to be retained by relatively high molecular
`
`weight cut-off membranes, demonstrating a simple technique to purify
`
`biosurfactants, including removing low molecular weight impurities, such as salts,
`
`free amino acids, peptides and small proteins to be easily removed.
`
`4.
`
`I am currently a Professor of Civil and Environmental Engineering at
`
`Concordia University, Montreal, Canada, and have held this position since 1999. I
`
`am also the Associate Dean in the Faculty of Engineering and Computer Science of
`
`Research and Graduate Studies, and Research Chair in Geoenvironmental
`
`Sustainability at Concordia University. I teach graduate level courses in
`
`Environmental Engineering at Concordia University, including engineering aspects
`
`of bioremediation, such as the industrial production, purification and use of
`
`biosurfactants.
`
`5.
`
`In all, I have more than 25 years of experience in fermentation
`
`engineering and purification of secondary metabolites from microbial cultures,
`
`such as biosurfactants, including cyclic lipopeptides.
`
`6.
`
`My research has resulted in the publication of over 220 refereed
`
`articles, conference proceedings and abstracts. I have also contributed or served as
`
`EXPERT DECLARATION OF CATHERINE N. MULLIGAN, PH.D.
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`4
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`editor of 14 book chapters and books. I recently served as a co-editor of the
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`reference book “Biosurfactants: Research Trends & Applications,” CRC Press
`
`2014 [Ex. 1019]. I authored several chapters, including a chapter entitled
`
`“Characterization, Production and Application of Lipopeptides.” The chapter
`
`reflects work in the field from the early 1980s to the present, and discusses in
`
`detail the production and purification of biosurfactant lipopeptides, including
`
`cyclic lipopeptides.
`
`7.
`
`In addition, I have held or currently hold various editorial positions
`
`for a number of scientific publications related to environmental engineering and
`
`biosurfactants, and have chaired, co-chaired and organized various meetings and
`
`conferences for the field.
`
`8.
`
`I am a member of the American Chemical Society, the American
`
`Institute of Chemical Engineering, the Canadian Society of Chemical Engineering
`
`and other professional and scientific society memberships.
`
`9.
`
`I am an inventor or co-inventor of at least three U.S. patents and
`
`international applications.
`
`10.
`
`I have not testified previously as an expert witness.
`
`11. My curriculum vitae is attached here as Exhibit A.
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`EXPERT DECLARATION OF CATHERINE N. MULLIGAN, PH.D.
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`EXHIBIT NO. 1005 Page 10 of 259
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`5
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`B.
`
`12.
`
`Bases for Opinions and Materials Considered
`
`Exhibit B includes a list of the materials I considered, in addition to
`
`my experience, education, and training, in providing the opinions contained herein.
`
`C.
`
`13.
`
`Scope of Work
`
`I have been retained by Mylan as a technical expert in this matter to
`
`provide various opinions regarding the ‘238 patent. I receive $325.00 per hour for
`
`my services. No part of my compensation is dependent upon my opinions given or
`
`the outcome of this case. I do not have any other current or past affiliation as an
`
`expert witness or consultant with Mylan. I do not have any current or past
`
`affiliation with Cubist Pharmaceuticals, Inc., or any of the named inventors on the
`
`‘238 patent.
`
`II.
`
`Summary of Opinions
`
`14.
`
`To summarize, for the reasons set forth below, it is my opinion that
`
`each claim of the ‘238 patent is anticipated and/or obvious in view of the prior art,
`
`including the use of micelles and ultrafiltration to purify lipopeptide preparations.
`
`15.
`
`I understand that the challenged claims are “product by process”
`
`claims, which are composition claims that list manufacturing process steps. I have
`
`been told that as a result of the claims being classified as “product by process”
`
`claims, the claims should be analyzed through the claimed composition only, and
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`EXPERT DECLARATION OF CATHERINE N. MULLIGAN, PH.D.
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`PETITIONERS
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`6
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`not through the methods that are recited in the claims. I have reviewed the
`
`daptomycin prior art, and find that one of ordinary skill in the art would have
`
`understood that U.S. Patent No. 5,912,226 (‘226 patent) [Ex. 1010] to Eli Lilly and
`
`Company anticipate and/or render obvious all claims of the ‘238 patent. The ‘226
`
`patent disclosed a daptomycin composition that one of ordinary skill in the art
`
`would have understood approached homogeneity through the combination of a
`
`variety of chromatography and adsorption process steps, combined with
`
`preparative HPLC (high-performance or high-pressure liquid chromatography)
`
`purification. The ‘226 patent also disclosed pharmaceutical formulations
`
`comprising the purified daptomycin composition, as well as administration of the
`
`formulations to humans. In my opinion, the ‘226 patent anticipates, and at the very
`
`least renders obvious, all of the challenged claims of the ‘238 patent.
`
`16. Moreover, the processes (if considered as part of the claim language)
`
`were all well-known and used by those of ordinary skill in the art. In 1990, ten
`
`years before the earliest filing of the ‘238 patent, my laboratory demonstrated that
`
`the propensity for biosurfactants such as lipopeptides (including the cyclic
`
`lipopeptide surfactin) to form micelles could be exploited to purify lipopeptide
`
`preparations when used in conjunction with high molecular weight ultrafiltration
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`EXPERT DECLARATION OF CATHERINE N. MULLIGAN, PH.D.
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`PETITIONERS
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`cells. Our results showed that this one-step process, which required only a fraction
`
`(approximately 2%) of the time as compared to conventional chemical extraction
`
`processes and required no organic solvents, retained in excess of 96% of surfactin
`
`in the crude fermentation preparation while simultaneously removing smaller
`
`molecular weight impurities in the process. This led to purification of the surfactin
`
`preparation by almost 10-fold. Because of the simplicity, time- and cost-savings, as
`
`well as the efficiency of the micelle/ultrafiltration process for purifying lipopeptide
`
`preparations, others in the field began to incorporate this technique into their
`
`biosurfactant purification protocols to obtain highly purified surfactin preparations.
`
`It would have thus been obvious by January 2000, as others were doing for cyclic
`
`lipopeptides, to employ a micelle formation/ultrafiltration protocol in the
`
`purification of daptomycin.
`
`17.
`
`The modification of environmental factors, such as pH, temperature,
`
`daptomycin concentration and ionic strength, to influence micelle structure and
`
`formation was also well-known by January 2000. pH, temperature, biosurfactant
`
`concentration and ionic strength are all known to influence micelle structure, and
`
`changes to the process can further drive and stabilize micelle formation. One of
`
`ordinary skill in the art would also know that increasing daptomycin concentration
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`above the critical micelle concentration will, by definition, induce the formation of
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`micelles. Accordingly, it would have also been obvious to manipulate pH,
`
`temperature, daptomycin concentration and ionic strength conditions in order to
`
`form daptomycin micelles.
`
`18.
`
`In addition, the combination of a micelle formation and ultrafiltration
`
`step with other purification processes, such as anion-exchange chromatography,
`
`hydrophobic interaction chromatography, HPLC preparative chromatography and
`
`other column chromatography techniques to reach certain purity levels and to
`
`further remove impurities in the preparation would have also been obvious to
`
`employ for cyclic lipopeptides, such as daptomycin, by January 2000. These
`
`techniques were standard to biochemists and chemists for the purification of
`
`lipopeptides; those of ordinary skill in the art, including my laboratory and others
`
`in the biosurfactant field, routinely employed these purification techniques to
`
`obtain biosurfactant preparations approaching homogeneity. Well before the filing
`
`of the ‘238 patent, biosurfactant preparations were routinely purified to greater
`
`than 98% and greater than 99% purity levels.
`
`19. Moreover, the use of HPLC to identify and analyze impurities in
`
`lipopeptide preparations was also well known to those of ordinary skill in the art
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`by January 2000. Chromatography and other mass- and charge-based analysis
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`techniques, including mass spectrometry and HPLC, were routinely employed by
`
`those of ordinary skill in the art. It would have thus been obvious to use HPLC to
`
`identify and analyze impurities in lipopeptide preparations, such as daptomycin.
`
`III.
`
`Legal Standards
`
`20.
`
`In preparation for forming the opinions set forth in this declaration, I
`
`have been informed regarding the relevant legal principles. I have used my
`
`understanding of those principles in forming my opinions. My understanding of
`
`those principles is summarized below.
`
`21.
`
`I have been told that Mylan bears the burden of proving invalidity by
`
`a preponderance of the evidence. I am informed that this preponderance of the
`
`evidence standard means that Mylan must show invalidity is more probable than
`
`not. I have taken these principles into account when forming my opinions in this
`
`case.
`
`22.
`
`I have also been told that claims should be construed given their
`
`broadest reasonable interpretation in light of the specification from the perspective
`
`of a person of ordinary skill in the art.
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`23.
`
`I am told that the concept of anticipation requires that each element of
`
`a claim be found in a single prior art reference as understood in the context of the
`
`skill and knowledge of one of ordinary skill in the art. I have also been told that
`
`the claims in the ‘238 patent are “product by process claims,” where a composition
`
`is claimed in temrs of recited process steps.
`
`24.
`
`I am told that the concept of patent obviousness involves four factual
`
`inquiries: (1) the scope and content of the prior art; (2) the differences between the
`
`claimed invention and the prior art; (3) the level of ordinary skill in the art; and (4)
`
`secondary considerations of non-obviousness.
`
`25.
`
`I am also informed that when there is some recognized reason to solve
`
`a problem, and there are a finite number of identified, predictable and known
`
`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 expected
`
`success, it is likely not the product of innovation but of ordinary skill and common
`
`sense. In such a circumstance, when a patent simply arranges old elements with
`
`each performing its known function and yields no more than one would expect
`
`from such an arrangement, the combination is obvious.
`
`IV.
`
`Person of Ordinary Skill in the Art
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`EXPERT DECLARATION OF CATHERINE N. MULLIGAN, PH.D.
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`26.
`
`I have been informed by counsel that the obviousness analysis is to be
`
`conducted from the perspective of a person of ordinary skill in the art (a “person of
`
`ordinary skill”) at the time of the invention.
`
`27.
`
`I have also been informed by counsel that in defining a person of
`
`ordinary skill in the art the following factors may be considered: (1) the
`
`educational level of the inventor; (2) the type of problems encountered in the art;
`
`(3) prior art solutions to those problems; (4) rapidity with which innovations are
`
`made; and (5) sophistication of the technology and educational level of active
`
`workers in the field.
`
`28. Aperson of ordinary skill in the art related to the ‘238 patent typically
`
`would have held a Masters or Ph.D. in Chemistry, Biochemistry or Chemical
`
`Engineering with experience in microbial fermentation and product purification. A
`
`person of ordinary skill in the art would have had the necessary skill set for
`
`purifying, for example, secondary metabolites from microbial fermentation,
`
`including but not limited to filtration and adsorption techniques, chemical
`
`extractions and analysis, including chromatography, such as anion exchange
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`chromatography, hydrophobic interaction chromatography, thin layer
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`chromatography (TLC), high-performance (high-pressure) liquid chromatography
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`EXPERT DECLARATION OF CATHERINE N. MULLIGAN, PH.D.
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`PETITIONERS
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`EXHIBIT NO. 1005 Page 17 of 259
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`12
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`(HPLC) and gel filtration analysis. Moreover, a person of ordinary skill in the art
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`for the ‘238 patent would have had the requisite skill set to analyze biosurfactant
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`products obtained, including the use of chromatography and mass- or charge-based
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`analytical techniques, such as mass spectrometry and HPLC. One of the first
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`pieces of equipment obtained for my laboratory when I started at the
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`Biotechnology Research Institute in Montreal, Canada in 1985 was an HPLC,
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`specifically for the purpose of analyzing biosurfactant preparations, as well as
`
`preparing highly purified preparations of surfactin. In my experience, an HPLC is
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`standard for biochemistry and chemistry laboratories.
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`V.
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`The ‘238 Patent
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`29.
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`I have read the ‘238 patent and the issued claims, entitled “High
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`Purity Lipopeptides.” ‘238 patent was filed August 16, 2007, and is a continuation
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`of US Patent Application No. 10/747,485, which was filed on December 29, 2003,
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`which is a divisional application of US Patent Application No. 09/735,191, which
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`was filed on November 28, 2000, now U.S. Patent No. 6,696,412. The ‘238 patent
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`claims priority to U.S. Provisional Application No. 60/177,190, filed on January 20,
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`2000. The ‘238 patent issued November 15, 2011, and names Thomas Kelleher,
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`EXPERT DECLARATION OF CATHERINE N. MULLIGAN, PH.D.
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`PETITIONERS
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`EXHIBIT NO. 1005 Page 18 of 259
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`Jan-Ji Lai, Joseph P. DeCourcey, Paul Lynch, Maurizio Zenoni and Auro Tagliani
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`13
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`as inventors.
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`30.
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`I understand that Mylan is challenging claims 1-192. The ‘238 patent
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`includes 11 independent claims, claims 1, 3, 8, 10, 21, 49, 50, 176, 180, 183 and
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`191. Independent claim 1 recites: A composition comprising essentially pure
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`daptomycin purified by a process comprising the steps of:
`
`(a)
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`subjecting daptomycin to conditions forming a daptomycin aggregate;
`
`and
`
`(b)
`
`obtaining the essentially pure daptomycin from the daptomycin
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`aggregate.
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`31.
`
`I understand that the claim terms in the ‘238 patent are presumed to
`
`take on their ordinary and customary meaning based on the “broadest reasonable
`
`construction in light of the specification of the patent in which it appears.” The
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`‘238 patent defines “essentially pure” daptomycin as “at least 98%” purity levels,
`
`or “at least 99%” daptomycin purity levels. See ‘238 patent at 7:41-46.
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`32.
`
`Independent claim 3 of the ‘238 patent recites: A composition
`
`comprising daptomycin that is substantially free of anhydro-daptomycin and
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`EXPERT DECLARATION OF CATHERINE N. MULLIGAN, PH.D.
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`PETITIONERS
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`EXHIBIT NO. 1005 Page 19 of 259
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`14
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`substantially free of β-isomer of daptomycin, the daptomycin being purified by a
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`process comprising the steps of:
`
`(a)
`
`subjecting daptomycin to conditions forming a daptomycin aggregate;
`
`and
`
`(b)
`
`obtaining the essentially pure daptomycin from the daptomycin
`
`aggregate.
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`The ‘238 patent defines “substantially free” daptomycin as daptomycin
`
`purity relative to another compound “in in an amount that is no more than 1% of
`
`the amount of the daptomycin.” See ‘238 patent at 7:47-51.
`
`33.
`
`Independent claim 8 of the patent recites: A composition comprising
`
`purified daptomycin that is substantially free of each of impurities 1 to 14 defined
`
`by peaks 1-14 shown in FIG. 12, the purified daptomycin being obtained by a
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`process comprising the steps of: (a) subjecting daptomycin to conditions forming a
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`daptomycin aggregate; (b) subjecting the daptomycin aggregate to conditions
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`forming monomeric daptomycin; and (c) obtaining the daptomycin from the
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`monomeric daptomycin, the daptomycin aggregate or a combination thereof
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`34.
`
`Figure 12 of the ‘238 patent (reproduced below) is a chromatogram of
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`“[a]n impurity profile of the bulk daptomycin prior to chromatography on the
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`EXPERT DECLARATION OF CATHERINE N. MULLIGAN, PH.D.
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`PETITIONERS
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`EXHIBIT NO. 1005 Page 20 of 259
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`15
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`Poros P150 anion exchange resin,” with demarcations aligned with different peaks
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`in the chromatogram, labeled 1 to 14. See ‘238 patent, Example 10, 33:63-67.
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`35.
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`Independent claim 10 of the ‘238 patent recites: A pharmaceutical
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`composition comprising essentially pure daptomycin purified by a process
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`comprising the steps of: (a) forming micelles comprising daptomycin; (b)
`
`converting the micelles to a non-micellar daptomycin composition comprising
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`EXPERT DECLARATION OF CATHERINE N. MULLIGAN, PH.D.
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`PETITIONERS
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`EXHIBIT NO. 1005 Page 21 of 259
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`16
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`daptomycin in a non-micellar state; and (c) obtaining the purified daptomycin from
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`the micelles, the non-micellar daptomycin composition, or a combination thereof.
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`36.
`
`The ‘238 patent defines micelles as “aggregates of amphipathic
`
`molecules.” See ‘238 patent at 8:20-26. The ‘238 patent further disclosed that
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`“[m]icelles form spontaneously in a solution containing amphipathic molecules if
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`the concentration of the molecules is high enough.” Id. at 15:15-48. Accordingly,
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`the ‘238 patent defines “micelles” as a subset of “aggregates.”
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`37.
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`Independent claim 21 recites a “composition comprising daptomycin
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`of greater than or about 93% purity relative to daptomycin impurities that arise in
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`fermentation or purification of daptomycin, and wherein the daptomycin impurities
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`comprise impurities 1-14 defined by peaks 1-14 shown in FIG. 12, and the
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`daptomycin is obtained by a process comprising the step of forming a micelle
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`comprising daptomycin.”
`
`38.
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`Independent claim 49 recites “[a] purified daptomycin composition
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`comprising daptomycin of greater than or about 93% purity relative to impurities
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`1-14 defined by peaks 1-14 shown in FIG. 12, the daptomycin being obtained by a
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`process comprising the step of forming an aggregate comprising daptomycin.”
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`EXPERT DECLARATION OF CATHERINE N. MULLIGAN, PH.D.
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`PETITIONERS
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`EXHIBIT NO. 1005 Page 22 of 259
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`17
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`39.
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`Independent claim 50 recites “A composition comprising purified
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`daptomycin obtained from a daptomycin aggregate, the purified daptomycin
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`selected from the group consisting of: (a) essentially pure daptomycin, (b)
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`daptomycin that is substantially free of anhydro-daptomycin and substantially free
`
`of β-isomer of daptomycin, (c) daptomycin that is essentially free of anhydro-
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`daptomycin and substantially free of β-isomer of daptomycin, (d) daptomycin that
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`is free of anhydro-daptomycin and substantially free of β-isomer of daptomycin, (e)
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`daptomycin that is substantially free of each of impurities 1 to 14 defined by peaks
`
`1-14 shown in FIG. 12, and (f) daptomycin that is essentially free of each of
`
`impurities 1 to 14 defined by peaks 1-14 shown in FIG. 12. The ‘238 patent
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`defines “essentially free” daptomycin as the daptomycin purity relative to another
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`compound “is present in an amount that is no more than 0.5% of the amount of the
`
`daptomycin.” ‘238 patent at 7:52-56.
`
`40.
`
`Independent claim 176 recites “purified daptomycin composition of
`
`greater than or 93% purity relative to impurities 1-14 defined by peaks 1-14 shown
`
`in FIG. 12, the purified daptomycin composition obtained by a process comprising
`
`the steps of: (a) subjecting daptomycin to conditions forming daptomycin micelles
`
`and (b) obtaining the purified daptomycin from the daptomycin micelles.”
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`EXPERT DECLARATION OF CATHERINE N. MULLIGAN, PH.D.
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`PETITIONERS
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`EXHIBIT NO. 1005 Page 23 of 259
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`18
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`41.
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`Independent claim 180 recites “[a] purified daptomycin composition
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`of greater than or about 93% purity relative to impurities 1-14 defined by peaks 1-
`
`14 shown in FIG. 12, the purified daptomycin composition obt
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