Filed on behalf of: Abraxis Bioscience, LLC
`Filed: November 7, 2017
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________________
`
`ACTAVIS LLC,
`Petitioner
`v.
`ABRAXIS BIOSCIENCE, LLC,
`Patent Owner
`_______________________
`Case IPR2017-01101
`U.S. Patent No. 7,820,788
`_______________________
`
`DECLARATION OF LISAMARIE LOGIUDICE
`
`

`

`I, Lisamarie LoGiudice, make the following Declaration pursuant to 28
`
`U.S.C. § 1746:
`
`1.
`
`2.
`
`I am an attorney with the law firm Jones Day.
`
`I provide this Declaration in response to Petitioner Actavis LLC’s
`
`Objections to Evidence in connection with the above-identified Inter Partes
`
`Review proceeding (served October 24, 2017). Unless otherwise stated, the facts
`
`stated in this Declaration are based on my personal knowledge.
`
`3.
`
`Exhibit 2006 is a true and accurate copy of the webpage located at
`
`http://www.fdanews.com/articles/print/98911-phase-iii-trial-of-tocosol-paclitaxel-
`
`does-not-meet-primary-endpoint as of June 26, 2017. The contents and substance
`
`of this document indicate that it is what it purports to be. The date on the
`
`document indicates that it was downloaded on June 16, 2017, the website is
`
`indicated as fdanews.com, the copyright information, such as the date, address,
`
`phone and fax numbers, is included, and the URL link appears on the bottom left
`
`of the page.
`
`4.
`
`Exhibit 2010 is a true and accurate copy of the webpage located at
`
`https://www.firstwordpharma.com/print/1398969?tsid=1 as of June 26, 2017. The
`
`contents and substance of this document indicate that it is what it purports to be.
`
`The date on the document indicates that it was downloaded on June 26, 2017, the
`
`website is indicated as www.firstwordpharma.com, the copyright information
`
`-2-
`
`

`

`appears in the document, the article has a date of July 12, 2016, and the URL link
`
`appears on the bottom left of the page.
`
`5.
`
`Exhibit 2015 is a true and accurate copy of the webpage located at
`
`http://www.webmd.com/breast-cancer/news/20090603/breast-cancer-drug-
`
`abraxane-is-effective?print=true as of June 26, 2017. The contents and substance
`
`of this document indicate that it is what it purports to be. The date on the
`
`document indicates that it was downloaded on June 26, 2017, the website is
`
`indicated as www.webmd.com, the copyright information appears in the document,
`
`the article has a date of June 3, 2009, and the URL link appears on the bottom left
`
`of the page.
`
`6.
`
`Exhibit 2032 is a true and accurate copy of the webpage located at
`
`http://blogs.sciencemag.org/pipeline/archives/2008/08/29/sticky_containers_vanish
`
`ing_drugs as of June 16, 2017. The contents and substance of this document
`
`indicate that it is what it purports to be. The date on the document indicates that it
`
`was downloaded on June 16, 2017, the article has a date of August 29, 2008, and
`
`the URL link appears on the bottom left of the page.
`
`7.
`
`Exhibit 2051 is a true and accurate copy of the webpage located at
`
`http://www.pharmacopeia.cn/v29240/usp29nf24s0_m60190.html. The webpage
`
`links to the The United States Pharmacopeia, USP 29 NF 24. The document also
`
`-3-
`
`

`

`includes the location where auxiliary information can be found, whichis set forth
`
`on the last page of the document.
`
`8.
`
`Attached hereto as Appendix A is a true and accurate copy of an excerpt of
`
`The United States Pharmacopeia, USP 29 NF 24. The excerpt attached hereto
`
`contains the identical content, with respect to Paclitaxel, contained in Exhibit 2051
`
`except that it does not identify the location of auxiliary information.
`
`Declaration
`
`9.
`
`I declare that all statements made herein on my own knowledgeare true and
`
`that all statements made on information and belief that are believed to be true, and
`
`further, that these statements were made with the knowledge that willful false
`
`statements and the like so made are punishable by fine or imprisonment, or both,
`
`under Section 1001 of Title 18 of the United States Code.
`
`Dated: November 7, 2017
`
`‘
`
`N
`
`-
`
`7
`Signature: WI,
`Lisamarie LoGiudice, Ph.D. (Reg. No. 71,047)
`JONES DAY
`250 Vesey Street
`New York, NY 10281-1047
`Telephone: 212-326-3939
`Facsimile: 212-755-7306
`
`4.
`
`

`

`APPENDIX A
`APPENDIX A
`
`

`

`USP 29
`THE UNITED STATES PHARMACOPEIA
`
`NEF 24
`THE NATIONAL FORMULARY
`
`By authority of The United States Pharmacopeial
`Convention, meeting at Washington, D.C., March 9-13,
`2005. Prepared by the Council of Experts and published
`by the Board of Trustees
`
`Official from January 1, 2006
`
`The designation on the coverof this publication, “USP NF
`2006,” is for ease of identification only. The publication
`contains two separate compendia: The United States
`Pharmacopeia, Twenty-Ninth Revision, and the National
`Formulary, Twenty-Fourth Edition.
`
`THE UNITED STATES PHARMACOPEIAL CONVENTION
`12601 Twinbrook Parkway, Rockville, MD 20852
`
`

`

`NOTICE AND WARNING
`
`Concerning U.S. Patent or Trademark Rights
`
`Theinclusion in The United States Pharmacopeia orin the National Formulary of a monograph on any drug
`in respect to whichpatentortrademark rights may exist shall not be deemed,andis not intended as, a grantof,
`or authority to exercise, any right or privilege protected by suchpatent ortrademark. All such rights and
`privileges are vested in the patent or trademark owner, and no other person may exercise the same without
`express permission, authority, or license secured from such patentor trademark owner.
`
`Concerning Use of USP or NF Text
`
`Attentionis called to the fact that USP and NFtext is fully copyrighted. Authors and others wishing to use
`portions of the text should request permission to do so from the Secretary of the USPC Boardof Trustees.
`
`Copyright © 2005 The United States Pharmacopeial Convention
`12601 Twinbrook Parkway, Rockville, MD 20852
`All rights reserved.
`ISSN 0195-7996
`ISBN 1-889788-39-2
`Printed in Canada by WebcomLimited, Toronto, Ontario
`
`

`

`Oxytocin / Official Monographs
`
`Labeling—Labelit to indicate its oxytocic activity in USP Oxytocin
`Units per mL. Label it also to state the animal source if naturally
`derived, or to state that it is synthetic.
`USP Reference standards (11)—USP Endotoxin RS. USP Oxytocin
`
`(85)—It contains not more than 35.7
`Bacterial endotoxins
`Endotoxin Units per USP Oxytocin Unit.
`between 3.0 and 5.0.
`Particulate matter
`(788): meets the requirements for small-
`volume injections.
`Residual solvents (467): meets the requirements.
`(Official January 1, 2007)
`Other requirements—It meets the requirements under /njections
`
`Assay—Proceed as directed for Oxytocin except to use undiluted
`Injection as the Assay preparation and to allow not less than 25
`minutes betweeninjections. Calculate the potency, in USP Oxytocin
`Units per mL, by the formula:
`
`
`
`C(ru/ 1's)
`
`Assay preparation—Quantitatively dilute an accurately mney,
`
`volume of Nasal Solution in Di/uent to obtain a solution opp
`
`la
`about 10 USP Oxytocin Units per mL.
`
`
`Procedure—Separately inject three equal volumes (about jp
`of the Assay preparation and the Standard preparationing
`
`chromatograph,
`record the chromatograms, and measije
`responses for the major peaks. Calculate the poteney, jy
`Oxytocin Units per mL,in the portion of Nasal Solution takey
`
`formula:
`
`i
`
`in whichC is the concentration, in USP Oxytocin Units perp
`
`USP Oxytocin RS in the Standardpreparation; and ry, andr;
`mean peak responses obtained for oxytocin from the.
`
`preparation and the Standard preparation, respectively,
`
`
`
`Q w
`
`e
`“|PeeBAK Cu?
`
`
`an o yt
`
`O H
`
`bs
`
`C(ru/ 1's),
`
`Paclitaxel
`
`in which C is the concentration, in USP Oxytocin Units per mL, of
`the Standard preparation; and ry and rs are the mean values of the
`peak responses obtained from the Assay preparation and the
`Standard preparation, respectively.
`
`Oxytocin Nasal Solution
`
`» Oxytocin Nasal Solution is a solution of Oxytocin in a
`suitable diluent. It contains suitable preservatives, and is
`packaged in a form suitable for nasal administration.
`Each mL of Oxytocin Nasal Solution possesses an
`oxytocic activity of not less than 85.0 percent and not
`more than 120.0 percent of that stated on the label in
`USP Oxytocin Units.
`Packaging and storage—Preserve in containers suitable for
`administering the contents by spraying into the nasal cavities with
`the patient in the upright position, or forinstillation in drop form.
`Labeling—Labelit to indicate thatit is for intranasal administration
`only. Labelit to state the origin (animalor synthetic), and the animal
`source of the product if of animal origin.
`USP Reference standards (11)—USP Oxytocin RS. USP Vaso-
`
`between 3.7 and 4.3.
`labeled of animal origin)—
`Vasopressor activity (for product
`Proceed as directed in the Assay under Vasopressin, except to use a
`Standard solution of USP Vasopressin RS containing 0.1 USP
`Vasopressin Unit per mL and to use a test solution prepared by
`diluting a volume of Nasal Solution to a concentration of 10 USP
`Oxytocin Units per mL. The vasopressic activity of the test solution
`is not more than 0.1 USP Oxytocin Unit per mL.
`
`Residual solvents (467): meets the requirements.
`(Official January 1, 2007)
`
`853.91
`CyHsNO,,
`/}-(benzoylamino)-7-hydroxy-,
`Benzenepropanoic acid,
`
`(acetyloxy)-12-(benzoyloxy)-2a,3,4,4a,5,6,9,10, 11,12,
`
`dodecahydro-4, | 1-dihydroxy-4a,8, 13, 13-tetramethyl
`7,11-methano- | H-cyclodeca[3,4]benz[ 1 ,2-b]Joxet-9-5
`
`[2aR-[2a%,4f4aP,63,9x(aR*,PS*), | 1y,120,12ax,12b4]]
`
`(2aR,4S,4aS,6R,9S,11S,12S,12aR, 12bS)-1,2a,3.4,4a,6,9,10
`12a, 12b-Dodecahydro-4,6,9, 1 1,12,12b-hexahydroxy
`
`4a,8,13,13-tetramethy|-7, 1 1-methano-5H-cyclodecal
`
`12-benzoate
`benz[1,2-bJoxet-5-one 6,12b-diacetate,
`
`[3306
`with (2R,35S)-N-benzoyl-3-phenylisoserine
`
`
`» Paclitaxel contains not less than 97.0 percen
`more than 102.0 percent of CayHs;NOja, calcul
`
`A
`the anhydrous, solvent-free basis.
`
`Caution—Paclitaxel is cytotoxic, Great care»
`
`be taken to prevent inhaling particles of Paclitaxe®
`
`exposing the skinto it.
`light-resistam
`Packaging and storage—Preserve in tight,
`_
`tainers, and store at controlled room temperature.
`
`Labeling—The labeling indicates the type of proces |
`
`produce the material and the Related compoundstest wit
`af
`material complies.
`j
`
`USP Reference standards (11)—USP Endotoxin ©
`Paclitaxel RS. USP Paclitaxel Related Compound
`Paclitaxel Related Compound B RS,
`
`Identification—
`A:
`Infrared Absorption (197K).
`
`B:
`Theretention time of the major peak in the chro!
`the Assay preparation corresponds to that in the chroma
`4
`the Standard preparation, as obtained in the Assay:
`
`
`
`10 mg per mL, in methanol.
`
`

`

`
`Staphylococcus aureus, Pseudomonas aeruginosa,
`Relative
`Relative
`species, and Escherichia coli.
`Retention
`Response
`
`
`ndotoxins (85)—It contains not more than 0.4 USP
`Time
`Factor (F)
`Name
`
`Unit per mg ofpaclitaxel.
`0.24
`1.29
`Baccatin IIT
`
`“\fethod Ic (921):
`not more than 4.0%,
`0.53
`1.00
`10-Deacetylpaclitaxel
`: Bon ignition (281):
`not more than 0.2%.
`0.57
`1.00
`7-Xylosylpaclitaxel
`
`Smetals, MethodII (231):
`0.002%.
`0.78
`1.26
`Cephalomannine(paclitaxel
`
`related compound A)
`edcompounds——
`.
`0.78
`1.26
`2”,3"-Dihydrocephaloman-
`weer|(for material labeledasisolatedfrom naturalsources)—If
`nine
`al complies with this test,
`the labeling indicates that
`it
`0.86
`1.00
`10-Deacety|-7-epipaclitaxel
`
`P Related compounds Test 1.
`(paclitaxel
`related com-
`Prepare as directedin the Assay.
`
`pound B)
`» A—Preparefiltered and degassed acetonitrile.
`Benzyl analog?
`1.00
`1.10
`BPrepare filtered and degassed water.
`
`3”.4’-Dehydropaclitaxel C
`1.00
`1.10
`hase—Use variable mixtures of Solution A and Solution
`7-Epicephalomannine
`1.00
`:
`ted for Chromatographic system. Make adjustments if
`
`1.85 0.5 1.00 7-Epipaclitaxel
`
`
`(see System Suitability under Chromatography(621)).
`
`suitability solution—Dissolve accurately weighed
`f USP Paclitaxel Related Compound A RS and USP
`Related Compound B RS in methanol to obtain a solution
`
`own concentrations of about 10 jig of each per mL.
`Q mL of this solution to a 50-mL volumetric flask, dilute
`
`7 to volume, and mix.
`
`d solution—Dissolve, with the aid of sonication, an
`weighed quantity of USP Paclitaxel RS in Diluent, and
`
`ntitatively, and stepwise if necessary, with Diluent
`to
`olution having a known concentration of about 5 jig per
`rf
`
`jist solution—Use the Assay preparation.
`
`lyomatographic system (see Chromatography (621))—The
`atograph is equipped with a 227-nm detector and a
`25-cm columnthat contains 5-jtm packing L43. The flow
`about 2.6 mL per minute. The column temperature is
`
`30°. The chromatograph is programmed as follows.
`
`
`Solution A
`Solution B
`
` (%) (%) Elution
`
`
`35
`65
`isocratic
`
`35-80
`6520
`linear gradient
`8035
`2065
`linear gradient
`
`35 isocratic 65
`
`
`
`
`ph the System suitability solution, and record the peak
`directed for Procedure: the relative retention times are
`
`for paclitaxel related compound A and 0.86 for paclitaxel
`
`npound B (relative to the retention time for paclitaxel
`om the Zest solution); and the resolution, R, between
`ted compound A andpaclitaxel related compound B is
`
`than 1.0. Chromatograph the Standardsolution, and record
`Oonses as directed for Procedure: the relative standard
`ah
`Mor replicate injections is not more than 2.0%,
`
`Inject a volume (about: 15 uL) of the Test solution
`
`OMmatograph, record the chromatogram, and measure the
`
`major peaks, Calculate the percentage of each impurity
`
`On of Paclitaxel taken by the formula:
`
`100(Fr,/1,),
`"is therelative response factor for each impurity peak (see
`
`. Values); 7, is the peak area for each individual impurity;
`Me peak area for paclitaxel.
`i.
`
`' Resolution maybe incomplete for these peaks, depending upontherelative
`amounts present; the sumofa, and a, is not more than 0.5%.
`~ Resolution may be incomplete for these peaks depending uponthe relative
`amounts present; the sumof b, and b, is not more than 0.5%.
`“ The following chemical name is assigned to the related compound, benzyl
`analog: Baccatin IIT 13-ester with (2R,35)-2-hydroxy-3-phenyl-3-(2-pheny
`lacetylamino)propanoic acid.
`for paclitaxel
`In addition to not exceeding the limits
`impurities in Table J, not more than 0.1% of any other single
`impurity is found; and not more than 2.0% of total
`impurities is
`found.
`TEST 2 (for material labeled as produced by a semisynthetic
`process)—If the material complies with this
`test,
`the labeling
`indicates that it meets USP Related compounds Test 2.
`Diluent—Useacetonitrile.
`Solution A—Use a filtered and degassed mixture of water and
`acetonitrile (3 : 2).
`Solution B—Usefiltered and degassedacetonitrile.
`Mobile phase—Use variable mixtures of Solution A and Solution
`B as directed for Chromatographic system. Make adjustments if
`necessary (see System Suitability under Chromatography (621)).
`System suitability solution—Dissolve accurately weighed
`quantities of USP Paclitaxel RS and USP Paclitaxel Related
`Compound B RS in Diluent, using shaking and sonication.
`necessary, to obtain a solution having knownconcentrations of about
`0.96 mg and 0.008 mg per mL,respectively.
`Test solution—Transfer about 10 mg ofPaclitaxel, accurately
`weighed, to a 10-mL volumetric flask; dissolve in and dilute with
`Diluent to volume, using shaking and sonication if necessary; and
`mix.
`Chromatographic. system (see Chromatography (621))—The
`liquid chromatograph is equipped with a 227-nmdetector and a
`4.6-mm x 15-cm columnthat contains 3-jum packing L1. The flow
`rate is about 1.2 mL per minute. The column temperature is
`maintained at 35°. The chromatograph is programmedas follows.
`
`Time
`Solution A
`Solution B
`
`(minutes)
`(%)
`(%)
`Elution
`0-20
`100
`0
`isocratic
`20-60
`10010
`0-90
`linear gradient
`60-62
`10 100
`900
`linear gradient
`62-70 isocratic 100 0
`
`
`
`
`Chromatograph the System suitability solution, and record the peak
`responses as directed for Procedure: the relative retention times are
`about 0.94 for paclitaxel related compound B and 1.0 for paclitaxel;
`the resolution, R, between paclitaxel
`related compound B and
`paclitaxel is not less than 1.2; and the relative standard deviation for
`replicate injections is not more than 2.0%,
`
`
`
`
`
`SS
`
`zt
`is
`it
`Bis
`uM
`
`

`

`Paclitaxel / Official Monographs
`
`Procedure—Separately inject equal volumes (about 15 tL) of the
`Diluent and the Test solution into the chromatograph, record the
`chromatograms, and measure the areas for all the peaks. Disregard
`any peaks due to the Dilwent. Calculate the percentage of each
`impurity in the portion of Paclitaxel taken by the formula:
`
`100(Fr;,/7.),
`
`in whichF is the relative response factor for each impurity (see Zuble
`2 for values); 7; is the peak area for each impurity obtained from the
`Test solution; and 1, is the sumoftheareasofall the peaks obtained
`from the Test solution.
`
`Table 2
`
`Relative
`Response
`factor (F)
`1.24
`1.29
`1.39
`1.00
`1.00
`
`1.00
`
`1.00
`1.00
`
`1.00
`1.00
`
`Name
`10-Deacetylbaccatin HI
`Baccatin III
`Photodegradant?
`10-Deacetylpaclitaxel
`2-Debenzoylpaclitaxel-2-
`pentenoate
`Oxetane ring opened,acetyl]
`and benzoyl?
`10-Acetoacetylpaclitaxel
`10-Deacetyl-7-epipaclitaxel
`(paclitaxel
`related com-
`pound B)
`7-Epipaclitaxel
`10,13-Bissidechainpacli-
`taxel?
`0.6
`7-Acetylpaclitaxel
`1.00
`0.1
`13-Tes-baccatin TIT
`1.75
`
`1.00
`7-Tes-paclitaxel
`0.3
`
`Limit
`(%)
`0.1
`0.2
`0.1
`0.5
`0.7
`
`X;
`
`xX
`x,
`
`0.4
`0.5
`
`' Resolution may be incomplete for these peaks depending uponthe relative
`amounts present; the sum of x,, .¥,, and x, is not more than 0.4%.
`~ The following chemical names are assigned to the related compounds
`Photodegradant, Oxetane ring opened, acetyl and benzoyl, and 10,13-
`Bissidechainpaclitaxel:
`;
`Photodegradant
`(1R,2R,4S,58,7R, 108,11 RB, 128,13S,15S,16S)-2,10-diacetyloxy-5,13-dihy-
`droxy-4,16,17,17-tetramethyl-8-oxa-3-oxo-12-phenylcarbonyloxypentacy-
`clof11.3.1.0''.0"'.0"'Theptadec-15-yl
`QR,3S)-2-hydroxy-3-pheny|-3-(phenylcarbonylamino)propanoate
`Oxetane ring opened, acetyl and benzoyl migrated
`(18.25,3R,45,5S,7S,8S, 1OR, 13S)-5,10-diacetyloxy-1,2,4,7-tetrahydroxy-
`8,12,15,15S-tetramethyl-9-oxo-4-(phenylearbonyloxymethyl)tricy-
`clo[9.3.1.0°*}pentadec-11-en-13-yl
`(2R,3S)-2-hydroxy-3-phenyl-3-(phenylcarbonylamino )propanoate
`10.13-Bissidechainpaclitaxel
`Baccatin HI 13-ester with (2R,3S)-2-hydroxy-3-phenyl-3-(phenylcarbonyl-
`amino)propanoic acid, 10-ester with (2S,3S)-2-hydroxy-3-pheny|-3-(phenyl-
`carbonylamino)propanoic acid
`related
`for paclitaxel
`In addition to not exceeding the limits
`impurities in Table 2, not more than 0.1% of any other single
`-impurity is found; and not more than 2.0% of total
`impurities is
`
`Organic volatile impurities, Method IV (467):
`requirements.
`Residual solvents (467):
`
`meets the requirements.
`(Official January 1, 2007)
`
`meets.
`
`the
`
`Diluent—Prepare a mixture of methanol andacetic acid (200: 1).
`Mobile phase—Prepare afiltered and degassed mixture of water
`and acetonitrile (11:9). Make adjustments if necessary (see System
`Suitability under Chromatography (621)).
`
`
`10 mg of Pach;
`Assay preparation—Transfer about
`accurately weighed,
`to a 10-mL volumetric flask, Dissoly
`Diluent, using sonicationif necessary, dilute with Diluenttgyo)
`
`and mix.
`
`Chromatographic. system (see Chromatography (62
`liquid chromatograph is equipped with a 227-nm deteg
`4.6-mm x 25-cm columnthat contains 5-j1mpacking L43, 7p,
`
`%
`rate is about 1.5 mL per minute. Chromatograph the
`and record the peak responses as dire
`preparation,
`
`is between 0.7 and 1,3: 4,
`Procedure:
`the tailing factor
`
`relative standard deviation for replicate injections is not my
`1.5%.
`Procedure—Separately inject equal volumes(about 10 UL)
`
`Standard preparation and the Assay preparation jpg
`chromatograph, record the chromatograms, and measure the
`for the major peaks. Calculate the quantity, in mg, of C,H.
`
`the portion of Paclitaxel taken by the formula:
`
`
`
`LOC,/7s),
`
`
`
`
`tax
`in the Standard preparation; and ry, and rs are the peak respon
`paclitaxel obtained from the Assay preparation and the Stan;
`preparation, respectively.
`:
`
`Paclitaxel Injection
`
`»» Paclitaxel Injection is a sterile, stabilized solut
`Paclitaxel, suitable for dilution for intravenous
`istration. It contains not less than 90.0 percen
`more than 110.0 percent of the labeled am
`
`paclitaxel (Cy7Hs;NOj,).
`
`
`containers, preferably of Type I glass, at contro
`temperature.
`
`Labeling—Labelit to indicate thatit is to be diluted with as
`parenteral vehicle prior to intravenous infusion.
`
`USP Reference standards (11)—USP Endotoxin
`Paclitaxel RS. USP Paclitaxel Related Compound B RS.
`|
`
`Identification—
`is
`
`A:
`The retention time of the major peak in the chrom
`the Zest solution corresponds to that
`in the chromatog
`
`Standard solution, as obtained in the test for Limit of di
`:
`products.
`B: The retention time of the major peak in the chromate
`
`the Assay preparation corresponds to that in the chrom
`
`the Standard preparation, as obtained in the Assay.
`Bacterial endotoxins (85)—It contains not more that
`Endotoxin Unit per mg ofpaclitaxel.
`7
`pH (791):
`between 3.0 and 7.0,inasolution (1 in 10 5
`Limit of degradation products—
`Solution A—Prepare a filtered and degassed mixture 0
`
`,
`acetonitrile (3:2).
`Solution B—Use filtered and degassed acetonitrile.
`Mobile phase—Use variable mixtures of Solution A an
`B as directed for Chromatographic system. Make adjus!
`necessary (see System Suitability under Chromatography§
`Standard solution—Dissolve accurately weighed q
`USP Paclitaxel RS and USP Paclitaxel Related Compoum™
`acetonitrile, and dilute quantitatively, and stepwise ! nt
`
`
`
`
`
`
`

`

`record the chromatograms, and measure the
`chromatograph,
`responses for the paclitaxel peaks. Calculate the quantity,
`of paclitaxel (C,,H,,NO,,) in each mL of the Injection taken by the
`formula:
`
`(LID)C(r-/ rs),
`
`in which Z is the labeled quantity, in mg, of paclitaxel in each mL of
`Injection; D is the concentration, in mg per mL, of paclitaxel in the
`Assay preparation, based on the labeled quantity; C is
`concentration, in mg per mL, of USP Paclitaxel RS in the Standard
`preparation; and 1, and rs; are the peak responses obtained from the
`Assay preparation and the Standard preparation, respectively.
`
`Padimate O
`
`
`aph the Standard solution, and record the peak responses
`for Procedure:
`the resolution, R, between paclitaxel
`mpound B and paclitaxel
`is not
`less than 1.2; and the
`standard deviation for replicate injections is not more than
`
`
`ye
`
`x [5-cm columnthat contains 3-11m packing L1. The flow
`m pout 1.2 mb per minute. The column temperature is
`
`
`» dat 35. Phe chromatograph is programmedas follows.
`
`Solution A
`Solution B
`
`(%)
`(eZ)
`Elution
`100
`0
`isocratic
`
`
`10017
`0-83
`linear gradient
`17— 100
`83-0
`linear gradient
`100 isocratic 0
`
`
`
`
`cedure—Separately inject equal volumes (about 10 {tL) of the
`od solution and the Test solution into the chromatograph,
`
`‘he
`chromatograms, and measure the areas ofthe analyte
`
`culate the percentage of each degradation product in the
`Injection taken by the formula:
`
`100(C,/ C,)(r;/1),
`
`
`
`
`is the concentration, in mg per mL, of USP Paclitaxel
`mpound B RS in the Standard solution; C,
`is the
`on, in mg per mL, ofpaclitaxel in the Jest solution, based
`Jed amount ofpaclitaxel per mL ofInjection;1; is the peak
`ch degradation product obtained from the Test solution;
`he peak area for paclitaxel related compound B obtained
`277.40
`C\,H,;NO,
`ndard solution. In addition to not exceeding the limits
`Benzoic acid, 4-(dimethylamino)-, 2-ethylhexy] ester.
`Table 1, not more than 0.1% of any other paclitaxel
`
`2-Ethylhexyl p-(dimethylamino)benzoate—[2/245-02-3].
`product
`is found; and not more than 2.0% oftotal
`gradation products is found.
`
`» Padimate O contains not less than 97.0 percent and
`not more than 103.8 percent of Cyz7H27NO>.
`
`Packaging and storage—Preserve in tight,
`tainers.
`
`light-resistant con-
`
`and 215,
`
`USP Reference standards (11)—USP Padimate O RS.
`Identification—
`Av
`Infrared Absorption (197F).
`B: Ultraviolet Absorption (197U)—
`Solution:
`5 jg per mL.
`Medium:
`alcohol.
`Absorptivities at 312 nm do not differ by more than 4.0%.
`Specific gravity (841):
`between 0.990 and 1.000.
`Refractive index (831):
`between 1.5390 and 1.5430.
`Acid value (401):
`not more than 1.0.
`Saponification value (401):
`between 195
`temperature being maintained for 4 hours.
`Chromatographic purity—
`Chromatographic system (see Chromatography (621))—The gas
`chromatographis equipped with a flame-ionization detector and a 3-
`mm x 1,.8-mstainless steel column packed with 10 percent liquid
`phase G9 on support SIA. The column temperature is programmed
`at a rate of 10° per minute from 150° to 250°, then maintainedat
`250° for 10 minutes, and helium is used as the carrier gas.
`Procedure—Chromatograph 2 wl of a
`|
`in 100 solution of
`Padimate O in chloroform: the response due to padimate O is not less
`than 98.0% of the sum of the responses on the chromatogram,
`exclusive of the chloroform peak.
`Residual solvents (467): meets the requirements.
`(Official January 1, 2007)
`Assay—Dissolve about 500 mg of Padimate O, accurately weighed,
`in 75 mL ofacetic anhydride, and titrate with 0.1 N perchloric acid
`VS, determining the endpoint potentiometrically. Each mL of 0.1 N
`perchloric acid is equivalent to 27.74 mg of C,,H.,;NO3.
`
`
`
`Table 1.
`
`
`
`Name
`Limit (%)
`0.8
`0.4
`0.8
`0.5
`
`BaccatinII]
`Ethyl ester side chain
`10-Deacetylpaclitaxel
`10-Deacetyl-7-epipaclitaxel
`(paclitaxel related compound
`B)
`7-Epipaclitaxel 0.6
`
`
`4
`il
`1.40
`
`dual solvents (467): meets the requirements.
`;
`(Official January 1, 2007)
`
`lirements—It meets the requirements under /njections
`
`|-liter
`Tansfer 200 «tL of glacial acetic acid to a.
`
`flask containing about 500 mL of methanol, mix, and
`
`sth methanol to volume.
`He
`phase—Preparea filtered and degassed mixture of water
`nitrile (11:9). Make adjustments if necessary (see System
`
`ite tder Chromatography (621)).
`pt
`Preparation—Dissolve an accurately weighed quantity
`faxel RS in Diluent to obtain a solution having a known
`
`On of about 0.6 mg per mL.
`aration—Quantitatively dilute an accurately measured
`i Injection with Diluent to obtain a solution containing
`
`“hg of paclitaxel per mL.
`5dlographic system (see Chromatography (621))—The
`
`~ Matograph is equipped with a 227-nmdetector and a
`5-em columnthat contains 5-um packing L43. The flow
`
`ut 1S mL per minute. Chromatograph the Standard
`and record the peak responses as directed for
`© the retention time ofthe paclitaxel peak is between 6.0
`ions ae and the relative standard deviation forreplicate
`Shot more than 1.5%.
`
`
`
`

`

`CERTIFICATE OF SERVICE
`
`The undersigned certifies that on the date indicated below a copy of the
`
`foregoing DECLARATION OF LISAMARIE LOGIUDICE was served
`
`electronically by filing this document through the PTAB E2E System, as well as
`
`by e-mailing copies to the following counsel of record for Petitioner Actavis LLC:
`
`Lead Counsel
`Samuel S. Park, Reg. No. 59,656
`WINSTON & STRAWN LLP
`35 W. Wacker Drive
`Chicago, IL 60601
`AbraxaneIPR@winston.com
`
`Dated: November 7, 2017
`
`Backup Counsel
`George C. Lombardi
`Charles B. Klein
`Kevin E. Warner
`Eimeric Reig-Plessis
`
`WINSTON & STRAWN LLP
`35 W. Wacker Drive
`Chicago, IL 60601
`AbraxaneIPR@winston.com
`
`/Lisamarie LoGiudice, Ph.D./
`Lisamarie LoGiudice, Ph.D. (Reg. No.
`71,047)
`JONES DAY
`250 Vesey Street
`New York, NY 10281-1047
`Telephone: 212-326-3939
`Facsimile: 212-755-7306
`
`Counsel for Patent Holder
`Abraxis Bioscience, LLC
`
`