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 IPR2017-01103
`U.S. Patent No. 7,923,536
`_______________________
`
`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, which is 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 knowledge are 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
`
`P
`
`\‘
`
`x
`
`\
`
`Signature: W
`Lisamarie LoGiudice, PhD. (Reg. No. 71,047)
`JONES DAY
`
`250 Vesey Street
`New York, NY 10281-1047
`
`Telephone: 212-326-3939
`Facsimile: 212-755-7306
`
`

`

`
`
`
`
`
`
`
`
`
`
`APPENDIX A
`
`APPENDIX A
`
`
`
`
`
`

`

`2006
`
`USP 29
`THE UNITED STATES PHARMACOPEIA
`
`NF 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 I, 2006
`
`The designation on the cover of this publication, “USP NP
`2006,” is for ease of identification only. The publication
`contains two separate compendia: The United States
`lermacopeia, Twenty-Ninth Revision, and the National
`Formulaly, Twenty-F0111th Edition.
`
`THE UNITED STATES PHARMACOPEIAL CONVENTION
`12601 Twinbrook Parkway, Rockville, MD 20852
`
`

`

`NOTICE AND WARNING
`
`Concerning US. Patent 0r Trademark Rights
`
`The inclusion in The Uni/ed States lermacapeia or in the National Forlnn/(njv of a monograph on any drug
`in respect to which patent or trademark rights may exist shall not be deemed, and is not intended as, a grant of,
`or authority to exercise, any right or privilege protected by such patent or trademark. 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 patent or trademark owner.
`
`Concerning Use ofUSP or NF Terr
`
`Attention is called to the fact that USP and NF text 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 Board of Trustees.
`
`Copyright (Q 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 chcom Limited, Toronto, Ontario
`
`

`

`Oxytocin / Official Monographs
`
`Labeling—Label it 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 (1 1)—USP Endotoxin RS. USP Oxytocin
`
`(85)—lt contains not more than 35.7
`Bacterial endotoxins
`Endotoxin Units per USP Oxytocin Unit.
`between 3.0 and 5.0.
`Particrrlate matter
`(788): meets the requirements for
`volrrrne injections.
`
`srnall—
`
`Residual solvents (467): meets the requirements.
`(Official January 1, 2007)
`Other reqrrirements—lt meets the requirements under Injections
`
`Assay—Proceed as directed for Oxytocin except to use undiluted
`Injection as the Assay preparation and to allow not less than 25
`rninrrtes between injections. Calculate the potency, in USP Oxytocin
`Units per mL, by the formula:
`
`Cor/ISL
`
`Paclitaxel
`
`in which C is the concentration, in USP Oxytocin Units per mL, of
`the Standard preparation; and rlv and r; are the mean values of the
`peak responses obtained from the Assay preparation and the
`Standard preparation. respectively.
`
`
`Assay pi'eparation—Quantitatively dilute an accurately m H
`volume of Nasal Solution in Diluent to obtain a solution coi-
`rim“
`about 10 USP Oxytocin Units per mL.
`Procedure—Separately inject three equal volumes (aboutv'
`
`of the Assay preparation and the Standard preparations.“ ‘
`
`record the chromatograms. and math
`chromatograph.
`responses for the major peaks. Calculate the potenCyI '-.,
`
`Oxytocin Units per mL, in the portion ofNasal Solution tak [5.1.
`.l.‘
`fonnula:
`
`..
`
`in which C is the concentration, in USP Oxytocin Units pe r
`
`USP Oxytocin RS in the Standard preparation: and "r and ,5
`
`mean peak responses obtained for oxytocin from th- '
`
`’
`preparation and the Standard preparation, respectively.
`
`C(I't /"5)~
`
`
`
`
`
`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 posrtion, or for instillation in drop form.
`Labeling—Label it to indicate that it is for intranasal administration
`only. Label it 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
`Vasopr'essin 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)
`
`CVHSINOH 853.91
`
`[i-(benzoylamino)-1-hydroxy-,
`Benzenepropanoic acid,
`
`(acetyloxy)-12-(benzoyloxy)—2a.3,4,4a.5,6.9,10,11,12:
`
`dodecahydro—4,l l-(lilrydr'oxy—4a,8.'13,13-tetramethyl
`
`7,1 l-methano-lH—cyclodeca[3.4]benz[1,2-b]oxet-9-'
`
`[221R-[2a1,4/i,4a/i.6/i,91(aR*./iS*),l Ia.l2a.l2aa,12baii
`
`(2aR,4S,4aS,6R,9S,l IS, 1 2S, lZaR. leS)- l .2a,3,4,4a,6,9,10
`
`]2a.] 2b-Dodecahydro-4.6.9.l 1,12,12b—hexahydr0xy
`
`4a.8.13,13-tetramethyl-7,l 1-methano—5H—cyclodeca[
`
`lZ-benzoa
`benz[l,2—b]oxet—5—one 6,12b-diacetate,
`
`[3306
`with (2R,3S)—N—benzoyl—3-phenylisoserine
`
`» Paclitaxel contains not less than 97.0 percen
`more than 102.0 percent of C47H51NOM, calc'
`,
`
`._:
`the anhydrous, solvent-free basis.
`CautioniPaclitaxel is cytotoxic. Great cat” .,
`‘
`
`be taken to prevent inhaling particles ofPaeht.
`°
`
`"
`exposing the skin to it.
`
`light-
`Packaging and storage—Preserve in tight.
`tainers, and store at controlled room temperature.
`
`Labeling—The labeling indicates the type of pl'OCF
`
`produce the material and the Related compounds test with“
`material complies.
`
`USP Reference standards (ll)—USP Endotoxin ,3.”
`Paelitaxel RS. USP PIIC‘Il/(M’el Related Compound
`Paclitaxel Related Compound B RS,
`
`Identification—
`21'"
`A:
`lit/rarer] Absorption (197K).
`B: The retention time of the major peak in the Chromfl.
`‘
`the Assay preparation corresponds to that in the chroma .
`the Standard preparation. as obtained in the Assay.
`- 0."
`
`‘
`
`‘
`
`
`
`

`

`
`SIap/n'lococeus aureus, Pseudomonas aernginosa.
`
`species. and Escherichia coli.
`ndotoxins (85)—It contains not more than 0.4 USP
`
`Unit per mg of paclitaxel.
`
`met/tot] [C (921):
`not more than 4.0%.
`KM] ignition (281):
`not more than 0.2%.
`
`“ “[5,1‘ltetltot/[I (231):
`0.002%.
`.
`tritiumlwlmds—
`.
`‘
`‘ l or material labeled as Isolatedfrom naturalsourees)—1f
`al complies wrtlr this test,
`the labeling indicates that
`it
`
`‘ Related compounds Test I.
`
`prepare as directed in the Assay.
`1 AfiPrepare filtered and degassed acetonitrile.
`
`‘
`B~Prepare filtered and degassed water.
`W, phase~Use variable mixtures of Solution A and Solution
`
`'
`=1
`ted for Chromatographic system. Make adjustments if
`(see System Suitability under Chromatography (621)).
`
`suitability solution~Dissolve accurately weighed
`fUSP Paclitaxel Related Compound A RS and USP
`Related Compound B RS in methanol to obtain a solution
`
`own concentrations of about 10 1.1g of each per mL.
`7 mL of this solution to a 50-mL volumetric flask, dilute
`
`(to volume, and mix.
`
`air
`r solutioniDissolve, with the aid of sonication,
`:weighed quantity of USP Paclitaxel RS in Diluent, and
`
`'rtitatively. and stepwise if necessary, with Dilnent
`to
`a‘lution having a known concentration of about 5 pg per
`r. Julian—Use the Assay preparation.
`
`blagraphie system (see Chromatography (621))—The
`atograph is equipped with a 227-rrm detector and a
`, 5-cm column that contains 5-um packing L43. The flow
`
`-
`'ut 2.6 mL per minute. The column temperature is
`t30". The chromatograph is programmed as follows.
`
`Solution A
`Solution B
`
`
`(%)
`(%)
`Elution
`
`35
`65
`isocratic
`
`35—>8O
`65 —+20
`linear gradient
`
`80—» 35
`20665
`linear gradient
`35 isocratic 65
`
`
`
`
`r
`
`‘
`
`4
`
`Relative
`Relative
`Retention
`Response
`
`Time
`Factor (F)
`Name
`0.24
`1.29
`Baccatin III
`0.53
`1.00
`lO—Deacetylpaclitaxel
`0.57
`1.00
`7—Xylosylpaclitaxel
`0.78
`1.26
`Cephalomannine (paclitaxel
`related compound A)
`2",3”-Dihydrocephalomarr—
`nine
`
`0.78
`
`1.26
`
`1.00
`
`0.86
`
`10-Deacetyl-7-epipaclitaxel
`(paclitaxel
`related corn-
`pouud B)
`Benzyl analog3
`1.00
`.
`3”,4"-Delrydropaclitaxel C
`1.00
`1.10
`7-Epicephalomannine
`1.00
`.
`
`1.85 0.5 1.00 7-Epipaclitaxel
`
`
`
`' Resolution may be incomplete for these peaks. depending upon the relative
`amounts present; the sum ofa, and a2 is not more than 0.5%.
`‘ Resolution may be incomplete for these peaks depending irpon the relative
`amounts present; the sum of bx and b2 is not rrrore than 0.5%.
`3 The following chemical name is assigned to the related compound. benzyl
`analog: Baccatin 111 I3-ester with (2R,3S)-2-lrydroxy-3—plrenyl—3—(2-plreny
`lacetylamirro)propanoic acid.
`
`for paclitaxel
`In addition to not exceeding the limits
`impurities in Table I, not more than 0.1% of airy other single
`impurity is found; and not more than 2.0% of total
`impurities is
`found.
`
`TEST 2 (for material labeled as producer] by a semisj'nthetie
`pr'oeess)—If the material complies with this
`test,
`the labeling
`indicates that it meets USP Related compounds Test 2.
`Diluent—Use acetonitrile.
`Solution A—Use a filtered and degassed mixture of water and
`acetonitrile (3 :2).
`Solution BfiUse filtered and degassed acetonitrile.
`Mobile phasefiUse variable mixtures of Solution A and Solution
`B as directed for Chromatographie system. Make adjustments if
`necessary (see System Suitability under Chromatography (621)).
`System suitability solutionfiDissolve accurately weighed
`quantities of USP Paclitaxel RS and USP Paclitaxel Related
`Compound B RS in Diluent,
`rising shaking and sonication if
`necessary, to obtain a solution having known concentrations of about
`0.96 mg and 0.008 mg per mL, respectively.
`Test solution—Transfer about 10 mg of Paclitaxel, accurately
`weighed, to a 10—mL volumetric flask; dissolve in and dilute with
`Dilnent to volume, using shaking and sonication if necessary; and
`mix.
`
`Cln'onratographic system (see Cltromatogt'aplty (621))—Tlrc
`liquid chromatograph is equipped with a 227—nm detector and a
`4.6—mm >< 15-crn column that contains 3-um packing L1. The flow
`rate is about 1.2 mL per minute. The column temperature is
`maintained at 35". The clrromatograph is programmed as follows.
`Time
`Solution A
`Solution B
`
`(minutes)
`(%)
`(%)
`Elution
`0~20
`100
`0
`isocratic
`20—60
`100—» 10
`0-»90
`linear gradient
`60762
`10—> 100
`90—>0
`linear gradient
`62770 isocratic 100 0
`
`
`
`
`Chromatograph the System suitability solution, and record the peak
`responses as directed for Procet/rn'e: 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 irot less than 1.2; and the relative standard deviation for
`replicate injections is not more than 2.0%.
`
`
`
`
`
`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
`I ound B (relative to the retention time for paclitaxel
`Im the Test solution); and the resolution, R, between
`ted compound A and paclitaxel related compound B is
`- WI! 1.0. Clrrornatograph the Standard solution, and record
`w
`onses as directed for Procedure: the relative standard
`,
`n' replicate injections is not more than 2.0%.
`
`Inject a volume (about 15 uL) of the Test solution
`
`matograph, record the chromatogram, and measure the
`
`B-major peaks. Calculate the percentage of each impurity
`
`on of Paclitaxel taken by the formula:
`1 ”'
`100(Fr,-/rl.),
`
`
`
`
`18 the relative response factor for each impurity peak (see
`.
`4 values); 1',
`IS the peak area for each individual impurity;
`
`rrghe peak area for paclitaxel.
`. 1:.
`
`l
`L:
`1'-
`
`e\
`
`
`
`

`

`Paclitaxel / Official illonograp/ts
`
`Proved:ire—Separately inject equal volumes (about 15 pL) ofthe
`Di/uent and the Test solution into the chromatograph. record the
`chromatograms. and measure the areas for all the peaks. Disregard
`any peaks due to the Diluent. Calculate the percentage of each
`impurity in the portion of Paclitaxel taken by the formula:
`
`100(Fz-,./t-.).
`
`in which F is the relative response factor for each impurity (see Table
`2 for values); r, is the peak area for each impurity obtained from the
`Test solution: and r. is the sum of the areas of all 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 111
`Baccatin III
`Photodegradantz
`lO-Deacetylpaclitaxel
`2—Debenzoylpaclitaxel-2-
`pentenoate
`Oxetane ring opened, acetyl
`and benzoyl2
`10-Acetoacetylpac1itaxe1
`IO—Deacetyl—7-epipaclitaxel
`(paclitaxel
`related corn-
`pound B)
`7—Epipaclitaxel
`10,13-Bissidechainpac1i-
`taxel2
`0.6
`7-Acety1paclitaxel
`1.00
`0.1
`13-Tes-baccatin 111
`1.75
`
`1.00
`7-Tes-paclitaxel
`0.3
`
`Limit
`
`(%)
`0.1
`0.2
`0.1
`0.5
`0.7
`
`.r.
`
`.\'2
`.r3
`
`0.4
`0.5
`
`' Resolution may be incomplete for these peaks depending upon the relative
`amounts present: the sum of A}. .\':. and .r. is not more than 0.4%.
`‘ The following chemical names are assigned to the related compounds
`l’hotodegradant. Oxetane ring opened. acetyl and benzoyl. and 10.13—
`Bissidechainpaclitaxel:
`’
`Photodcgradant
`(1R.2R,4S.55.7R.10S.11R.125.13S.15S,16S)-2.10—diacctyloxy-5J3—dihy-
`droxy-4.16.17.17—tetramethyl-8-oxa—3—ox0—l2—pheny[carbonyloxypentacy—
`clo[l1.3.1.0"".0"“.0“"']heptadec-15-y1
`(2R,3S)-2-hydroxy-3-phenyl—3—(phenylcarbonylamino)pr0panoate
`Oxetane ring opened acetvl and benzovl migrated
`(1S.2S.3R,4S.SS.7S.85.10R. l3S)—5.lO-diacetyloxy-l.2.4,7-tetrahydroxy—
`8.1 2. 15. lS»tetramethyl—9—oIto—4—(phenylcarbonyloxymethyl)tricy—
`clo[9.3.1.0”]pentadec-l1«en-13—yl
`(2R.3S)—2-hydroxy—3-plteny1—3-(phenylearbonylamino)propanoate
`10.13-Bissidechainpaclitaxel
`Baccatin 111 13-ester with (2R.3S)-2—hydroxy-3«plterlyl-3-(phcnylcarbonyl-
`amino)propanoic acid.
`lO-ester with (253$)-2-hydroxy—3—pltenyl»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 rs found; and not more than 2.0% of total
`impurities rs
`
`Organic volatile impurities. Met/rod IV (467): meets
`requirements.
`
`the
`
`Residual solvents (467): meets the requirements.
`(Official January 1. 2007)
`
`Diluentr—Prepare a mixture of methanol and acetic acid (200: 1).
`Mobile pltase~Prepare a filtered and degassed mixture of water
`and acetonitrile (1 1 :9). Make adjustments if necessary (see Srstetn
`Suitabilitr under Clrromatograp/n' (621)).
`
`10 mg of Pa'
`Assay preparation—Transfer about
`.—
`accurately weighed.
`to a
`10—mL volumetric flask. D‘
`to"
`Diluent, using sonication ifnecessary, dilute with Diluent
`
`and mix.
`
`Cln'omatograp/iic system (see Chromatography (62‘
`liquid chromatograph is equipped with a 227-11111 dete'c
`46—min >< 25~cm column that contains 5-rrm packing L43;
`t. ‘
`
`‘
`rate is about 1.5 mL per minute. Chromatograph the
`and record the peak responses as dir
`preparation,
`
`;
`.
`Procedure:
`the tailing factor
`is betWeen 0.7 and 1.3-
`‘
`relative standard deviation for replicate injections is not
`1.501L
`
`(m
`Procedure—Separately inject equal volumes (about 10 ‘
`Standard preparation and the Assay preparation m ‘
`chromatograph, record the chromatograms, and measure“ ,‘
`for the major peaks. Calculate the quantity, in mg, of CWH‘
`the portion of Paclitaxel taken by the formula:
`
`‘
`
`10C(er/ r3).
`
`in which C is the concentration, in mg per mL, of USP Pacl’ .1;
`in the Standard preparation; and rt and r; are the peak res. “.1
`paclitaxel obtained from the Assay preparation and the tint.
`preparation, respectively.
`'
`
`.
`
`“
`
`
`
`
`
`
`Paclitaxel Injection
`
`‘
`
`
`
`1
`
`» Paclitaxel Injection is a sterile, stabilized sol
`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 (C47H5,NOH).
`
`
`containers. preferably of Type 1 glass, at contra
`temperature.
`
`Labeling—Label it to indicate that it is to be diluted wit.
`parenteral vehicle prior to intravenous infusion.
`USP Reference standards (11)——USP Endotoxin
`
`Paclitaxel RS. USP Paciitaxel Related Compound B RS.
`Identification—
`
`The retention time of the major peak in the chro t
`A:
`the Test solution corresponds to that
`in the chromato
`Standard solution, as obtained in the test for Limit old
`
`products.
`‘
`B: The retention time of the major peak in the chroma
`the Assav preparation corresponds to that in the chr'OIIl
`
`the Standard preparation, as obtained in the Assay.
`Bacterial endotoxins (85)—lt contains not more thanl
`"
`Endotoxin Unit per mg of paclitaxel.
`pH (791):
`between 3.0 and 7.0.
`in a solution (I i" 10 1
`Limit of degradation products—
`Solntion .4—Prepare a filtered and degassed mixture 0
`'
`acetonitrile (3 :2).
`A
`Solution BiUse filtered and degassed acetonitrile.
`sirloin/e phase—Use variable mixtures of Solution Ala"?1H
`B as directed for C/tromatogl'aplzic stzvtem. Make fldlu‘
`necessary (see St‘stem Suitability under Chromatography ‘
`
`Standard solution—Dissolve accurately weighed q '3
`USP Paclitaxel RS and USP Paclitaxel Related CompO "
`acetonitrile. and dilrrte quantitatively. and stepwise If n'
`
`
`
`
`
`
`
`

`

`1"]5-cm column that contains 3—trm packing L1. The flow
`but 1.2 mL per minute. The column temperature is
`
`72:35“ 35", The chromatograph is programmed as follows.
`‘
`
`Solution A
`Solution B
`
`
`(%)
`("0)
`Elution
`100
`0
`isocratic
`100—» 17
`0—>83
`linear gradient
`17a 100
`83 —>0
`linear gradient
`100 isocratic 0
`
`
`
`
`
`
`:ph 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
`
`m dard deviation for replrcate Injections is not more than
`
`.
`,Jfreflseparately inject equal volumes (about 10 trL) of the
`‘ olution and the Test solution into the chromatograph,
`i'
`chromatograms, and measure the areas of the analyte
`
`culate the percentage of each degradation product in the
`
`Injection taken by the formula:
`100(C5/CU)(r,-/r5),
`
`
`
`is the concentration, in mg per mL, of USP Paclitaxel
`mpound B RS in the Standard solution; CL-
`is the
`on, in mg per rnL, of paclitaxel in the Test solution, based
`
`led amount of paclitaxel per mL oflnjection; r,- is the peak
`ch degradation product obtained from the Test solution;
`te peak area for paclitaxel related compound B obtained
`
`ndard solution. In addition to not exceeding the limits
`'able 1. not more than 0.1% of any other paclitaxel
`product
`is found; and not more than 2.0% of total
`gradation products is found.
`
`Table 1.
`
`
`
`
`
`Name
`Limit ("0)
`0.8
`0.4
`0.8
`0.5
`
`Baccatin 111
`Ethyl ester side chain
`lO-Deacetylpaclitaxel
`l0—Deacetyl-7-epipac1itaxel
`(paclitaxel related compound
`B)
`
`7—Epipaclitaxel
`0.6
`
`m
`
`.‘
`V‘L
`
`“'I'till'olvents (467): meets the requirements.
`‘1
`(Official January 1. 2007)
`
`irements—It meets the requirements under Injections
`
`l-liter
`ransfer 200 uL of glacial acetic acid to a
`
`flask containing about 500 ml. of methanol. mix, and
`”in methanol to volume.
`
`lime—Prepare a filtered and degassed mixture of water
`ll'lle (ll :9). Make adjustments if necessary (see System
`_
`‘
`
`“ """-|lnder Cluonialograpln' (621)).
`'
`Pl‘epai‘ationiDissolve an accurately weighed quantity
`taxel RS in Di/uent to obtain a solution having a known
`
`'n of about 0.6 mg per mL.
`{Nation-Quantitatively dilute an accurately measured
`W Injection with Diluent to obtain a solution containing
`
`,
`H "8 0f paclitaxel per mL.
`‘
`ullf gl'aphic system (see Chromatography (621)1—The
`
`‘ matOgl‘aph is equipped with a 227—nm detector and a
`5-cm column that contains 5-trm packing L43. The flow
`
`11‘
`|.5 mL per mirurte. Chromatograph the Standard
`. and record the peak responses as directed for
`
`‘
`..
`t e retention time of the paclitaxel peak is between 6.0
`PEI-flutes; and the relative standard deviation for replicate
`3 mm more than 1.5%.
`
`
`
`record the chromatograms, and measure the
`cln‘omatograph,
`responses for the paclitaxel peaks. Calculate the quantity,
`ofpaclitaxel (CMHSINOH) in each mL of the Injection taken by the
`formula:
`
`(L/D)(’(rf - / r5).
`
`in which L is the labeled quantity, in mg, ofpaclitaxel in each mL of
`Injection; D is the concentration, in mg per mL, of paclitaxel in the
`Astra)" preparation, based on the labeled quantity; C is
`concentration, in mg per mL. of USP Paclitaxel RS in the Standard
`preparation; and rl- and r; are the peak responses obtained from the
`Assar preparation and the Standard preparation, respectively.
`
`Padimate O
`
`277.40
`C17H37N03
`Benzoic acid, 4—(dimethylamino)-, 2-ethylhexyl ester.
`2—Ethylhexylp-(dimethylamino)benzoate
`[21245-02—3].
`
`>> Padimate 0 contains not less than 97.0 percent and
`not more than 103.8 percent of C17H37N02.
`
`Packaging and storage—Preserve in tight,
`tainers.
`
`light-resistant con-
`
`USP Reference standards (11)—USP Padimate 0 RS.
`Identification—
`
`Infrared Absorption (197F).
`A:
`B: Ultraviolet Absorption (197U)7
`Solution:
`5 tlg per mL.
`tllediam:
`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 and 215.
`temperature being maintained for 4 hours.
`Chromatographic purity—
`Cln‘omatograpltic‘ state/u (see C/u'ontatograplrt* (621))7The gas
`chromatograph is equipped with a flame-ionization detector and a 3-
`mm X 1.8-m stainless steel column packed with 10 percent liquid
`phase G9 on support 81A. The column temperature is programmed
`at a rate of 10' per minute from 150‘ to 250‘. then maintained at
`250" for 10 minutes, and helium is used as the carrier gas.
`Pi‘ot'edul'ciChromatograph 2 ttL of a
`1
`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 of acetic anhydride. and titrate with 0.1 N perchloric acid
`VS. determining the endpoint potentiornetrically. Each mL of 0.1 N
`perchloric acid is equivalent to 27.74 mg of Cpl-INNOJ.
`
`

`

`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
`
`