PTOISB'30 (OHI9)
`Approvi<: ,,,, use hough 0713112012 OM8 0651'o()31
`U.S. Palent and Trademark OH,=<>: U.S. OEPARTMENT Of COMMERCE
`Unr;!er fl. Paperwork FIo;;;ko;Iion Act <11995, "" f""W'" a .... req<.>ired 10 "'''f'''''d 10 a cole<1ion <I information ""Ies. it displioy. a vaid OM8 "",,!rol n~
`Request
`A
`for
`Continued Examination (RCE)
`Transmittal
`
`Filina Date
`
`O ctober 26 2006
`
`First Named Inventor
`
`Neil P. DESAI
`
`licalion Number
`
`1 11553,339
`
`Ad(t"css 10'
`Mail Slop RCE
`Commissioner lor Palenls
`P.O. Box 1450
`Alexandria, VA 22313·1450
`
`Art Unit
`
`1656
`
`Examiner Nama
`
`M. T say
`
`Attorney Docket Number 638772000301
`
`This Is a Request for Continued Examination (RCE) under 37 CFR 1.114 01 the above·ldenll11ed application.
`R"",est jOl" Continued Examination (RCE) practice undar37 CFR 1.1 14 doos not apply to any uti itv or plant applicahon r~ed prior to June
`8, 1995, or \() any des:gn a~1ic.a~on. see Instruction Shetot for RCEs (OOt to be submitted to the USPTO) on page 2
`1. I Sul:mission re quired under 37 CFR 1.114 I NOle: If the flC E is proper. any previously filed unen1f!.ed amendments and
`
`ame.-.:;lments enclosed wi m 1he RCE will be anlared in the order in wh:ch may ware mad unless applicant insln.>c1s Qlharwise. If
`applicanl doe-s nQl wish 10 Ilav .. any p>eviO".JSly filed un"nterad am .. r.d",.ml(s) etlte.e<J, applicant lIl""t ~esl non· .. nlry 01 :oudl
`a", .. .-.:;I"''''nl(,,).
`
`a. O
`
`Pre\llously submitted. If a final Office aellon Is ol,llstand lng, any amendments "led after lhe Iinal Of nee action
`may be conSidered as a Sl,lbmission even II th iS box is not checked
`
`,. o Considerthe arguments in the Appeal Brief or Reply Brief previol,lsly filed on
`ii o Other
`L o AmendmenflReply (14 pages)
`iii. o Information Disclosl,lr9 Statement (IDS) (3 pages)
`o Affioo\llt(s)lDeciarallon(Sj
`0",,,,,, Declaration (6 1 pages), PTO/SBl08NB (1
`"
`"
`2. I Misccllancol,ls I
`
`b. 0
`
`Enclosed
`
`E!!!gel. Referencos (3l
`
`a. O
`
`Suspension of action on the above·identified applicalion is requested under 37 CFR " 103(c) for a
`period 01
`monlhs. (~fiod of suspension snail not"'XC<lW 3 months: Fw \lrW 37 CfR 1.17(i) required)
`
`b. O Other
`
`I Fees I The RCE roo unoor 37 CFR I. 17(e) is required by 37 CFR , . I 14 l..tten the RCE is filed
`
`3.
`
`a. 0
`
`The Director is hereby a uthorized to charge Ihe follov.ing fees . any underpayment of fees . or credit any
`03·1952
`Overpaymenls . to Deposit Account No.
`
`L [;] RCE fe!! reql,lired under 37 CFR 1.17(e}
`
`". o Extension of time ree (.17 CFR ! .! .1Band 1.17)
`'" o Other
`
`b.O Check In the amount of $
`
`enclosed
`
`c.O Paymenl by credit card (Form PTO-2038 enclosed)
`WARNING: InfD.mal iDn Dn this form may be<;Dme public. C,edit card infOl"malion should nDI be included on Ihis ID.m. PrDvide
`credil card Inform .. llon and authorlzatlDn Dn PT0-2038.
`
`Sognawre
`
`SIGNATURE OF APPLICANT, A TTORNE Y, OR AGENT REQUIRED
`Oat'" I April 14, 2010
`
`{Jian Xiao/
`
`Name (PtintlTy;>af
`
`Jian X iao
`
`Registration No.
`
`55,748
`
`pa-1399413
`
`Apotex v. Abraxis - IPR20 18-00 151 , Ex. 1022, p.O I of 15
`
`

`

`Docket No.: 63877200030 1
`(PATENT)
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re Patent Appl ication of:
`Neil P. DESAI et al.
`
`Application No.: 11/553.339
`
`Confilmation No.: 3605
`
`Filed: October 26, 2006
`
`Foe COM POSITIONS AND METHODS OF
`DELIVERY OF PHARMACOLOGICAL
`AGENTS
`
`Art Uni t: 1656
`
`Examiner: M. Tsay
`
`AMENDMENT AFTER FINAL ACTION UNDER 37 c'F.R. 1.116
`
`MS RCE
`Commissioner for Patent s
`P.O. Box 1450
`AlexandJia, VA 223 1 3~ 1450
`
`Dear Sir:
`
`I NTRODUCTORY COMMENTS
`
`This response accompani es a Request fo r Contin ued Exam ination . Amendments and
`
`remarks presented by this amendment are responsive to the Final Office Action dated
`
`December 31, 2009 (Paper No. 20091228), for which a response is d ue on March 31, 2010. A
`
`Petition and fee for a one month extension of time was filed on April 12,2010, thereby extending
`
`the deadline for filing the response to ApJil 30, 2010. Accordingly, th is response is timely filed.
`
`Reconsideration and al lowance of the pending claims, as amended , in light of the remarks presented
`
`herein are respectfully requested .
`
`Amendments to the Claims are reflected in the listi ng of claims wh ich begins on page 2
`
`of this paper.
`
`Remarks/Arguments begin on page 4 of th is paper.
`
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`

`

`Application No.: 111553,339
`
`2
`
`Docket No.: 638772000301
`
`AMENDMENTS TO THE CLAIMS
`
`This listing of claims wi ll replace all pJior versions, and listings of claims in the
`
`application:
`
`Claim I (cancelled)
`
`Claim 2 (currently Amended): A pharmaceutical composition for injection complising
`
`pacli taxel a J3Aarmaeel:ltieal ageAt and a phannaceutically acceptable carrier, wherein the
`
`phmmaceutically acceptable carrier comprises albumin , wherein the albumin and the
`
`J3AftfffiReeutienl ageflt pacl itaxel in the composi tion are formulated as nanoparticles, wherein the
`
`nanoparticles have a pm1icle size of less than about 200 nm, and wherein the weight ratio of
`
`albumin to J3AafIHaeCl:ltieai agent paclitaxel in the compos ition is about I: I to about 9: 1.
`
`Claim 3 (cancelled).
`
`Claim 4 (oliginal): The phalmaceutical compos it ion of claim 2. wherein
`
`the albumin is human serum albumin.
`
`Claims 5-12 (cancelled).
`
`Claim 13 (currently amended): The pharmaceutical composition of claim [[ 12]) 2..
`wherein the pharmaceutical composition is free of Cremophor.
`
`Claim 14 (w ithdrawn): A method of treating a disease compri sing
`
`administering an effective amount of a pharmaceutical composition of claim 2.
`
`Claim 15 (withdrawn): The method of claim 14, wherein the disease is
`
`cancer.
`
`arthriti s.
`
`Claim 16 (withdrawn): The method of claim 14, wherein the disease is
`
`Claim 17 (withdrawn): The method of claim 14, wherein the disease is
`
`cardiovascular disease.
`
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`

`

`Application No.: 111553,339
`
`3
`
`Docket No.: 638772000301
`
`Claim 18 (withdrawn): The method of claim 17, wherein the disease is
`
`restenos is.
`
`Claim 19 (withdrawn): The method of c laim 14, wherein the composi tion
`
`is administered intravenously, intraarterially, intrapulmonary, oral ly, by inhalation,
`
`intravasicuiarly, intramuscularly, intra-tracheally, subcutaneously, intraoculariy,
`
`intrathecally, or transdermally.
`
`Claim 20 (withdrawn): 'rhe method of claim 19, wherein the
`
`phannaceutical composition is admi ni stered intravenously.
`
`Claims 21-23 (cancelled).
`
`Claim 24 (currently amended): The pharmaceutical compos ition of claim 2, wherein the
`
`ratio (w/w) of albumin to the I3Rarrna€ eBti€a l agent paclitaxel in the phannaceutical composition is
`
`about I: I to about 5: I.
`
`Claim 25 (currently amended); The phmmaceutical composition of claim 2, wherein the
`
`ratio (w/w) of albumin to the f'AftffflAeeBtieftl agent paclitaxel in the pharnlaceutical composition is
`
`1:1109: 1.
`
`Claim 26 (new); The phannaceutical composi tion of claim 2, wherein the ratio (w/w) of
`
`albumin 10 the pacli laxel in the phannaceutical composition is about 9: I.
`
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`

`

`Application No.: 111553,339
`
`4
`
`Docket No.: 638772000301
`
`REMARKS
`
`Claims 2-25 were pending in the present application. Claims 7-9 and 14-23 were
`
`withdrawn from consideration. By virtue of {his response, claims 3, 5-12, and 21 -23 have been
`
`cancelled, claims 2, 13, 24, and 25 have been amended, and new claim 26 has been added.
`
`Accordingly, claims 2, 4, 13, and 24-26 are currently under consideration.
`
`Support for the amendment of claim 2 can be found at paragraphs (0016]-[00 17] , [0028],
`
`and (0033] of the specification , as well as previously pending claim 12 of [he specification. Support
`
`for new claim 26 can be found at paragraph lOO4 1J of the specification. Claims 13,24, and 2S are
`
`amended to correct claim dependencies and/or antecedent bases. No new matter is added.
`
`Wi th respect to the cancellation and amendment of claims, Applicants have not
`
`dedicated or abandoned any uncl ai med subject matter an d moreover, have not acquiesced to any
`
`rejections and/or objections made by the Office. Applicants express ly reserve the right to pursue
`
`prosecution of any presentl y excluded claim embodiments in future continuat ion, continuat ion-in(cid:173)
`
`part, and/or divisional appl ications.
`
`Interview Summary
`
`Applicants th ank Examiners Marsha Tsay and Maryam Monshipouri for the courtesy
`
`in conducting the in-person interview with invemor Dr. Neil Desai and Applicants' representatives
`
`Catherine Polizzi and Jian Xiao on Janu ary 14,2010. The guidance provided by the Examiners
`
`dllting the imerview is greatl y apprec iated.
`
`During the interview, Dr. Desai discussed the invention. The Examiners suggested
`
`that previously pending claims be amended to a narrower scope. The present claim amendmem has
`
`nan'owed the scope of [he claims as the Examiner has suggested.
`
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`

`

`Application No.: 111553,339
`
`5
`
`Docket No.: 63877200030 1
`
`FUlthermore, one of the cited references, Desai et al. (U.S. Pat. No. 6,537,579, "the
`
`579 palent"), was discussed. It was nOled that the assignee of the '579 patent was the same as that
`
`of the present application.
`
`Claim Kejec:tioll.\· - .1.5 USC § /OJ
`
`Claims 2·6, 10- 13 and 24+25 are rejected under 35 U.S.c. § 100(a) as allegedly being
`
`unpaten table over Damascel li et al. ("Damascell i", 2001 Cancer 92( 10): 2592-2602) in view of
`
`Desai et al. (U.S. Pat. No. 6,537,579, "the '579 patent") as evidenced by Ibrahim et al. ("Ibrahim",
`
`2000 Proc Am Soc Clin Oncol 19: abstract 609F). Applicants respectfull y traverse th is rejection.
`
`Solely in an eff0l1 to expedite prosecution and without acquiescing to the Examiner's
`
`rejection, claim I has been amended to recite "[a] phalmaceut ical composition fo r inj ection
`
`comprising paclitaxel and a pharmaceutically acceptable calTier, wherein the pharmaceuticall y
`
`acceptable carrier compli ses albumin, wherein the albumin and the pacl itaxel in the composi tion
`
`are formula ted as nanopm1icles, wherein the nanoparticles have a panicle size of less than about
`
`200 nm , and wherein the weight ratio of albumin 10 paclitaxel in the composition is about I: I to
`
`about 9: 1."1 Applicants respec tfu lly submi t that points presen ted in the Response to Office Action
`
`dated October 27, 2009 apply to the amended claims.
`
`Applicants further submil a 37 C.F.R. § 1.1 32 Declaration by Dr. Neil Desai (herei nafter
`
`refen-ed to as "the Desai Dec laration "), wh ich provides further ev idence of nonobviousness.
`
`The cited references do not render the claimed compo:iitiolls prima facie obvious
`
`The Examiner acknowledges that Damascelli does not disclose a phannaceutical
`
`composition having an al bumin to paclitaxel weight ratio of about I: I to about 9: I, and in tum relies
`
`on the '579 patent as allegedly disclosi ng a pharmaceutical composition having an albumin to
`
`1 For the sake of brevily. Applicants folio\\' the Desai Declaration and rcler to a pharmacculical composition lo r
`injection comprising paclitaxel and a pharmaceutically acceptable carrier. wherein thc pharmaccutically acceplablc
`carrier comprises albumin. wherein Ihc <tlbumin 11IId Ihc pharmaceut'ical agent in Ihe cOmposi1ion are fornllllilted ~s
`nal1oparticles, wherei n the nanoparticles have a particle size of less than about 200 I1Ill as an "albumi n-based paclitll;>;d
`nanoparticlc composition."
`
`pa-1386628
`
`Apotex v. Abraxis - IPR20 18-00 151 , Ex. 1022 , p.06 of 15
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`

`

`Application No.: 111553,339
`
`6
`
`Docket No.: 638772000301
`
`pacli taxel weight ratio of 9: I. The Examiner concl udes that "[ilt would have been obvious to one of
`
`ordinary skill in the art at the time the invention was made to modify the teachings of Dam ascell i et
`
`al. by determining the optimum weight ratio of albumin to paclitaxel, i.e., 9: I, as suggested by
`
`Desai et al. which will result in a composition that will deliver pacl itaxel most effectively in an
`
`albumin delivery system." Page 3 of the Office Action. Applicants respectfully disagree.
`
`As an initial matter, Applicants respectfully submit that the '579 patent and the present
`
`application are co-owned by Abraxis BioScience, LLC.
`
`Applicants further respectfully submit that the '579 paten t docs not disclose a
`
`pharmaceutical composition having an albuminlpaditaxel ratio of 9: I. According to the Examiner,
`
`the '579 patent discloses dosage forms of AB I-007 that contai n 30 mg, 100 mg, or 300 mg of
`
`paclitaxel in a vial (col. 14, lines 4-5), and that unit vessels of AB1-OO7 may contain between 1 mg
`
`to 1000 mg of active drug (col. 15, lines 39-40). Page 3 of the Office Action. The Examiner
`
`concluded that. since the '579 patent di scloses that ABI-007 can contai n up to 1000 mg of acti ve
`
`drug and further discloses that AB I-007 can contain 100 mg pac1i taxel, it would be reasonable for
`
`one of ordinary skill to nore that a 1000 mg vial of ABI-007 wou ld contain 100 mg paclitaxel and
`
`900 mg albumin, i.e., a weight ratio of9: I of albumin to paclitaxel. Page 3 of the Office Action.
`
`However, as Dr. Desai explained during the interview, the term "active drug" used in the '579
`
`patent refers to paclitaxel rather than the entire pharmaceutical composition. See column 12, lines
`
`14-20 (refening to pacl itaxel as the "acti ve drug substance"). Accordingly, the basis of the
`
`Examiner's conversion is incorrect.
`
`Applicants further respectfully submit that, as discussed in the Desai Declarati on and
`
`discussed below, the cited references do nut render claims uf the present application obviuus.
`
`As stated in the Desai Declaration. the three references cited in the Office Action repmt
`earlier clinical studies either conducted or supported by Abraxis. 2 The a lbumin-based paclitaxel
`
`2 Paragraph 16 of the Desai Declaration.
`
`pa-1386628
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`Apotex v. Abraxis - IPR2018-00151 , Ex. 1022, p.07 of 15
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`

`

`Application No.: 111553,339
`
`7
`
`Docket No.: 638772000301
`
`nanopartic1e composi tions used for the clinical studies reported in the c ited references represent an
`
`old formulation developed by Abraxi s plioI' to the fil ing of the present appl ication and have an
`
`albuminlpaclitaxel ratio of 19: I (referred to as "the old fOlTIlU lation" or " the 19: I fonnulation,,). 3
`
`According to Dr. Desai, the old fo rmu lation allowed paclitaxel to be administered
`
`without using tox ic organic solvents, thus avoiding allergic reactions and side effects caused by the
`
`organic so lvents used in standard paclitaxel formu lation s. 4 Furthermore, according to Dr. Desai, the
`old formulation was shown to be efficacious in treati ng cancers.s For example, Damascelli repol1ed
`a clinical study using the old form ulation. and demonstrated that intraarterial administration of the
`
`old fOlmulation had "acceptable toxicity" and at most dose level s showed considerable anti tumor
`
`activity in treating advanced head and neck cancel' and recurrent anal canal squamous cell
`carcinoma.6 Thus, according to Dr. Desai, because the o ld fOlmu lation was shown to be safe and/or
`
`have considerable antitumor activity, there was no need or desirabilit y based on the teaching of the
`
`ci ted references to further modify the old fonnulation fo r the purpose of obtaining a safer or more
`
`efficacious fonnulation, much less to modify it for thi s purpose by reducing the albuminlpaclitaxel
`ratio in the formulation. 7
`
`Furthermore, according to Dr. Desai , it was believed that the fOlmation of stable
`
`colloidal dispersions of al bumin-based paclitaxei nanoparticie compos itions is facilitated by the
`
`combination of electrical repu lsion (negative zeta potenti al), steric stabili zation , and viscosi ty, all
`attributable to albumin. s Because albumin has a net negative charge and is a macromolecule, a
`higher albumin/pacli taxel ratio in the formulat ion could lead to increased steric and electrostatic
`
`intermolecu lar repulsion as well as higher vi scosity, and cou ld thus create a favorable environmen t
`for nanoparticles .9 According to Dr. Desai, one wou ld expect that , based on these favorable
`
`~ Paragraph! 7 of the Desai Dec!aralion.
`4 Paragraph 18 of the Desai Declarmion.
`~ Paragraph 19 of the Desai Declaralion.
`6 Paragraph 19 of the Desai Declarmion.
`I Paragraph 20 of Ihe Iksai tkclaralion
`6 Paragraph 21 of the Desai Declaralion.
`9 Paragraph 21 of the Desai Declaration.
`
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`

`Application No.: 111553,339
`
`8
`
`Docket No.: 638772000301
`
`propelties imparted by albumin, reducing the albuminlpaclitaxel ratio in the albumin-based
`
`paclitaxel nanoparticle composition could destabil ize the nanopatticle composition. to
`
`Thus, according to Dr. Desai, there was no basis in the teachings of the cited references to
`
`further modify the old formula tion by reducing the albuminipaclitaxel ratio in the formulation, and
`
`the biological significance of albumin/paclitaxel ratio in the claimed composition could not be
`
`predicted based on the cited references. 1 1
`
`Unexpected properties of the claimed composilions overcome Ihe obviousllesJ rejection
`
`Applicants respectfully su bmit that the evidence of unexpected propelties of the claimed
`
`compositions overcome the obviousness rejection. As provided in the Desai Declaration and
`
`di scussed below in more detail, the albumin/paclitaxel ratio of about I: I to about 9: I recited in the
`
`present claims unexpectedly showed increased cell ular binding. I~ Moreover, it was unexpectedly
`
`found that there is a dramatic change in the binding of paclitaxei that occurs at an
`albuminlpac1itaxel ratio of about 9: 1. 13 FUlthermore, an albumin-based pac1itaxel nanopartic1e
`composition having an albumin/pac1itaxel ratio of 9: I unexpectedly showed higher therapeutic
`
`efficacy and substantiall y reduced toxic ity compared with the old fonnu lation disclosed in the ci ted
`references. 14 Thus, even assuming a prima Jade case of obv iousness co uld be established,
`
`compelling evidence of unexpected advantageou s propelties of the claimed compos ition rebuts any
`
`alleged finding of priflUlfacie obviousness.
`
`An albumin/paclitaxel ratio of about 1: I to about 9: I unexpectedly showed increased cellular
`binding
`
`As stated in the Desai Declaration, it was found, unexpectedl y, that the ratio of albumin to
`
`pacli taxel in an albumin-based pac\itaxei nanopartic1e compos ition affects the abi lity of pacl itaxel to
`
`](I Paragraph 21 of lhe Desai De.::Jaration.
`11 Paragraph 22 of the Desai Declaralion.
`J2 Paragraphs 7- 13 and 15 of Ihe Desai Declaration
`]} Paragraphs 14-15 of the Desai Declaration.
`I~ Paragr:lphs 23-30 of the Desai Declaration.
`
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`

`

`Application No.: 111553,339
`
`9
`
`Docket No.: 638772000301
`
`bind to endothelial cells.15 Higher albumin/paclitaxel ratios are assoc iated with poor cellular
`binding of paclitaxel, whi le lower albumin/paclitaxel ratios are associated wi th enhanced cel lular
`binding of paclitaxel. 16 Consistent evidence was obtained both in an endothelial cel l binding assay
`
`and in an aJ1ificial assay system that simulates binding of paclitaxel to a cell membrane in the milieu
`of albumin, such as endothelial cells exposed to albumin in the blood. 17
`
`According to Dr. Desai, it was further unexpectedly found that the effect of
`
`albuminlpaclitaxel ratio on the bi nding of paclitaxel changes dramatically at an albumin/paclitaxel
`weight ratio of about 9: 1. 18 As stated in the Desai Declaration, when the albuminlpaclitaxel ratios
`
`were above about 9: I, the pacl itaxel binding decreased linearl y as the log of the al bumin/pacl itaxcl
`
`ratio increased wi th a slope of -14 . When the album in/pacl itaxel ratios were about 9: 1 or less, the
`
`pac li taxel binding decreased linearly as the log of the albumi n/paclitaxel ratio increased wi th a slope
`
`of -95, a nearly seven fold increase in the slope. The two lines intersect creating an unexpected
`
`inflection point in the bindi ng curve at an al bumin/paclit axel ratio of about 9: I. J9 According to Dr.
`
`Desai, this suggests a dramatic change in the binding of pacl itaxel that occurs at an
`alhuminlpaclitaxcl ratio of about 9: 1.20
`
`As explained in the Desai Declaration, albumin -based paclitaxel nanoparticle composi tions
`
`utilize the natural receptor-mediated albumin transpoJtatioll process to facili tate the delivery of
`pacli taxel to tumor si tes.H It is believed that when an albumi n-based paclitaxel nanoparticle
`
`composi tion is injected into the blood vessel, the albumin -bound paclitaxel binds to albumin
`receptor gp60 on endothelial cells and is transported to the endothelial ceJls.22 According to Dr.
`
`Desai, the findings that the albumin/pacl itaxel ratio affects the binding of paclitaxel to endothel ial
`
`cells and simulated cellular membrane and fhat fhere is a dramatic change in the binding of
`
`I~ Paragraph 7 of the Desai Declaration.
`16 Paragraph 7 of the Desai Declar.ttion.
`17 I'ilragrilphs 9- 13 of the Desai Deelilrmion.
`J8 Paragraph 14 of lhe Desai Declaration.
`19 Paragraph 14 of Ihe Desai Declaration.
`2(1 1'aragraph 14 of lhc Desai Declaration
`21 Paragraph 15 of Jhe Desai Declaration.
`22 Paragraph 15 of the Desai Declaration.
`
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`

`

`Application No.: 111553,339
`
`10
`
`Docket No.: 63877200030 1
`
`pacli taxel that occurs at an albu min/paclitaxel ratio of about 9: I suggest a biological significance of
`
`albuminlpaclitaxel ratio in an al bumin-based paclitaxel nanoparticle formulation. Such biological
`significance was neither taught nor suggested by the c ited references.23
`
`A nanopatticle composition having albumin/paclitaxel mtio of about 9: I unexpectedly showed
`highcr theraocutic efficacy and substantially reduced toxicity compared wi th the old formulat ion
`
`According to Dr. Desai, Abraxane®, an albumin-based paclilaxel nanopalticie
`
`composition having about 9: I albuminlpaclitaxel weight ratio (also refelTed to as "the 9: I
`
`formulation"), was unexpectedly fou nd ro be more efficacio us than the old formulati on in the ci ted
`
`references, which had an albumin/paclitaxel ratio of about 19: I ("the 19: I fonnulation").Z4 Further,
`
`Abraxane® was unexpectedly fo und to have substantiall y reduced tox icity compared with the old
`fO lmulation. 15
`
`According to Dr. Desai, two clinical studies were conductcd in China with cancer
`
`patients having variou s sol id tum ors?!> In the first study, twenty-two patients having differe nt
`cancers were enrolled to be treated with the 19: I fonnu lation at dose level s of 135-350 mg/m2
`(mean dose of about 250 mg/m2). In the second study, 104 breast cancer patients were enrolled to
`be treated with the 9: I fo nnulation at the dose level of 260 mglm2
`.27 According to Dr. Desai,
`
`among the 2 1 evaluable patients treated wi th the 19: I formulation, 8 showed substantial tumor
`
`shrinkage upon treatment, leading to an overall response rate of 38%. Among the 104 evaluable
`
`patients treated with the 9: I formu lation, 56 showed substantial tumor shri nkage upon treatment,
`
`leading to an overall response rate of 54%.2~
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`Accordi ng to Dr. Desai, the response rates of the patients treated wi th the 19: 1
`fO lmulation at a dose of 260 mg/m2 or higher were further compared with those of patients treated
`
`2) I'nnlgrnph 15 of thc Desai Declaration.
`24 Paragraph 23 of [he Desai J)e.::Jaration.
`2S Paragraph 23 of the Desai Declaration.
`26 I'nragraph 25 of the Desai Declaration
`27 Paragraph 25 of the Desai Declaration.
`" Paragraph 26 of the Desai Declaration.
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`pa -1386628
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`Apotex v. Abraxis - IPR201 8-00151 , Ex. 1022, p. 11 of 15
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`

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`Application No,: 111553,339
`
`II
`
`Docket No,: 63877200030 1
`
`with the 9: I formulation at a dose of 260 mg/m2
`,29 Among the twelve pat ients treated wi th the 19: 1
`formulation at a dose of 260 mg/m2 or higher, three showed su bstant ial tu mor shrinkage upon
`treatment, leading to an overall response rate of 25%,30 Among the 104 evaluable patients treated
`
`
`with the 9: I formulation at dose level of 260 mg/m2, 56 showed substantial tumor shrinkage upon
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`treatment, leading to an overall response rate of 54%, more than double the 25% respon se rate
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`observed in the study wi th the 19: I formulation,31
`
`In his declaration, Dr, Desai fUl1her provides ev idence that the 9: I formulation showed
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`substanti ally reduced toxici ty compared with the 19: I fonnuiation,J2 As stated in the Desai
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`Dcc laration, the toxici ty profiles of the 9: I formu lation and the 19: I fo mm lation were compared by
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`quantifying treatment-related adverse events of aU grades based on National Cancer Institute
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`Common Toxicity Criteria Adverse Events (NC I CTCAE), For the majority of adverse even ts
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`commonly observed with the tJ'eatment of paclitaxel, the 9: 1 form ulation showed substantially
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`reduced number of incidents than the 19: 1 formuiation,J3 According to Dr. Desai, these data
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`demon strate that the 9: I formulation has substantiall y reduced toxicity compared wi th the 19: 1
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`fOlmulation ,34
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`The advantages of the cl ai med compositions were unex pected
`
`According to Dr. Desai, the advantages of the claimed composi ti ons di scussed above were
`
`unexpected and could not be predicted based on the teachi ngs of the cited references ,3~
`
`As di scussed above and staled in the Desai Declaration, the cited references provide no
`
`indication of the biological sign ifica nce of albumin/paclitax el ratio in an albumin -based pacli taxel
`
`29 Paragraph 27 o f lhe J)e~ai D<.."{;laralion.
`J() I'nnlgrnph 27 o f thc Des[)i Dcclflnltion .
`31 Paragraph 27 o f [he Desai De.::laration.
`'2 Paragraph 28 of the Desai Declaration.
`JJ Paragraph 28 o f the Desai Declaration
`J4 Paragraph 28 o f Jhe Desai Declaration.
`JS Paragraphs 29, 30. and 35-38 of the Desai Declaration.
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`Apotex v. Abraxis - IPR201 8-00151 , Ex. 1022, p.12 of 15
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`

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`Application No .: 111553,339
`
`12
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`Docket No .: 63877200030 1
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`nanopartic1e composi tion.36 Because the old formulation was shown to be safe and have
`con siderab le antitumor acti vity, there was no need or desirabilit y based on the teaching of the cited
`
`references to further modify the old fonnulation for the purpose of obtaining a safer andior more
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`efficacious fOlmulation, much less to modify it by reducing the albuminJpac1itaxel ratio in the
`formu lation .37 Furthermore, because al bu min is a major contribu ting factor to the stability of an
`
`albumin-based pacii taxel nanopml icie com position, one would expect that reducing the
`albuminJpacii taxel ratio in the composit ion would destabil ize the nanopmt ic1e fonnulation. 3s
`According to Dr. Desai, there was therefore no reason to further mod ify the old formu lation by
`reducing the albuminJpac1i taxel ratio in the formulation.39
`
`According to Dr. Desai, the finding that an increased albumi n/pac1itaxel ratio negatively
`
`affects the binding of paclitaxel to endothelial cells was unexpected. The finding that there is a
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`dramat ic change in the binding of paclitaxel that occurs at an albuminlpaclitaxel ratio of about 9: 1
`was even more surprising and unex pected.4o
`
`FUlt hcnnorc, according to Dr. Desai, the clinical data demonstrating that the 9: I formulation
`leads to a higher therapeu tic efficacy than the old fOlmu lation was unexpected.4 1 Moreover, as Dr.
`
`Desai states, since the amount of albumin in the phanllaceu tical compos ition injected in to the blood
`
`vessel is relatively small comparing to the high concentration of albumin present in the blood, it was
`
`further unexpected that reducing the albumin/paclitaxel ratio in the al bumin-based pacl itaxel
`
`nanoparticle composition would make any difference in the therapeutic efficacy of the composition
`at all, much less result in the increased efficacy observed in the cl in ical studies. 42
`
`J6 Paragraph 36 of lhe De~ai D<.."{;laration.
`J7 I'nnlgrnph 36 of the Dcsni Dcclflnltion .
`38 Paragraph 36 of [he Desai De.::laration.
`'9 Paragraph 36 of the Desai Declaration.
`4(1 1'aragraph 37 of thc Desai Dcdaralion
`4\ Paragraph 29 of Jhe Desai Declaration.
`42 Paragraph 29 of the Desai DednfUtion.
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`Apotex v. Abraxis - IPR201 8-00 15 1, Ex. 1022, p. 13 of 15
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`Application No.: 111553,339
`
`13
`
`Docket No.: 63877200030 1
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`Similarly, according to Dr. Desai, the finding that the 9: I fOimulation has substantially
`reduced toxicity compared with the old formulation was also unexpec ted.43 Moreover, a s Dr. Desai
`
`states, since the amount of albumin in the pharmaceutical composi tion injected into the blood vessel
`
`is relatively small comparing to the high concentration o f albumin present in the blood, it was
`
`fUlther unexpected that red ucing the albu min/paclitaxel ratio in the albumin-based pacli taxel
`
`nanoparticle composi tion would lead to substantiall y reduced tox ici ty in the albumin -based
`pac litaxel nanopallicle fo rmu iation. 4 4
`
`As stated in the Desai Declaration, Abraxane® was approved in the United States in 2005
`
`for treating metastatic breast cancer and has beco me one of the leading drugs for treating metastatic
`brC<.1st cancer within five years after its ini tial approval.45 In recent stud ies, Abraxane® has also
`
`sho wn substantial ly improved therapeutic efficacies in various cl in ical trials for treating difficult-to(cid:173)
`Ire a! cancers such as pancreatic cancer, lung cancer, melanoma, and oval"ian cancer. 46
`
`In view of the compelling evidence of unexpected propelties and significant practical
`
`ad vantages of the claimed compos itions, Applicants respectfully submit that the compositions
`
`claimed in the present application are nonobvious and inventive.
`
`4) Paragraph 30 of the Desai Declaration.
`44 l'aragraph 30 of thc Desai ))cclaration
`4S Paragraphs 31 -32 o f the Desai Declaration .
`.u; Paragr:lphs 33-34 of the Desai Declaration.
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`Apotex v. Abraxis - IPR20 18-00 15 1, Ex. 1022 , p. 14 of 15
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`Application No.: 111553,339
`
`14
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`Docket No.: 63877200030 1
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`CONCLUSION
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`In view of the above, each of the presently pend ing claims in this application is believed
`
`to be in immed iate condition for allowance. Accordingly, the Examiner is respectfully requested to
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`withdraw the outstanding rejection of the claims and to pass this application to issue. If it is
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`determined that a telephone conference would ex pedite the prosecution of this applicati o n, the
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`Examiner is in vited to telephone the unders igned at the number given be low.
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`In the event the U.S. Patent and Trademark Office determines that an extension and/or
`
`other relief is required , appl icant s petition for any requ ired relief including extensions of time and
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`authorizes the Co mmi ssioner to charge the cost of such petitions and/or other fees due in connection
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`wi th the filing of thi s document to Deposit Account No. 03-1952 refere nci ng docket no.
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`638772000301. However, the Commissioner is not authorized to charge the cost of the issue fee to
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`the Deposi t Account.
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`Dated: April 14, 2010
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`Respectfu ll y submitted ,
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`Electronic signature: /Jilln Xiaol
`Jian Xiao
`Regi stration No.: 55,748
`MORRISON & FOERSTER LLP
`755 Page Mill Road
`Palo Alto, Cal iforn ia 94304- I 0 I 8
`(650) 813-5736
`
`pa-1386628
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`Apotex v. Abraxis - IPR20 18-00ISI , Ex. 1022, p.IS of 15
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