Docket No.: 638772000109
`(PATENT)
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re Patent Application of:
`Neil P. DESAI et al.
`
`Application No.: 111520,479
`
`Confirmation No.: 8972
`
`Filed: September 12, 2006
`
`For: NOVEL FORMULATIONS OF
`PHARMACOLOGICAL AGENTS, METHODS
`FOR THE PREPARATION THEREOF AND
`METHODS FOR THE USE THEREOF
`
`Art Unit: 1611
`
`Examiner: T. Love
`
`AMENDMENT IN RESPONSE TO NON-FINAL OFFICE ACTION
`
`MS Amendment
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Dear Sir:
`
`INTRODUCTORY COMMENTS
`
`This is in response to the non-final Office Action dated March 30, 2010 (Paper No.
`
`20100324), for which a response is due on June 30, 2010. Filed herewith is a Petition and fee for a
`
`three months extension of time, thereby extending the deadline for response to September 30, 2010.
`
`Accordingly, this response is timely filed. Reconsideration and allowance of the pending claims, as
`
`amended, in light of the remarks presented herein are respectfully requested.
`
`Amendments to the Claims are reflected in the listing of claims which begins on page 2
`
`of this paper.
`
`Remarks/ Arguments begin on page 5 of this paper.
`
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`Actavis - IPR2017-01100, Ex. 1018, p. 1 of 14
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`

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`Application No.: 111520,479
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`2
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`Docket No.: 638772000109
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`AMENDMENTS TO THE CLAIMS
`
`This listing of claims will replace all prior versions, and listings of claims in the
`
`application:
`
`Claims 1-65 (Cancelled).
`
`Claim 66 (Previously presented):
`
`A pharmaceutical formulation comprising:
`
`paclitaxel at a concentration between 5 mg/ml and 15 mg/ml,
`
`wherein the pharmaceutical formulation is an aqueous suspension that is stable for at least 3 days
`
`under at least one of room temperature or refrigerated conditions, wherein the pharmaceutical
`
`formulation comprises nanoparticles comprising paclitaxel and albumin.
`
`Claim 67 (Previously presented):
`
`The pharmaceutical formulation of claim 66, wherein the
`
`pharmaceutical formulation is a stable aqueous suspension reconstituted from a sterile lyophilized
`
`powder.
`
`Claim 68 (Previously presented):
`
`The pharmaceutical formulation of claim 67, wherein the
`
`pharmaceutical formulation comprises paclitaxel at a concentration of 5 mg/ml.
`
`Claim 69 (Cancelled).
`
`Claim 70 (Previously presented):
`
`The pharmaceutical formulation of claim 67, wherein the
`
`average diameter of the nanoparticles is no greater than 220 nm.
`
`Claim 71 (Previously presented):
`
`The pharmaceutical formulation of claim 67, wherein there is
`
`substantially no precipitation of paclitaxel for at least 3 days under at least one of room temperature
`
`or refrigerated conditions.
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`pa-1400734
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`

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`Application No.: 111520,479
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`3
`
`Docket No.: 638772000109
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`Claim 72 (Previously presented):
`
`The pharmaceutical formulation of claim 70, wherein the
`
`average nanoparticle size does not substantially change for at least 3 days under at least one of room
`
`temperature or refrigerated conditions.
`
`Claim 73 (Previously presented):
`
`The pharmaceutical formulation of claim 70, wherein the
`
`nanoparticles comprise paclitaxel and have an albumin coating.
`
`Claim 74 (Previously presented):
`
`The pharmaceutical formulation of claim 70, wherein the
`
`nanoparticles have a core and the nanoparticle core is substantially free of polymeric material.
`
`Claim 75 (Previously presented):
`
`The pharmaceutical formulation of claim 73, wherein the
`
`albumin coating has free albumin associated therewith, and wherein a portion of the paclitaxel is
`
`contained within the albumin coating and a portion of the paclitaxel is associated with the free
`
`albumin.
`
`Claim 76 (Previously presented):
`
`The pharmaceutical formulation of claim 70, wherein at least a
`
`portion of the albumin is crosslinked by disulfide bonds.
`
`Claim 77 (Previously presented):
`
`The pharmaceutical formulation of claim 70, wherein the
`
`paclitaxel is substantially amorphous.
`
`Claim 78 (Previously presented):
`
`The pharmaceutical formulation of claim 70, wherein the
`
`paclitaxel is substantially crystalline.
`
`Claim 79 (Withdrawn):
`
`A method, comprising administering an effective amount of the
`
`composition of claim 70 to a patient to treat a tumor.
`
`pa-1400734
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`

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`Application No.: 111520,479
`
`4
`
`Docket No.: 638772000109
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`Claim 80 (Withdrawn):
`
`The method of claim 79, wherein the composition is administered
`
`parenterally, orally, intravenously, subcutaneously, intraperitoneally, intrathecally, intramuscularly,
`
`by inhalation, topically, transdermally, rectally, or vaginally.
`
`Claim 81 (Withdrawn):
`
`The method of claim 80, wherein the composition is administered
`
`intravenously.
`
`Claim 82 (Withdrawn):
`
`The method of claim 81, wherein the pharmaceutical formulation is
`
`infused, and the infusion volume is no greater than 200 ml.
`
`Claim 83 (Withdrawn):
`
`A method of treatment, comprising administering an effective amount
`
`of the composition of claim 70 to a patient to treat rheumatoid arthritis.
`
`Claim 84 (Withdrawn):
`
`The method of claim 83, wherein the composition is administered
`
`parenterally, orally, intravenously, subcutaneously, intraperitoneally, intrathecally, intramuscularly,
`
`by inhalation, topically, transdermally, rectally, or vaginally.
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`pa-1400734
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`Actavis - IPR2017-01100, Ex. 1018, p. 4 of 14
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`

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`Application No.: 111520,479
`
`5
`
`Docket No.: 638772000109
`
`REMARKS
`
`Claims 66-68 and 70-84 were pending in the present application. Claims 79-84 are
`
`withdrawn. No amendment is made to the claims. Accordingly, claims 66-68 and 70-78 are
`
`currently under examination.
`
`Withdrawn Rejections
`
`Applicants acknowledge with appreciation that the rejection of claims 66-68 and 70-76
`
`under 35 U.S.C. § 103(a) over Trissel (US Pat. No. 5,681,846) in view of Yen (U.S. Pat. No.
`
`5,725,804) is withdrawn. Applicants acknowledge with appreciation that the rejection of claims
`
`77-78 under 35 U.S.C. § 103(a) over Trissel and Yen, further in view ofUeda (U.S. Pat. No.
`
`5 ,272,171) is withdrawn.
`
`Applicants acknowledge with appreciation that the rejection of claims 66-68 and 70-78
`
`on the ground of nonstatutory obviousness-type double patenting over claims 1-14, 17-19, and 34 of
`
`Pat. No. 6,096,331 in view of Trissel and further in view of Yen is withdrawn. Applicants further
`
`acknowledge with appreciation that the rejection of claims 77-78 on the ground of nonstatutory
`
`obviousness-type double patenting over claim 34 of U.S. Pat. No. 6,096,331 in view of Trissel
`
`further in view of Yen and Ueda is withdrawn.
`
`Desai in view of Shively
`
`Claim Rejections- 35 USC§ 103
`
`Claims 66-68 and 70-77 stand rejected under 35 U.S.C. § 103(a) as allegedly being
`
`unpatentable over Desai et al. ("Desai," U.S. Pat. No. 5,439,686) in view of Shively ("Shively,"
`
`U.S. Pat. No. 5,407,683). Applicants respectfully traverse this rejection.
`
`The Examiner states that Desai teaches 2 mg/ml paclitaxel and that "a higher loading of
`
`taxol can be achieved by utilizing an additional solvent .... " While acknowledging that "Desai fails
`
`to directly teach that the concentration of taxol (paclitaxel) is 5 mg/ml," the Examiner relies on
`
`Shively as allegedly teaching that "[f]or therapeutic use, emulsion containing between about 0.5 and
`
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`

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`Application No.: 111520,479
`
`6
`
`Docket No.: 638772000109
`
`about 5 mg/ml taxol [ ... ] are [ ... ] administered orally or intravenously." The Examiner states that
`
`"one would have been motivated to do so since Shively teaches that 5 mg/ml is a therapeutically
`
`effective amount, wherein Desai directly teaches methods of obtaining "higher loading of drug."
`
`The Examiner further states that "[t]here would be a reasonable expectation of success since Desai
`
`teaches how to achieve higher amounts of taxol, and [Shively] teaches that the amount (5mg/ml)
`
`one would desire." Applicants respectfully disagree.
`
`First, Shively teaches an oil-in-water emulsion formulation of paclitaxel that is
`
`completely different from the albumin-based nanoparticle suspension claimed in the present
`
`application. In the oil-in-water emulsion composition of Shively, the paclitaxel is dissolved in oil
`
`droplets suspended in an aqueous solution. The paclitaxel recited in the present claims, by contrast,
`
`is present in the form of albumin-containing nanoparticles. There is no teaching or suggestion in
`
`Shively that the 5 mg/ml concentration taught therein for an oil-in-water paclitaxel emulsion can be
`
`extrapolated to a nanoparticle paclitaxel formulation recited in the present claims, much less to
`
`achieve this without compromising the stability of the nanoparticle formulation.
`
`Second, the Examiner has taken statements in Desai out of context in finding that Desai
`
`teaches how to achieve higher concentration of paclitaxel in the composition disclosed therein.
`
`Specifically, the Examiner states that the paclitaxel composition of Example 4 of Desai comprises
`
`13 mg of taxol (2 mg/ml). Page 4 of the Office Action. The concentration the Examiner points to,
`
`however, is the concentration of paclitaxel dissolved in soybean oil, prior to the addition of albumin
`
`and prior to the sonication process required for making the paclitaxel particles. The Examiner also
`
`states that Desai teaches that a higher loading of paclitaxel can be achieved by utilizing an
`
`additional solvent. Page 4 of the Office Action. The loading discussed in Desai, however, refers to
`
`the amount of drug per particle rather than the amount of drug per unit volume of the aqueous
`
`suspension. See Column 12, lines 65-68 of Desai ("In order to obtain a higher loading of drug into
`
`the crosslinked protein shell, a mutual solvent for the oil and the drug ... can be mixed with the
`
`oil."). The Examiner further points to Example 5 of Desai and states that "Desai is stable for 27
`
`days at temperatures of 4 °C, 25°C, and 38°C." Page 5 of the Office Action. The stability discussed
`
`in Example 5 of Desai, however, refers to the stability of polymeric shells containing buoyant
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`Application No.: 111520,479
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`7
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`Docket No.: 638772000109
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`soybean oil in the absence of any drug, much less a water insoluble drug such as paclitaxel.
`
`Nowhere does Desai teach or suggest a pharmaceutical formulation comprising paclitaxel at a
`
`concentration between 5 mg/ml and 15 mg/ml, or that one skilled in the art could expect to achieve
`
`such concentrations without compromising the stability of the paclitaxel particles.
`
`Furthermore, even assuming that one of ordinary skill in the art reading Desai and
`
`Shively would be motivated to attempt to make an albumin-based paclitaxel nanoparticle
`
`formulation at the concentration of 5 mg/ml, there is no teaching or reasonable expectation that an
`
`albumin-based nanoparticle formulation of paclitaxel at a concentration of 5 mg/ml, much less at a
`
`concentration higher than 5 mg/ml, would be stable in an aqueous suspension. As stated in the
`
`present application, the major limitation of paclitaxel in its clinical use is its poor water solubility.
`
`Page 25, lines 11-18 of the present application. The most commonly used paclitaxel formulation
`
`Taxol® is provided in 0.6 mg/ml paclitaxel dissolved in an ethanol:Cremophor EL:saline (5:5:90)
`
`solution and is physically stable for only a short time (3 hours). Column 2, lines 8-10 of Shively.
`
`An increase in paclitaxel concentration in an aqueous suspension would be expected to exacerbate
`
`the stability problem of the paclitaxel formulation. Thus, one or ordinary skill in the art reading
`
`Desai and Shively would not have reasonably expected that a nanoparticle paclitaxel formulation at
`
`paclitaxel concentration of between 5 mg/ml and 15 mg/ml would be stable in an aqueous
`
`suspensiOn.
`
`Applicants also respectfully bring the Examiner's attention to Exhibit 1, which reports a
`
`study conducted to compare the physiochemical characteristics and stability of three commercially(cid:173)
`
`approved formulations of paclitaxel, namely, Abraxane® (an albumin/paclitaxel nanoparticle
`
`formulation covered by the present application), Nanoxel® (a solvent-based formulation of
`
`paclitaxel), and Genexol® (a polymeric-micelle formulation of paclitaxel), each at two different
`
`paclitaxel concentrations (0.7 mg/ml and 5 mg/ml). As shown in Exhibit 1, following
`
`reconstitution, Abraxane® was stable at room temperature and 40°C over 24 hrs, with no evidence
`
`of nanoparticle size growth at either 0.7 mg/ml or 5 mg/ml. While reconstituted Genexol® was
`
`stable at room temperature over 24 hrs, micelle instability resulting in precipitation of paclitaxel in
`
`the form of large needle-like crystals for both 0.7 mg/ml and 5 mg/ml formulations was seen
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`pa-1400734
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`Application No.: 111520,479
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`8
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`Docket No.: 638772000109
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`between 2 to 4 hrs at 40°C. For Nanoxel® at 0.7 mg/ml, a minor, but consistent, increase in particle
`
`size was observed at room temperature over 24 hrs. Moreover, significant aggregation, particle-size
`
`growth, and crystallization were seen within 4 hrs at 40°C. Thus, the stability of paclitaxel
`
`formulations indeed varies in different formulations.
`
`Thus, Applicants respectfully submit that Desai and Shively, alone or in combination, do
`
`not render claims of the present application obvious.
`
`When discussing dependent claim 67, which further requires that the composition is a
`
`stable suspension reconstituted from a sterile lyophilized powder, the Examiner states that since
`
`Applicants are "claiming a product, wherein the instant final product and the final product of the
`
`prior art are substantially identical, the steps utilized to achieve said final product are not required to
`
`be the same." The Examiner has made a similar statement when discussing dependent claims 71 and
`
`72, which require that no precipitation of paclitaxel or change in particle size for at least 3 days
`
`under at least one or room temperature or refrigerated conditions. Page 6 of the Office Action
`
`("[S]ince the products are the same, the features are also necessarily present."). Applicants
`
`respectfully submit that the Examiner has provided no basis in finding that the pharmaceutical
`
`composition claimed in the present application, namely, a pharmaceutical formulation comprising
`
`paclitaxel at a concentration between 5 mg/ml and 15 mg/ml, wherein the pharmaceutical
`
`formulation comprises nanoparticles comprising paclitaxel and albumin, is the same as what is
`
`disclosed in any of the cited references. At least for the reasons discussed in the sections above,
`
`claims 67, 71, and 72 are nonobvious over the cited references.
`
`Thus, Applicants respectfully submit that claims of the present application are
`
`nonobvious over Desai and Shively, and request that the rejection of claims 66-68 and 70-78 over
`
`Desai and Shively be withdrawn.
`
`Desai in view of Shively, further in view of Klein
`
`Claims 66-68 and 70-78 stand rejected under 35 U.S.C. § 103(a) as allegedly being
`
`unpatentable over Desai in view of Shively as applied to claims 66-68 and 70-77 and further in view
`
`pa-1400734
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`Actavis - IPR2017-01100, Ex. 1018, p. 8 of 14
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`Application No.: 111520,479
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`9
`
`Docket No.: 638772000109
`
`of Klein et al. ("Klein," U.S. Patent number 5,440,056). Applicants respectfully traverse this
`
`rejection.
`
`As discussed above, neither Shively nor Desai teaches or suggests an albumin-based
`
`nanoparticle formulation of paclitaxel at a concentration between 5 mg/ml and 15 mg/ml, much less
`
`to achieve such concentrations without compromising the stability of the paclitaxel particles.
`
`Furthermore, even assuming that one of ordinary skill in the art reading Desai and Shively would be
`
`motivated to attempt to make a paclitaxel nanoparticle formulation at the concentration of 5 mg/ml,
`
`there is no teaching or reasonable expectation that an albumin-based nanoparticle formulation of
`
`paclitaxel at a concentration of 5 mg/ml, much less at a concentration higher than 5 mg/ml, would
`
`be stable in an aqueous suspension.
`
`Klein does not cure the deficiencies of Desai and Shively. Specifically, Klein teaches
`
`analogs of paclitaxel. It neither teaches nor suggests a pharmaceutical composition recited in the
`
`claims of the present application.
`
`Based solely on a boilerplate paragraph in Klein, which allegedly teaches that slow
`
`absorption of a drug "may be accomplished by the use of a liquid suspension of crystalline or
`
`amorphous material with poor water solubility," the Examiner concludes that "[i]t would have been
`
`obvious to one of ordinary skill in the art at the time the invention was made to utilize the
`
`amorphous form in addition to the crystalline form of taxol in the invention of Desai." The
`
`Examiner states that "[t]here would be a reasonable expectation of success since combining two
`
`components which are taught in the art for the same purpose to arrive at a third composition useful
`
`for the same purpose is obvious." Applicants respectfully disagree.
`
`Nowhere does Klein teach how an amorphous form of paclitaxel can be incorporated
`
`into an albumin/paclitaxel nanoparticle composition, much less an albumin/paclitaxel nanoparticle
`
`composition that is stable for at least three days. It is not even clear from Klein whether it is
`
`desirable to make a crystalline form of paclitaxel or an amorphous form of paclitaxel in order to
`
`pa-1400734
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`Application No.: 111520,479
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`10
`
`Docket No.: 638772000109
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`slow absorption of the drug. Thus, Applicants respectfully submit that the Examiner has failed to
`
`establish that claims of the present application are obvious in view of Desai, Shively, and Klein.
`
`Accordingly, Applicants respectfully submit that claims of the present application are
`
`nonobvious over Desai, Shively, and Klein, and request that rejection of claims 66-68 and 70-78
`
`under 35 U.S.C. § 103(a) be withdrawn.
`
`Double Patenting
`
`Claims 66-68 and 70-78 stand rejected on the ground of nonstatutory obviousness-type
`
`double patenting as allegedly being unpatentable over U.S. Patent No. 6,537,579 (claims 1-53);
`
`5,362,478 (claims 1-16); 5,498,421 (claims 1-30); 5,505,932 (claims 1-36); 5,508,021 (claims 1-
`
`23); 5,512,268 (claims 1-37); 5,635,207 (claims 1-44); 5,639,473 (claims 1-26); 5,650,156 (claims
`
`1-9); 5,665,382 (claims 1-11); 5,665,383 (claims 1-9); 5,916,596 (claims 1-31); 5,560,933 (claims
`
`1-28) and 5,439,686 (claims 1-17) in view of Desai et al., Shively and Klein et al. Applicants
`
`respectfully traverse this rejection.
`
`As discussed above, neither Shively nor Desai teaches or suggests an albumin-based
`
`nanoparticle formulation of paclitaxel at a concentration between 5 mg/ml and 15 mg/ml, much less
`
`to achieve such concentration without compromising the stability of the paclitaxel particles.
`
`Furthermore, even assuming that one of ordinary skill in the art reading Desai and Shively would be
`
`motivated to attempt to make a paclitaxel nanoparticle formulation at the concentration of 5 mg/ml,
`
`there is no teaching or reasonable expectation that an albumin-based nanoparticle formulation of
`
`paclitaxel at a concentration of 5 mg/ml, much less at a concentration higher than 5 mg/ml, would
`
`be stable in an aqueous suspension.
`
`Accordingly, Applicants respectfully request that the nonstatutory obviousness-type
`
`double patenting rejection be withdrawn.
`
`pa-1400734
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`Actavis - IPR2017-01100, Ex. 1018, p. 10 of 14
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`

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`Application No.: 111520,479
`
`11
`
`Docket No.: 638772000109
`
`CONCLUSION
`
`In view of the above, each of the presently pending claims in this application is believed
`
`to be in immediate condition for allowance. Accordingly, the Examiner is respectfully requested to
`
`withdraw the outstanding rejection of the claims and to pass this application to issue. If it is
`
`determined that a telephone conference would expedite the prosecution of this application, the
`
`Examiner is invited to telephone the undersigned at the number given below.
`
`In the event the U.S. Patent and Trademark Office determines that an extension and/or
`
`other relief is required, applicants petition for any required relief including extensions of time and
`
`authorizes the Commissioner to charge the cost of such petitions and/or other fees due in connection
`
`with the filing of this document to Deposit Account No. 03-1952 referencing docket no.
`
`638772000109. However, the Commissioner is not authorized to charge the cost of the issue fee to
`
`the Deposit Account.
`
`Dated: September 30, 2010
`
`Respectfully submitted,
`
`Electronic signature: /Jian Xiao/
`Jian Xiao
`Registration No.: 55,748
`MORRISON & FOERSTER LLP
`755 Page Mill Road
`Palo Alto, California 94304-1018
`(650) 813-5736
`
`pa-1400734
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`

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`EXHIBIT
`EXHIBIT
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`pa-1400734
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`Actavis - IPR2017-01100, Ex. 1018, p. 12 of 14
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`Actavis - IPR2017-01100, Ex. 1018, p. 12 of 14
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`

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`Comparison of physicochemical characteristics and stability ofthree novel formulations o... Page 1 of2
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`Proffered Abstracts
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`Abstract #5622
`
`Comparison of physicochemical
`characteristics and stability of three novel
`formulations of paclitaxel: Abraxane,
`Nanoxel, and Genexol PM
`
`[advanced]
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`Author:
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`• Articles by Ron, N.
`~ Articles by Desai, N.
`
`Niles Ron, Jon Cordia, Andrew Yang, Sherry Ci, Phithi Nguyen, Melissa Hughs and Neil Desai
`
`Abraxis Bioscience, Inc., Los Angeles, CA
`
`Background: Abraxane (Abraxis BioScience, Inc., Los Angeles, CA, approved in USA and Canada),
`Nanoxel (Dabur Pharma, H.P., India, approved in India), and Genexol PM (Samyang Pharmaceuticals,
`Seoul, Korea, approved in Korea) are 3 commercially approved, novel formulations ofpaclitaxel.
`Abraxane consists of albumin-bound injectable nanoparticles ofpaclitaxel, while Genexol and Nanoxel
`(utilizing cosolvents) are polymeric-micelle formulations. Abraxane and Genexol are lyophilized products
`approved for 25°C ± 2°C storage, while Nanoxel is a liquid formulation approved for 2-8°C storage. This
`study investigated the physicochemical characteristics and short-term stability of the 3 products under
`recommended clinical use conditions and under accelerated conditions.
`Methods: The drugs were reconstituted and prepared per the instructions provided in the respective
`package inserts. Abraxane and Genexol were reconstituted using the recommended saline diluent, while
`Nanoxel was mixed and diluted in 10% dextrose. Each drug was reconstituted to 0. 7 mg/mL and 5
`mg/mL. Physical stability was monitored both visually and microscopically; particle size was measured
`and monitored over time at room temperature (RT, measured to be 23°C) and 40°C using photon
`correlation spectroscopy (PCS) (Zetasizer 3000, Malvern, UK). Chemical purity was measured by reduced
`reversed-phase HPLC (Shimadzu Scientific Instruments, MD).
`Results: Following reconstitution, Abraxane was determined to be stable both physically and chemically
`at RT and 40°C over 24 hrs, with no evidence ofnanoparticle size growth at either 0.7 mg/mL or 5
`mg/mL. While reconstituted Genexol was stable at R T over 24 hrs, micelle instability resulting in
`
`http://www.aacrmeetingabstracts.org/cgi/contentlmeeting_ abstract/2008/1_ Annual_ Meetin... 9/30/2010
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`Actavis - IPR2017-01100, Ex. 1018, p. 13 of 14
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`

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`Comparison of physicochemical characteristics and stability of three novel formulations o. .. Page 2 of 2
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`precipitation of paclitaxel in the form of large needle-like crystals for both 0.7 mg/mL and 5 mg/mL
`formulations was seen between 2 to 4 hrs at 40°C. These observations were confirmed using orthogonal
`techniques, visual assessment from photomicrographs, and PCS particle size measurement. For Nanoxel at
`0.7 mg/mL, a minor, but consistent, increase in particle size was observed at RT over 24 hrs. However,
`significant aggregation, particle-size growth, and crystallization were seen within 4 hrs at 40°C. HPLC
`data comparing pre- and post-filtration confirmed that the crystal formation for both Nanoxel and Genexol
`resulted from paclitaxel precipitation and aggregation. In addition, analytical results showed that Nanoxel
`had slightly lower paclitaxel purity as compared to either Abraxane or Genexol.
`Conclusions: Nanoparticle albumin-bound paclitaxel, Abraxane, showed excellent physicochemical
`stability as compared to the micellar formulations, Nanoxel and Genexol. Particle size growth and crystal
`formation were readily apparent in Nanoxel and Genexol, especially in the short term under accelerated
`conditions.
`
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`Articles by Desai, N.
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`http:/ /www.aacrmeetingabstracts.org/cgi/content/meeting_ abstract/2008/1_ Annual_ Meetin. .. 9/30/2010
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`Actavis - IPR2017-01100, Ex. 1018, p. 14 of 14
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