I hereby certify that this paper is being transmitted via the Office electronic filing
`system in accordance with § t . 6( a) ( 4).
`
`Dated: November t, 20t3 Signature: /Krista Chaffin-Pennv/
`(Krista Chaffin-Penny)
`
`Docket No.: 638772000109
`(PATENT)
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re Patent Application of:
`Neil P. DESAI et al.
`
`Application No.: 11/520,479
`
`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 Madam:
`
`INTRODUCTORY COMMENTS
`
`This is in response to the non-final Office Action dated May 2, 2013 (Paper No.
`
`20130429), for which a response was due on August 2, 2013. Filed herewith is a Petition and fee
`
`for a three months extension of time, thereby extending the deadline for response to November 2,
`
`2013. 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.
`
`Claims are reflected in the listing of claims which begins on page 2 of this paper.
`
`Remarks/Arguments begin on page 6 of this paper.
`
`pa-1613114
`
`Actavis - IPR2017-01100, Ex. 1023, p. 1 of 16
`
`

`

`Application No.: 11/520,479
`
`2
`
`Docket No.: 638772000109
`
`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 (Currently amended):
`
`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 a solid core of paclitaxel and an albumin coating,
`
`and wherein the size of the nanoparticles in the composition formulation is less than 400 nm.
`
`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.
`
`pa-1613114
`
`Actavis - IPR2017-01100, Ex. 1023, p. 2 of 16
`
`

`

`Application No.: 11/520,479
`
`3
`
`Docket No.: 638772000109
`
`Claim 72 (Previously presented):
`
`The pharmaceutical formulation of claim 66, 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 (Cancelled).
`
`Claim 74 (Previously presented):
`
`The pharmaceutical formulation of claim 66, wherein the solid
`
`core is substantially free of polymeric material.
`
`Claim 75 (Previously presented):
`
`The pharmaceutical formulation of claim 66, 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 66, wherein at least a
`
`portion of the albumin is crosslinked by disulfide bonds.
`
`Claim 77 (Previously presented):
`
`The pharmaceutical formulation of claim 66, wherein the
`
`paclitaxel is substantially amorphous.
`
`Claim 78 (Previously presented):
`
`The pharmaceutical formulation of claim 66, wherein the
`
`paclitaxel is substantially crystalline.
`
`Claim 79 (Withdrawn):
`
`A method of treatment, comprising administering an effective amount
`
`of the composition of claim 66 to a patient to treat a tumor.
`
`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.
`
`pa-1613114
`
`Actavis - IPR2017-01100, Ex. 1023, p. 3 of 16
`
`

`

`Application No.: 11/520,479
`
`4
`
`Docket No.: 638772000109
`
`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 66 to a patient to treat breast cancer.
`
`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.
`
`Claim 85 (Previously presented):
`
`The pharmaceutical formulation of claim 66, wherein the
`
`average diameter of the nanoparticles is no greater than about 200 nm.
`
`Claim 86 (Previously presented):
`
`The pharmaceutical formulation of claim 67, wherein the
`
`average diameter of the nanoparticles is no greater than about 200 nm.
`
`Claim 87 (Previously presented):
`
`The pharmaceutical formulation of claim 68, wherein the
`
`average diameter of the nanoparticles is no greater than about 200 nm.
`
`Claim 88 (Previously presented):
`
`The pharmaceutical formulation of claim 7 4, wherein the
`
`average diameter of the nanoparticles is no greater than about 200 nm.
`
`Claim 89 (Previously presented):
`
`The pharmaceutical formulation of claim 77, wherein the
`
`average diameter of the nanoparticles is no greater than about 200 nm.
`
`pa-1613114
`
`Actavis - IPR2017-01100, Ex. 1023, p. 4 of 16
`
`

`

`Application No.: 11/520,479
`
`5
`
`Docket No.: 638772000109
`
`Claim 90 (Previously presented):
`
`The pharmaceutical formulation of claim 66, wherein the
`
`albumin is human albumin.
`
`Claim 91 (Previously presented):
`
`The pharmaceutical formulation of claim 67, wherein the
`
`albumin is human albumin.
`
`Claim 92 (Previously presented):
`
`The pharmaceutical formulation of claim 68, wherein the
`
`albumin is human albumin.
`
`Claim 93 (Previously presented):
`
`The pharmaceutical formulation of claim 7 4, wherein the
`
`albumin is human albumin.
`
`Claim 94 (Previously presented):
`
`The pharmaceutical formulation of claim 77, wherein the
`
`albumin is human albumin.
`
`pa-1613114
`
`Actavis - IPR2017-01100, Ex. 1023, p. 5 of 16
`
`

`

`Application No.: 11/520,479
`
`6
`
`Docket No.: 638772000109
`
`REMARKS
`
`Claims 66-68, 70-72, and 74-94 were pending in the present application. Claims 79-84
`
`were withdrawn. By this amendment, claim 66 is amended to correct antecedent basis. No new
`
`matter is added. Upon entry of the present amendment, claims 66-68, 70-72, 74-78, and 85-94 are
`
`under consideration.
`
`With respect to claim amendments and cancellation, Applicants have not dedicated or
`
`abandoned any unclaimed subject matter and moreover have not acquiesced to any rejections and/or
`
`objections made by the Patent Office. Applicants expressly reserve the right to pursue prosecution
`
`of any presently excluded subject matter or claim embodiments in one or more future continuation
`
`and/or divisional application(s).
`
`Summary of Interview
`
`Applicants thank Examiner Love for the courtesy in conducting the videoconference
`
`interview with inventor Dr. Neil Desai, Applicants' representatives Catherine Polizzi and Jian Xiao,
`
`and Dr. Carla Kuhner from Celgene Corporation on September 25, 2013. The guidance provided by
`
`the Examiner during the interview is greatly appreciated.
`
`During the interview, Dr. Desai clarified several aspects of the invention, and identified
`
`several differences by which instant claims distinguish over the cited references. Discussion was
`
`further made as to the possibility of submitting additional evidence of non-obviousness.
`
`Information Disclosure Statement
`
`Applicants hereby submit a Supplemental Information Disclosure Statement and
`
`respectfully request that the references submitted therein be considered and entered into record.
`
`pa-1613114
`
`Actavis - IPR2017-01100, Ex. 1023, p. 6 of 16
`
`

`

`Application No.: 11/520,479
`
`7
`
`Docket No.: 638772000109
`
`Claim Rejections- 35 USC§ 103
`
`Desai in view of Shively
`
`Claims 66-68,70-72,74-77, and 85-94 stand rejected under 35 U.S.C. § 103(a) as
`
`allegedly being unpatentable over Desai et al. (U.S. Patent No. 5,439,686, "Desai") in view of
`
`Shively (U.S. Patent No. 5,407,683, "Shively). Applicants respectfully traverse this rejection for
`
`reasons of record.
`
`Claim 66 as amended recites "[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
`
`a solid core of paclitaxel and an albumin coating, and wherein the size of the nanoparticles in the
`
`formulation is less than 400 nm." Applicants respectfully submit that the cited references do not
`
`render claim 66 and its dependent claims obvious.
`
`Applicants hereby submit a Supplemental Declaration under 37 C.P.R. § 1.132 by Dr.
`
`Neil Desai (hereinafter referred to as "the Supplemental Declaration"), which supplements the
`
`declaration previously submitted to the Office on January 27, 2012 ("the Previous Declaration").
`
`These two declarations are collectively referred to as "the Desai Declarations." As discussed in the
`
`Desai Declarations and below, it is unpredictable based on the teaching of either Desai or Shively
`
`whether a solid nanoparticle formulation of paclitaxel would be stable at 5 mg/ml or higher.
`
`Furthermore, the albumin-coated solid nanoparticle formulations recited in the present claims show
`
`unexpected stability. In view of the unpredictability about the stability of solid nanoparticle
`
`formulations of paclitaxel at 5 mg/ml or higher, and the unexpected stability of the nanoparticle
`
`formulations recited in the amended claims, Applicants respectfully submit that the claimed
`
`nanoparticle formulations are non-obvious over the cited references.
`
`pa-1613114
`
`Actavis - IPR2017-01100, Ex. 1023, p. 7 of 16
`
`

`

`Application No.: 11/520,479
`
`8
`
`Docket No.: 638772000109
`
`It is unpredictable based on the teaching of either Desai or Shively whether a solid nanoparticle
`formulation of paclitaxel would be stable at 5 mg/ml or higher
`
`In finding claims of the present application obvious, the Examiner reasons that Desai
`
`teaches stable albumin-coated nanoparticle formulations, and that a higher loading of paclitaxel can
`
`be achieved by utilizing an additional solvent such as ethyl acetate. Page 4 of the Office Action.
`
`While acknowledging that Desai fails to teach a nanoparticle formulation at paclitaxel concentration
`
`of 5 mg/ml to 15 mg/ml as presently claimed, the Examiner relies on Shively as allegedly teaching
`
`that 5 mg/ml is a therapeutically effective amount. Page 4 of the Office Action. The Examiner thus
`
`concludes that it would have been obvious for one of ordinary skill in the art "to utilize 5 mg/ml of
`
`[paclitaxel] in the invention of Desai." Page 5 of the Office Action. The Examiner reasons that
`
`"[t]here would be a reasonable expectation of success since Desai teaches how to achieve higher
`
`amounts of [paclitaxel], and [Shively] teaches the amount (5 mg/ml) one would desire." Page 5 of
`
`the Office Action. Applicants respectfully disagree.
`
`As discussed in the Previous Declaration, Shively teaches nothing about paclitaxel in the
`form of solid nanoparticles. 1 Rather, Shively's teaching pertains to emulsions which involve
`
`different stability considerations than the solid nanoparticle formulations recited in the present
`
`claims? The Examiner himself has acknowledged in the Office Action that Shively "is relied upon
`
`for the teaching of the preferred therapeutic amount of [paclitaxel] .... " Page 8 of the Office Action.
`
`Applicants further respectfully submit that Desai does not teach or suggest the solid
`
`nanoparticle formulations recited in the present claims. As explained in the Desai Declarations,
`
`Example 5 of Desai, which the Examiner relies on as teaching stability of albumin-coated
`
`nanoparticle formulations, refers to the stability of polymeric shells containing buoyant soybean oil
`with density less than water. No drug was present within the polymeric shell. 3 As stated in the
`
`Supplemental Declaration, the stability of the "drugless" oil-containing polymeric shells discussed
`
`in Example 5 of Desai provides no suggestion that a nanoparticle formulation comprising a solid
`
`1 Paragraph 8 of the Previous Declaration.
`2 Paragraph 9 of the Previous Declaration.
`
`pa-1613114
`
`Actavis - IPR2017-01100, Ex. 1023, p. 8 of 16
`
`

`

`Application No.: 11/520,479
`
`9
`
`Docket No.: 638772000109
`
`core of paclitaxel and an albumin coating would be stable at paclitaxel concentration of between 5
`mg/ml and 15 mg/ml. 4 Furthermore, as stated in the Supplemental Declaration, although Example 9
`
`of Desai teaches preparation of polymeric shells containing a solid core of pharmaceutically active
`
`agents such as paclitaxel, there is no information about the concentration of paclitaxel in such
`
`polymeric shell formulation, and a substantial portion of the particles in the formulation taught in
`Example 9 are larger than 400 nm. 5 Thus, the formulations taught in Desai differ from the
`
`formulation recited in the present claims in at least two aspects: paclitaxel concentration and particle
`
`size. As discussed further below, both of these differences have significant stability implications
`
`with respect to expectation and unpredictability.
`
`As explained in the Supplemental Declaration, to arrive at the claimed formulation from
`
`Desai's nanoparticle formulations, one would at least need to: 1) substantially decrease the size of
`
`the particles in the formulation to less than 400 nm; and 2) substantially increase the paclitaxel
`concentration to 5-15 mg/ml.6 According to Dr. Desai, Desai provides no teaching on how to obtain
`a nanoparticle formulation having a particle size of less than 400 nm. 7 Furthermore, according to
`
`Dr. Desai, the estimated particle concentration of an albumin-coated paclitaxel nanoparticle
`
`formulation having a particle size less than 400 nm at paclitaxel concentration of 5 mg/ml is 1000
`
`fold higher than those reported in Desai. Since the aggregation rate of nanoparticles is proportional
`
`to the square of the particle concentration, Dr. Desai concludes that one would not have expected
`
`that the claimed formulation, whose particle concentration is at least 1000 fold higher than those
`reported in Desai, would be stable. 8
`
`Thus, neither Shively nor Desai teaches or suggests the albumin-coated solid paclitaxel
`
`nanoparticle formulations as presently claimed, and it is unpredictable based on the teaching of
`
`3 Paragraph 10 of the Previous Declaration; Paragraph 13 of the Supplemental Declaration.
`4 Paragraph 13 of the Supplemental Declaration.
`5 Paragraph 14 of the Supplemental Declaration.
`6 Paragraph 15 of the Supplemental Declaration.
`7 Paragraph 15 of the Supplemental Declaration.
`8 Paragraph 15 of the Supplemental Declaration.
`
`pa-1613114
`
`Actavis - IPR2017-01100, Ex. 1023, p. 9 of 16
`
`

`

`Application No.: 11/520,479
`
`10
`
`Docket No.: 638772000109
`
`either Desai or Shively whether a solid nanoparticle formulation of paclitaxel would be stable at 5
`
`mg/ml or higher.
`
`The albumin-coated solid nanoparticle formulations recited in the present claims show unexpected
`
`stability
`
`Applicants further respectfully submit that the nanoparticle formulations recited in the
`
`amended claims show unexpected stability as demonstrated in the present application as well as in
`
`subsequent studies. Such unexpected stability further supports non-obviousness.
`
`Specifically, as stated in the Previous Declaration, Example 37 of the present application
`
`has shown, unexpectedly, that a pharmaceutical formulation with nanoparticles having a size less
`
`than 400 nm and having a solid core of paclitaxel and an albumin coating can be reconstituted to a
`
`paclitaxel concentration between 5 mg/ml and 15 mg/ml without compromising the stability of the
`formulation. 9
`
`In the Desai Declarations, Dr. Desai further presents data from a subsequent experiment
`
`which compared the physical stability of two pharmaceutical formulations containing nanoparticles
`
`comprising a solid core of paclitaxel and an albumin coating, namely, Composition 1 and
`Composition 2. 1° Composition 1 contains no detectable percentage of nanoparticles that have a size
`above 400 nm with 99% of the particles lying below 282 nm. Composition 2 contains at least 10%
`
`of the nanoparticles having a particle size that was above 400 nm with 99% of the particles lying
`below 633 (Lot 1) and 638 nm (Lot 2). 11 As noted in the Supplemental Declaration, although both
`
`Composition 1 and Composition 2 are albumin-coated paclitaxel nanoparticle formulations having a
`particle size below 1000 nm, they behave differently in stability assays. 12 Composition 1, which
`
`contains no detectable percentage of nanoparticles that have a size above 400 nm, was shown to be
`
`9 Paragraph 14 of the Previous Declaration.
`10 Paragraphs 15-18 of the Previous Declaration; paragraphs 3-6 of the Supplemental Declaration.
`11 Paragraph 15 of the Previous Declaration; Paragraphs 6-7 of the Supplemental Declaration.
`12 Paragraph 8 of the Supplemental Declaration.
`
`pa-1613114
`
`Actavis - IPR2017-01100, Ex. 1023, p. 10 of 16
`
`

`

`Application No.: 11/520,479
`
`11
`
`Docket No.: 638772000109
`
`stable at paclitaxel concentration of 5 mg/ml. By contrast, Composition 2, which contains
`
`nanoparticles slightly greater than 400 nm, was unstable at the same paclitaxel concentration under
`the same conditions. According to Dr. Desai, such result was unexpected. 13
`
`Further, as explained by Dr. Desai, the estimated particle concentration for Composition
`
`1 discussed above, namely, the albumin-coated solid paclitaxel nanoparticle formulation having a
`particle size less than 400 nm at paclitaxel concentration of 5 mg/ml, is about 8.0 x 1013/ml. 14 As
`
`the aggregation rate of particles is proportional to the square of the particle concentration, the
`
`stability of such a formulation at 5 mg/ml or higher is unexpected based on the high particle
`concentration, particularly with reference to the particle concentration reported in Desai. 15
`
`Moreover, according to Dr. Desai, the stability of albumin-coated nanoparticle
`
`formulation having particle size less than 400 nm is also in stark contrast with that of a different
`
`non-albumin based paclitaxel nanoparticle formulation having particle size less than 400 nm,
`
`namely, Genexol-PM®, which in a comparative study with Abraxane® (an albumin-coated solid
`
`paclitaxel nanoparticle formulation having particle size less than 400 nm) was shown to be unstable
`under the same condition at 5 mg/ml. 16 See Ron et al. (Exhibit 6 of the Supplemental Declaration).
`
`As stated in the Supplemental Declaration, the study reported in Ron et al. further illustrates the
`
`difficulty and challenge in obtaining paclitaxel nanoparticle formulations having particle size less
`
`than 400 that are stable at paclitaxel concentration of 5 mg/ml or higher, and the unexpected
`stability of the claimed albumin-coated solid nanoparticle formulation. 17
`
`In summary, in view of the increased tendency of nanoparticle formulations to
`
`precipitate and increase in size (for example by aggregation) as the drug concentration increases, it
`
`was unexpected that a pharmaceutical formulation comprising nanoparticles having a size of less
`
`than 400 nm and comprising a solid core of paclitaxel and an albumin coating can be reconstituted
`
`13 Paragraph 8 of the Supplemental Declaration.
`14 Paragraph l 0 of the Supplemental Declaration.
`15 Paragraphs lO and 15 of the Supplemental Declaration.
`16 Paragraph ll of the Supplemental Declaration.
`17 Paragraph ll of the Supplemental Declaration.
`
`pa-1613114
`
`Actavis - IPR2017-01100, Ex. 1023, p. 11 of 16
`
`

`

`Application No.: 11/520,479
`
`12
`
`Docket No.: 638772000109
`
`to a paclitaxel concentration between 5 mg/ml and 15 mg/ml without compromising the stability of
`
`the formulation. As explained in the Supplemental Declaration, the unexpected stability of the
`
`claimed formulation is in stark contrast with an albumin-coated paclitaxel nanoparticle formulation
`
`which contains particles slightly greater than 400 nm, and a non-albumin based paclitaxel
`
`nanoparticle formulation having particle size less than 400 nm, both shown to be unstable under the
`same conditions at paclitaxel concentration of 5 mg/ml. 18 According to Dr. Desai, these results
`
`demonstrate the advantageous and unexpected stability of albumin-coated paclitaxel nanoparticle
`
`formulation recited in the claims, especially in view of the high particle concentration in such a
`
`formulation and the well-known principle that the aggregation rate of nanoparticles is proportional
`to the square of the particle concentration. 19
`
`Applicants thus respectfully submit that the unexpected and advantageous stability of the
`
`formulation recited in the present claims provides further evidence of non-obviousness.
`
`Response to various statements made by the Examiner
`
`The Examiner relies on Example 4 of Desai as allegedly teaching methods of obtaining
`
`"higher loading of drug," and reasons that such statement provides means and motivation to
`
`increase drug concentration in Desai's formulation. Pages 4 and 5 of the Office Action. Applicants
`
`respectfully disagree. As discussed in the Desai Declarations, an increase in loading of paclitaxel
`
`within the polymeric shells as taught in Example 4 of Desai would be expected to increase the
`
`particle size and/or density of the particles, which in tum could increase the tendency of the
`particles to precipitate. 2° Furthermore, as discussed in the Supplemental Declaration, since the
`particle concentration in the albumin-coated paclitaxel nanoparticle formulation having a particle
`
`size less than 400 nm at paclitaxel concentration of 5 mg/ml is 1000 fold higher than those reported
`
`in Desai, and the aggregation rate of nanoparticles is proportional to the square of the particle
`
`concentration, one would not have expected that the albumin-coated paclitaxel nanoparticle
`
`18 Paragraph 12 of the Supplemental Declaration.
`19 Paragraph 12 of the Supplemental Declaration.
`20 Paragraph 11 of the Previous Declaration; Paragraph 13 of the Supplemental Declaration.
`
`pa-1613114
`
`Actavis - IPR2017-01100, Ex. 1023, p. 12 of 16
`
`

`

`Application No.: 11/520,479
`
`13
`
`Docket No.: 638772000109
`
`formulation having a particle size less than 400 nm at paclitaxel concentration of 5 mg/ml would be
`stable?1 Thus, even assuming a person of ordinary skill in the art would be motivated to increase
`
`the loading of the drug concentration in Desai's formulation to arrive at the nanoparticle
`
`formulation recited in the present claims, one would not have expected that such formulation would
`
`be stable.
`
`The Examiner states that "the composition of Desai in view of Shively is the same as the
`
`instant composition. Therefore, since the composition is the same, the features are also necessarily
`
`present." Page 8 of the Office Action. Applicants respectfully disagree. As discussed above and in
`
`the Supplemental Declaration, the formulations taught in Desai differ from the formulation recited
`in the present claims in at least two aspects: paclitaxel concentration and particle size. 22 Even
`
`assuming that a personal of ordinary skill in the art would have been motivated to combine the
`
`teachings of Desai and Shively, the resultant formulation would contain particles larger than 400
`
`nm, which as discussed above would be unstable. See results with Composition 2 discussed above.
`
`The Examiner dismissed evidence of unexpected results presented in the Previous
`
`Declaration. Page 9 of the Office Action. As discussed above, the results presented in the Desai
`
`Declarations show the stark contrast between an albumin-coated paclitaxel nanoparticle formulation
`
`having particle size less than 400 nm, which was stable, and an albumin-coated paclitaxel
`
`nanoparticle formulation which contains particles slightly greater than 400 nm, which was unstable.
`
`This demonstrates the advantageous and unexpected stability of the albumin-coated paclitaxel
`
`nanoparticle formulation recited in the present claims, especially in view of the expected high
`
`particle concentration in such a formulation and the well-known principle that the aggregation rate
`
`of nanoparticles is proportional to the square of the particle concentration.
`
`The Examiner dismissed Ron et al., previously submitted by Applicants in the response
`
`to Office Action dated September 30, 2010. Page 7 of the Office Action. As discussed above, Ron
`
`et al. shows that, unlike the albumin-coated paclitaxel nanoparticle formulation having particle size
`
`21 Paragraph 15 of the Supplemental Declaration.
`
`pa-1613114
`
`Actavis - IPR2017-01100, Ex. 1023, p. 13 of 16
`
`

`

`Application No.: 11/520,479
`
`14
`
`Docket No.: 638772000109
`
`less than 400 nm, a non-albumin based paclitaxel nanoparticle formulation having particle size less
`
`than 400 nm was unstable under the same conditions at paclitaxel concentration of 5 mg/ml.
`
`According to Dr. Desai, this study further illustrates the difficulty and challenge in obtaining
`
`paclitaxel nanoparticle formulations having particle size less than 400 nm that are stable at
`
`paclitaxel concentration of 5 mg/ml or higher, and the unexpected stability of the claimed albumin(cid:173)
`coated solid nanoparticle formulation. 23
`
`In summary, it is unpredictable based on the teaching of either Desai or Shively whether
`
`a solid nanoparticle formulation of paclitaxel would be stable at 5 mg/ml or higher. The albumin(cid:173)
`
`coated solid nanoparticle formulations recited in the present claims show unexpected stability. In
`
`view of the foregoing, Applicants respectfully submit that claims of the present application are non(cid:173)
`
`obvious over Desai and Shively, and respectfully request that the rejection of claims 66-68, 70-72,
`
`74-77, and 85-94 over Desai and Shively be withdrawn.
`
`Desai in view of Shively, further in view of Klein
`
`Claim 78 stands rejected under 35 U.S.C. § 103(a) as allegedly being unpatentable over
`
`Desai in view of Shively as applied to 66-68,70-72,74-77, and 85-94, and further in view of Klein
`
`et al. (U.S. Patent No. 5,440,056, "Klein"). Applicants respectfully traverse this rejection.
`
`Shively and Desai are discussed above. As discussed above, it is unpredictable based on
`
`the teaching of either Desai or Shively whether a solid nanoparticle formulation of paclitaxel would
`
`be stable at 5 mg/ml or higher. The albumin-coated solid nanoparticle formulations recited in the
`
`present claims show unexpected stability. Applicants thus respectfully submit that the claimed
`
`nanoparticle formulations are non-obvious over the cited references.
`
`Klein does not cure the deficiencies of Desai and Shively. Specifically, Klein is cited as
`
`allegedly teaching an amorphous form of paclitaxel. It neither teaches nor suggests the claimed
`
`22 Paragraph 14 of the Supplemental Declaration.
`23 Paragraph 11 of the Supplemental Declaration.
`
`pa-1613114
`
`Actavis - IPR2017-01100, Ex. 1023, p. 14 of 16
`
`

`

`Application No.: 11/520,479
`
`15
`
`Docket No.: 638772000109
`
`nanoparticle formulation. Nor does Klein teach how an amorphous form of paclitaxel can be
`
`incorporated into an albumin/paclitaxel nanoparticle formulation, much less an albumin/paclitaxel
`
`nanoparticle formulation that is stable at paclitaxel concentration of between 5 mg/ml and 15
`
`mg/ml.
`
`Accordingly, Applicants respectfully submit that claim 78 of the present application is
`
`non-obvious over Desai, Shively, and Klein, and request that the rejection of claims 66-68 and 70-
`
`78 under 35 U.S.C. §103(a) be withdrawn.
`
`Double Patenting
`
`Claims 66-68, 70-72, 7 4-78, and 85-94 are 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-ll); 5,665,383 (claims 1-9); 5,916,596 (claims 1-31);
`
`5,560,933 (claims 1-28); and5,439,686 (claims 1-17) in view of Desai, Shively, and Klein.
`
`Applicants respectfully traverse this rejection.
`
`The non-obviousness of the claimed invention has been discussed above, including
`
`Shively, Desai, and Klein. Applicants respectfully submit that the claims are patentably distinct
`
`over the cited claims.
`
`Accordingly, Applicants respectfully request that the nonstatutory obviousness-type
`
`double patenting rejections against claims 66-68, 70-72, 7 4-78, and 85-94 be withdrawn.
`
`pa-1613114
`
`Actavis - IPR2017-01100, Ex. 1023, p. 15 of 16
`
`

`

`Application No.: 11/520,479
`
`16
`
`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: November 1, 2013
`
`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-1613114
`
`Actavis - IPR2017-01100, Ex. 1023, p. 16 of 16
`
`