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`Application Number
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`11/553,339
`
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`N
`ame
`Irst
`Art Unit
`
`dl
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`nventor
`
`Examiner Name
`
`Attorne Docket Number
`
`October 26, 2006
`N -| P DESAI
`6|
`-
`1656
`
`M. Tsay
`
`638772000301
`
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`SIGNATURE OF APPLICANT, ATTORNEY, OR AGENT REQUIRED
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`Signature
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`/Jian Xiao/
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`
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`April 145 2010
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`Registration No.
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`pa-1399413
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`

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`Docket No.: 638772000301
`
`(PATENT)
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re Patent Application of:
`Neil P. DESAI et al.
`
`Application No.: 11/553,339
`
`Confirmation No.: 3605
`
`Filed: October 26, 2006
`
`Art Unit: 1656
`
`For: COMPOSITIONS AND METHODS OF
`DELIVERY OF PHARMACOLOGICAL
`
`Examiner: M. Tsay
`
`AGENTS
`
`AMENDMENT AFTER FINAL ACTION UNDER 37 C.F.R. 1.116
`
`MS RCE
`
`Commissioner for Patents
`
`PO. Box 1450
`
`Alexandria, VA 22313— 1450
`
`Dear Sir:
`
`INTRODUCTORY COMMENTS
`
`This response accompanies a Request for Continued Examination. 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 due 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 April 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 4 of this paper.
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`Application No.: 11/553,339
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`2
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`Docket No.: 638772000301
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`AMENDMENTS TO THE CLAIMS
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`This listing of claims will replace all prior versions, and listings of claims in the
`
`application:
`
`Claim 1 (cancelled)
`
`Claim 2 (currently Amended): A pharmaceutical composition for injection comprising
`
`paclitaxel a—pharmaeeutieal—agent and a pharmaceutically acceptable carrier, wherein the
`
`pharmaceutically acceptable carrier comprises albumin, wherein the albumin and the
`
`pharmaceutical—agent paclitaxel in the composition are formulated as nanoparticles, wherein the
`
`nanoparticles have a particle size of less than about 200 nm, and wherein the weight ratio of
`
`albumin to pharmaceutical—agent paclitaxel in the composition is about 1:1 to about 9:1.
`
`Claim 3 (cancelled).
`
`Claim 4 (original): The pharmaceutical composition 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 (withdrawn): A method of treating a disease comprising
`
`administering an effective amount of a pharmaceutical composition of claim 2.
`
`Claim 15 (withdrawn): The method of claim 14, wherein the disease is
`
`CEII’ICCI'.
`
`arthritis .
`
`Claim 16 (withdrawn): The method of claim 14, wherein the disease is
`
`Claim 17 (withdrawn): The method of claim 14, wherein the disease is
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`cardiovascular disease.
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`3
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`Docket No.: 638772000301
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`Claim 18 (withdrawn): The method of claim 17, wherein the disease is
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`restenosis.
`
`Claim 19 (withdrawn): The method of claim 14, wherein the composition
`
`is administered intravenously, intraarterially, intrapulmonary, orally, by inhalation,
`
`intravasicularly, intramuscularly, intra—tracheally, subcutaneously, intraocularly,
`
`intrathecally, or transdermally.
`
`Claim 20 (withdrawn): The method of claim 19, wherein the
`
`pharmaceutical composition is administered intravenously.
`
`Claims 21—23 (cancelled).
`
`Claim 24 (currently amended): The pharmaceutical composition of claim 2, wherein the
`
`ratio (w/w) of albumin to the pharmaceutical—agent paclitaxel in the pharmaceutical composition is
`
`about 1:1 to about 5:1.
`
`Claim 25 (currently amended): The pharmaceutical composition of claim 2, wherein the
`
`ratio (w/w) of albumin to the pharmaceutical—agent paclitaxel in the pharmaceutical composition is
`
`1:1 to 9:1.
`
`Claim 26 (new): The pharmaceutical composition of claim 2, wherein the ratio (w/w) of
`
`albumin to the paclitaxel in the pharmaceutical composition is about 9: 1.
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`Actavis - IPR201 7-01 1
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`Application No.: 11/553,339
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`4
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`Docket No.: 638772000301
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`REMARKS
`
`Claims 2—25 were pending in the present application. Claims 7—9 and 14—23 were
`
`withdrawn from consideration. By virtue of this 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]—[0017], [0028],
`
`and [0033] of the specification, as well as previously pending claim 12 of the specification. Support
`
`for new claim 26 can be found at paragraph [0041] of the specification. Claims 13, 24, and 25 are
`
`amended to correct claim dependencies and/or antecedent bases. No new matter is added.
`
`With respect to the cancellation and amendment of claims, Applicants have not
`
`dedicated or abandoned any unclaimed subject matter and moreover, have not acquiesced to any
`
`rejections and/or objections made by the Office. Applicants expressly reserve the right to pursue
`
`prosecution of any presently excluded claim embodiments in future continuation, continuation—in—
`
`part, and/or divisional applications.
`
`Interview Summary
`
`Applicants thank Examiners Marsha Tsay and Maryam Monshipouri for the courtesy
`
`in conducting the in—person interview with inventor Dr. Neil Desai and Applicants’ representatives
`
`Catherine Polizzi and Jian Xiao on January 14, 2010. The guidance provided by the Examiners
`
`during the interview is greatly appreciated.
`
`During the interview, Dr. Desai discussed the invention. The Examiners suggested
`
`that previously pending claims be amended to a narrower scope. The present claim amendment has
`
`narrowed the scope of the claims as the Examiner has suggested.
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`5
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`Docket No.: 638772000301
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`Furthermore, one of the cited references, Desai et al. (U.S. Pat. No. 6,537,579, “the
`
`579 patent”), was discussed. It was noted that the assignee of the ‘579 patent was the same as that
`
`of the present application.
`
`Claim Rejections — 35 US C § 103
`
`Claims 2—6, 10—13 and 24—25 are rejected under 35 U.S.C. § 103(a) as allegedly being
`
`unpatentable over Damascelli et al. (“Damascelli”, 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 respectfully traverse this rejection.
`
`Solely in an effort to expedite prosecution and without acquiescing to the Examiner’s
`
`rejection, claim 1 has been amended to recite “[a] pharmaceutical composition for injection
`
`comprising paclitaxel and a pharmaceutically acceptable carrier, wherein the pharmaceutically
`
`acceptable carrier comprises albumin, wherein the albumin and the paclitaxel in the composition
`
`are formulated as nanoparticles, wherein the nanoparticles have a particle size of less than about
`
`200 nm, and wherein the weight ratio of albumin to paclitaxel in the composition is about 1:1 to
`
`about 9:1.”1 Applicants respectfully submit that points presented in the Response to Office Action
`
`dated October 27, 2009 apply to the amended claims.
`
`Applicants further submit a 37 CPR. § 1.132 Declaration by Dr. Neil Desai (hereinafter
`
`referred to as “the Desai Declaration”), which provides further evidence of nonobviousness.
`
`The cited references do not render the claimed compositions primafacie obvious
`
`The Examiner acknowledges that Damascelli does not disclose a pharmaceutical
`
`composition having an albumin to paclitaxel weight ratio of about 1:1 to about 9:1, and in turn relies
`
`on the ‘579 patent as allegedly disclosing a pharmaceutical composition having an albumin to
`
`1 For the sake of brevity, Applicants follow the Desai Declaration and refer to a pharmaceutical composition for
`injection comprising paclitaxel and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable
`carrier comprises albumin, wherein the albumin and the pharmaceutical agent in the composition are formulated as
`nanoparticles, wherein the nanoparticles have a particle size of less than about 200 nm as an “albumin-based paclitaxel
`nanoparticle composition.”
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`Application No.: 11/553,339
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`6
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`Docket No.: 638772000301
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`paclitaxel weight ratio of 9: 1. 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 modify the teachings of Damascelli et
`
`al. by determining the optimum weight ratio of albumin to paclitaxel, i.e., 9:1, as suggested by
`
`Desai et al. which will result in a composition that will deliver paclitaxel 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 patent does not disclose a
`
`pharmaceutical composition having an albumin/paclitaxel ratio of 9:1. According to the Examiner,
`
`the ‘579 patent discloses dosage forms of ABI—007 that contain 30 mg, 100 mg, or 300 mg of
`
`paclitaxel in a vial (col. 14, lines 4—5), and that unit vessels of ABI—007 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 discloses that ABI—007 can contain up to 1000 mg of active
`
`drug and further discloses that ABI—007 can contain 100 mg paclitaxel, it would be reasonable for
`
`one of ordinary skill to note that a 1000 mg vial of ABI—007 would contain 100 mg paclitaxel and
`
`900 mg albumin, i.e., a weight ratio of 9:1 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 (referring to paclitaxel as the “active drug substance”). Accordingly, the basis of the
`
`Examiner’s conversion is incorrect.
`
`Applicants further respectfully submit that, as discussed in the Desai Declaration and
`
`discussed below, the cited references do not render claims of the present application obvious.
`
`As stated in the Desai Declaration, the three references cited in the Office Action report
`
`earlier clinical studies either conducted or supported by Abraxis.2 The albumin—based paclitaxel
`
`2 Paragraph 16 of the Desai Declaration.
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`nanoparticle compositions used for the clinical studies reported in the cited references represent an
`
`old formulation developed by Abraxis prior to the filing of the present application and have an
`
`albumin/paclitaxel ratio of 19:1 (referred to as “the old formulation” or “the 19:1 formulation”).3
`
`According to Dr. Desai, the old formulation allowed paclitaxel to be administered
`
`without using toxic organic solvents, thus avoiding allergic reactions and side effects caused by the
`
`organic solvents used in standard paclitaxel formulations. 4 Furthermore, according to Dr. Desai, the
`
`old formulation was shown to be efficacious in treating cancers.5 For example, Damascelli reported
`
`a clinical study using the old formulation, and demonstrated that intraarterial administration of the
`
`old formulation had “acceptable toxicity” and at most dose levels showed considerable antitumor
`
`activity in treating advanced head and neck cancer and recurrent anal canal squamous cell
`
`carcinoma.6 Thus, according to Dr. Desai, because the old formulation was shown to be safe and/or
`
`have considerable antitumor activity, there was no need or desirability based on the teaching of the
`
`cited references to further modify the old formulation for the purpose of obtaining a safer or more
`
`efficacious formulation, much less to modify it for this purpose by reducing the albumin/paclitaxel
`
`ratio in the formulation.7
`
`Furthermore, according to Dr. Desai, it was believed that the formation of stable
`
`colloidal dispersions of albumin—based paclitaxel nanoparticle compositions is facilitated by the
`
`combination of electrical repulsion (negative zeta potential), steric stabilization, and viscosity, all
`
`attributable to albumin.8 Because albumin has a net negative charge and is a macromolecule, a
`
`higher albumin/paclitaxel ratio in the formulation could lead to increased steric and electrostatic
`
`intermolecular repulsion as well as higher viscosity, and could thus create a favorable environment
`
`for nanoparticles.9 According to Dr. Desai, one would expect that, based on these favorable
`
`3 Paragraph 17 of the Desai Declaration.
`4 Paragraph 18 of the Desai Declaration.
`5 Paragraph 19 of the Desai Declaration.
`6 Paragraph 19 of the Desai Declaration.
`7 Paragraph 20 of the Desai Declaration.
`8 Paragraph 21 of the Desai Declaration.
`9 Paragraph 21 of the Desai Declaration.
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`Docket No.: 638772000301
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`properties imparted by albumin, reducing the albumin/paclitaxel ratio in the albumin—based
`
`paclitaxel nanoparticle composition could destabilize the nanoparticle composition.10
`
`Thus, according to Dr. Desai, there was no basis in the teachings of the cited references to
`
`further modify the old formulation by reducing the albumin/paclitaxel 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.11
`
`Unexpected properties of the claimed compositions overcome the obviousness rejection
`
`Applicants respectfully submit that the evidence of unexpected properties of the claimed
`
`compositions overcome the obviousness rejection. As provided in the Desai Declaration and
`
`discussed below in more detail, the albumin/paclitaxel ratio of about 1:1 to about 9:1 recited in the
`
`present claims unexpectedly showed increased cellular binding.12 Moreover, it was unexpectedly
`
`found that there is a dramatic change in the binding of paclitaxel that occurs at an
`
`albumin/paclitaxel ratio of about 9:1.13 Furthermore, an albumin—based paclitaxel nanoparticle
`
`composition having an albumin/paclitaxel ratio of 9:1 unexpectedly showed higher therapeutic
`
`efficacy and substantially reduced toxicity compared with the old formulation disclosed in the cited
`
`references.14 Thus, even assuming a prima facie case of obviousness could be established,
`
`compelling evidence of unexpected advantageous properties of the claimed composition rebuts any
`
`alleged finding of prima facie obviousness.
`
`An albumin/paclitaxel ratio of about 1:1 to about 9:1 unexpectedly showed increased cellular
`binding
`
`As stated in the Desai Declaration, it was found, unexpectedly, that the ratio of albumin to
`
`paclitaxel in an albumin—based paclitaxel nanoparticle composition affects the ability of paclitaxel to
`
`10 Paragraph 21 of the Desai Declaration.
`11 Paragraph 22 of the Desai Declaration.
`12 Paragraphs 7-13 and 15 of the Desai Declaration.
`13 Paragraphs 14-15 of the Desai Declaration.
`14 Paragraphs 23-30 of the Desai Declaration.
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`bind to endothelial cells.15 Higher albumin/paclitaxel ratios are associated with poor cellular
`
`binding of paclitaxel, while lower albumin/paclitaxel ratios are associated with enhanced cellular
`
`binding of paclitaxel.16 Consistent evidence was obtained both in an endothelial cell binding assay
`
`and in an artificial 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
`
`albumin/paclitaxel ratio on the binding of paclitaxel changes dramatically at an albumin/paclitaxel
`
`weight ratio of about 9: 1.18 As stated in the Desai Declaration, when the albumin/paclitaxel ratios
`
`were above about 9:1, the paclitaxel binding decreased linearly as the log of the albumin/paclitaxel
`
`ratio increased with a slope of —14. When the albumin/paclitaxel ratios were about 9:1 or less, the
`
`paclitaxel binding decreased linearly as the log of the albumin/paclitaxel ratio increased with a slope
`
`of —95, a nearly seven fold increase in the slope. The two lines intersect creating an unexpected
`
`inflection point in the binding curve at an albumin/paclitaxel ratio of about 9:1.19 According to Dr.
`
`Desai, this suggests a dramatic change in the binding of paclitaxel that occurs at an
`
`albumin/paclitaxel ratio of about 9: 1 .20
`
`As explained in the Desai Declaration, albumin—based paclitaxel nanoparticle compositions
`
`utilize the natural receptor—mediated albumin transportation process to facilitate the delivery of
`
`paclitaxel to tumor sites.21 It is believed that when an albumin—based paclitaxel nanoparticle
`
`composition is injected into the blood vessel, the albumin—bound paclitaxel binds to albumin
`
`receptor gp60 on endothelial cells and is transported to the endothelial cells.22 According to Dr.
`
`Desai, the findings that the albumin/paclitaxel ratio affects the binding of paclitaxel to endothelial
`
`cells and simulated cellular membrane and that there is a dramatic change in the binding of
`
`15 Paragraph 7 of the Desai Declaration.
`16 Paragraph 7 of the Desai Declaration.
`17 Paragraphs 9-13 of the Desai Declaration.
`18 Paragraph 14 of the Desai Declaration.
`19 Paragraph 14 of the Desai Declaration.
`20 Paragraph 14 of the Desai Declaration.
`21 Paragraph 15 of the Desai Declaration.
`22 Paragraph 15 of the Desai Declaration.
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`paclitaxel that occurs at an albumin/paclitaxel ratio of about 9:1 suggest a biological significance of
`
`albumin/paclitaxel ratio in an albumin—based paclitaxel nanoparticle formulation. Such biological
`
`significance was neither taught nor suggested by the cited references.23
`
`A nanoparticle composition having albumin/paclitaxel ratio of about 9:1 unexpectedly showed
`higher therapeutic efficacy and substantially reduced toxicity compared with the old formulation
`
`According to Dr. Desai, Abraxane®, an albumin—based paclitaxel nanoparticle
`
`composition having about 9:1 albumin/paclitaxel weight ratio (also referred to as “the 9:1
`
`formulation”), was unexpectedly found to be more efficacious than the old formulation in the cited
`
`references, which had an albumin/paclitaxel ratio of about 19:1 (“the 19:1 formulation”).24 Further,
`
`Abraxane® was unexpectedly found to have substantially reduced toxicity compared with the old
`-
`25
`formulation.
`
`According to Dr. Desai, two clinical studies were conducted in China with cancer
`
`patients having various solid tumors.26 In the first study, twenty—two patients having different
`
`cancers were enrolled to be treated with the 19:1 formulation at dose levels 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 9:1 formulation at the dose level of 260 mg/m2.27 According to Dr. Desai,
`
`among the 21 evaluable patients treated with the 19:1 formulation, 8 showed substantial tumor
`
`shrinkage upon treatment, leading to an overall response rate of 38%. Among the 104 evaluable
`
`patients treated with the 9:1 formulation, 56 showed substantial tumor shrinkage upon treatment,
`
`leading to an overall response rate of 54%.28
`
`According to Dr. Desai, the response rates of the patients treated with the 19:1
`
`formulation at a dose of 260 mg/m2 or higher were further compared with those of patients treated
`
`23 Paragraph 15 of the Desai Declaration.
`24 Paragraph 23 of the Desai Declaration.
`25 Paragraph 23 of the Desai Declaration.
`26 Paragraph 25 of the Desai Declaration.
`27 Paragraph 25 of the Desai Declaration.
`28 Paragraph 26 of the Desai Declaration.
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`Docket No.: 638772000301
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`with the 9:1 formulation at a dose of 260 mg/m2.29 Among the twelve patients treated with the 19:1
`
`formulation at a dose of 260 mg/m2 or higher, three showed substantial tumor shrinkage upon
`
`treatment, leading to an overall response rate of 25 %.30 Among the 104 evaluable patients treated
`
`with the 9:1 formulation at dose level of 260 mg/m2, 56 showed substantial tumor shrinkage upon
`
`treatment, leading to an overall response rate of 54%, more than double the 25% response rate
`
`observed in the study with the 19:1 formulation.31
`
`In his declaration, Dr. Desai further provides evidence that the 9:1 formulation showed
`
`substantially reduced toxicity compared with the 19:1 formulation.32 As stated in the Desai
`
`Declaration, the toxicity profiles of the 9:1 formulation and the 19:1 formulation were compared by
`
`quantifying treatment—related adverse events of all grades based on National Cancer Institute
`
`Common Toxicity Criteria Adverse Events (NCI CTCAE). For the majority of adverse events
`
`commonly observed with the treatment of paclitaxel, the 9:1 formulation showed substantially
`
`reduced number of incidents than the 19:1 formulation.33 According to Dr. Desai, these data
`
`demonstrate that the 9:1 formulation has substantially reduced toxicity compared with the 19:1
`-
`34
`formulation.
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`The advantages of the claimed compositions were unexpected
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`According to Dr. Desai, the advantages of the claimed compositions discussed above were
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`unexpected and could not be predicted based on the teachings of the cited references.35
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`As discussed above and stated in the Desai Declaration, the cited references provide no
`
`indication of the biological significance of albumin/paclitaxel ratio in an albumin—based paclitaxel
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`29 Paragraph 27 of the Desai Declaration.
`30 Paragraph 27 of the Desai Declaration.
`31 Paragraph 27 of the Desai Declaration.
`32 Paragraph 28 of the Desai Declaration.
`33 Paragraph 28 of the Desai Declaration.
`34 Paragraph 28 of the Desai Declaration.
`35 Paragraphs 29, 30, and 35-38 of the Desai Declaration.
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`pa-1386628
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`Actavis - IPR2017—O1103, Ex. 1022, p. 12 of 15
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`Actavis - IPR2017-01103, Ex. 1022, p. 12 of 15
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`Application No.: 11/553,339
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`12
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`Docket No.: 638772000301
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`nanoparticle composition.36 Because the old formulation was shown to be safe and have
`
`considerable antitumor activity, there was no need or desirability based on the teaching of the cited
`
`references to further modify the old formulation for the purpose of obtaining a safer and/or more
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`efficacious formulation, much less to modify it by reducing the albumin/paclitaxel ratio in the
`
`formulation.37 Furthermore, because albumin is a major contributing factor to the stability of an
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`albumin—based paclitaxel nanoparticle composition, one would expect that reducing the
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`albumin/paclitaxel ratio in the composition would destabilize the nanoparticle formulation.38
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`According to Dr. Desai, there was therefore no reason to further modify the old formulation by
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`reducing the albumin/paclitaxel ratio in the formulation.39
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`According to Dr. Desai, the finding that an increased albumin/paclitaxel ratio negatively
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`affects the binding of paclitaxel to endothelial cells was unexpected. The finding that there is a
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`dramatic change in the binding of paclitaxel that occurs at an albumin/paclitaxel ratio of about 9:1
`.
`.
`40
`was even more surpr1s1ng and unexpected.
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`Furthermore, according to Dr. Desai, the clinical data demonstrating that the 9:1 formulation
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`leads to a higher therapeutic efficacy than the old formulation was unexpected.41 Moreover, as Dr.
`
`Desai states, since the amount of albumin in the pharmaceutical composition injected into 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 albumin—based paclitaxel
`
`nanoparticle composition would make any difference in the therapeutic efficacy of the composition
`
`at all, much less result in the increased efficacy ob served in the clinical studies.42
`
`36 Paragraph 36 of the Desai Declaration.
`37 Paragraph 36 of the Desai Declaration.
`38 Paragraph 36 of the Desai Declaration.
`39 Paragraph 36 of the Desai Declaration.
`40 Paragraph 37 of the Desai Declaration.
`41 Paragraph 29 of the Desai Declaration.
`42 Paragraph 29 of the Desai Declaration.
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`pa-1386628
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`Actavis - IPR2017—O1103, Ex. 1022, p. 13 of 15
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`Actavis - IPR2017-01103, Ex. 1022, p. 13 of 15
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`Application No.: 11/553,339
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`13
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`Docket No.: 638772000301
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`Similarly, according to Dr. Desai, the finding that the 9:1 formulation has substantially
`
`reduced toxicity compared with the old formulation was also unexpected.43 Moreover, as Dr. Desai
`
`states, since the amount of albumin in the pharmaceutical composition injected into 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 albumin—based paclitaxel
`
`nanoparticle composition would lead to substantially reduced toxicity in the albumin—based
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`paclitaxel nanoparticle formulation.44
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`As stated in the Desai Declaration, Abraxane® was approved in the United States in 2005
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`for treating metastatic breast cancer and has become one of the leading drugs for treating metastatic
`
`breast cancer within five years after its initial approval.45 In recent studies, Abraxane® has also
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`shown substantially improved therapeutic efficacies in various clinical trials for treating difficult—to—
`.
`.
`46
`treat cancers such as pancreatic cancer, lung cancer, melanoma, and ovarian cancer.
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`In view of the compelling evidence of unexpected properties and significant practical
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`advantages of the claimed compositions, Applicants respectfully submit that the compositions
`
`claimed in the present application are nonobvious and inventive.
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`Actavis - IPR201 7-01 1
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`43 Paragraph 30 of the Desai Declaration.
`44 Paragraph 30 of the Desai Declaration.
`45 Paragraphs 31-32 of the Desai Declaration.
`46 Paragraphs 33-34 of the Desai Declaration.
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`pa-1386628
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`Actavis - IPR2017-01103, Ex. 1022, p. 14 of 15
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`Application No.: 11/553,339
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`14
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`Docket No.: 638772000301
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`CONCLUSION
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`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
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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 expedite the prosecution of this application, the
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`Examiner is invited to telephone the undersigned at the number given below.
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`In the event the U.S. Patent and Trademark Office determines that an extension and/or
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`other relief is required, applicants petition for any required relief including extensions of time and
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`authorizes the Commissioner to charge the cost of such petitions and/or other fees due in connection
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`with the filing of this document to Deposit Account No. 03-1952 referencing 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 Deposit Account.
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`Dated: April 14, 2010
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`Respectfully submitted,
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`Electronic signature:
`Jian Xiao
`
`/Jian Xiao/
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`Registration No.: 55,748
`MORRISON & FOERSTER LLP
`
`755 Page Mill Road
`Palo Alto, California 94304—1018
`
`(650) 813—5736
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`Actavis - IPR201 7-01 1
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`pa-1386628
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`Actavis - IPR2017-01103, Ex. 1022, p. 15 of 15
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`