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 AFTER FINAL ACTION UNDER 37 C.F.R. 1.114
`
`MSRCE
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Dear Sir:
`
`INTRODUCTORY COMMENTS
`
`This response accompanies a Request for Continued Examination. Amendments and
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`remarks presented by this amendment are responsive to the Final Office Action dated December 29,
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`2010 (Paper No. 20101207), for which a response was due on March 29, 2011. On June 28, 2011,
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`Applicants filed a Notice of Appeal along with a Petition and fee for a three months extension of
`
`time. The deadline for filing an appeal brief or a Request for Continued Examination was August
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`28, 2011. Filed herewith is a Petition and fee for a five months extension of time, thereby extending
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`the deadline for response to January 28, 2012. 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.
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`Amendments to the Claims are reflected in the listing of claims which begins on page 3
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`of this paper.
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`Remarks/Arguments begin on page 7 of this paper.
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`Application No.: 11/520,479
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`Docket No.: 638772000109
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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:
`
`Claims 1-65 (Cancelled).
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`Claim 66 (Currently amended):
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`A pharmaceutical formulation comprising:
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`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
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`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 is less than 400 nm.
`
`Claim 67 (Previously presented):
`
`The pharmaceutical formulation of claim 66, wherein the
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`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.
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`Claim 69 (Cancelled).
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`Claim 70 (Previously presented):
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`The pharmaceutical formulation of claim 67, wherein the
`
`average diameter of the nanoparticles is no greater than 220 nm.
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`Claim 71 (Previously presented):
`
`The pharmaceutical formulation of claim 67, wherein there is
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`substantially no precipitation of paclitaxel for at least 3 days under at least one of room temperature
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`or refrigerated conditions.
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`Claim 72 (Currently amended):
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`The pharmaceutical formulation of claim [[70]] 66, wherein
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`the average nanoparticle size does not substantially change for at least 3 days under at least one of
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`room temperature or refrigerated conditions.
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`Claim 73 (Cancelled).
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`Claim 74 (Currently amended):
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`The pharmaceutical formulation of claim [[70]] 66, wherein
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`the nanoparticles have a core and the nanoparticle solid core is substantially free of polymeric
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`material.
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`Claim 75 (Currently amended):
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`The pharmaceutical formulation of claim [[73]] 66, wherein
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`the albumin coating has free albumin associated therewith, and wherein a portion of the paclitaxel is
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`contained within the albumin coating and a portion of the paclitaxel is associated with the free
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`albumin.
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`Claim 76 (Currently amended):
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`The pharmaceutical formulation of claim [[70]] 66, wherein at
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`least a portion of the albumin is crosslinked by disulfide bonds.
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`Claim 77 (Currently amended):
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`The pharmaceutical formulation of claim [[70]] 66, wherein
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`the paclitaxel is substantially amorphous.
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`Claim 78 (Currently amended):
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`The pharmaceutical formulation of claim [[70]] 66, wherein
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`the paclitaxel is substantially crystalline.
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`Claim 79 (Withdrawn, currently amended): A method of treatment, comprising administering an
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`effective amount of the composition of claim [[70]] 66 to a patient to treat a tumor.
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`Claim 80 (Withdrawn):
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`The method of claim 79, wherein the composition is administered
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`parenterally, orally, intravenously, subcutaneously, intraperitoneally, intrathecally, intramuscularly,
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`by inhalation, topically, transdermally, rectally, or vaginally.
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`Claim 81 (Withdrawn):
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`The method of claim 80, wherein the composition is administered
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`intravenously.
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`Claim 82 (Withdrawn):
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`The method of claim 81, wherein the pharmaceutical formulation is
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`infused, and the infusion volume is no greater than 200 ml.
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`Claim 83 (Withdrawn, currently amended): A method of treatment, comprising administering an
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`effective amount of the composition of claim [[70]] 66 to a patient to treat rheumatoid arthritis
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`breast cancer.
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`Claim 84 (Withdrawn):
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`The method of claim 83, wherein the composition is administered
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`parenterally, orally, intravenously, subcutaneously, intraperitoneally, intrathecally, intramuscularly,
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`by inhalation, topically, transdermally, rectally, or vaginally.
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`Claim 85 (New):
`
`The pharmaceutical formulation of claim 66, wherein the average diameter of
`
`the nanoparticles is no greater than about 200 nm.
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`Claim 86 (New):
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`The pharmaceutical formulation of claim 67, wherein the average diameter of
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`the nanoparticles is no greater than about 200 nm.
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`Claim 87 (New):
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`The pharmaceutical formulation of claim 68, wherein the average diameter of
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`the nanoparticles is no greater than about 200 nm.
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`Claim 88 (New):
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`The pharmaceutical formulation of claim 7 4, wherein the average diameter of
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`the nanoparticles is no greater than about 200 nm.
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`Claim 89 (New):
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`The pharmaceutical formulation of claim 77, wherein the average diameter of
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`the nanoparticles is no greater than about 200 nm.
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`Claim 90 (New):
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`The pharmaceutical formulation of claim 66, wherein the albumin is human
`
`albumin.
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`Claim 91 (New):
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`The pharmaceutical formulation of claim 67, wherein the albumin is human
`
`albumin.
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`Claim 92 (New):
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`The pharmaceutical formulation of claim 68, wherein the albumin is human
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`albumin.
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`Claim 93 (New):
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`The pharmaceutical formulation of claim 7 4, wherein the albumin is human
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`albumin.
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`Claim 94 (New):
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`The pharmaceutical formulation of claim 77, wherein the albumin is human
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`albumin.
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`Docket No.: 638772000109
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`REMARKS
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`Claims 66-68 and 70-84 were pending in the present application. Claims 79-84 were
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`withdrawn from consideration. By virtue of this response, claim 73 has been cancelled, claims 66,
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`72, 74-79, and 83 have been amended, and new claims 85-94 have been added. Accordingly, claims
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`66-68, 70-72, 7 4-78, and 85-94 are currently under consideration.
`
`Support for the amendment of claim 66 can be found at page 37, lines 2-8 and page 59,
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`lines 17-18 of the specification. Support for the amendment of claim 83 can be found at Examples
`
`65 and 66 of the specification. Support for new claims 85-89 can be found at page 36, lines 4-5 of
`
`the specification. Support for new claims 90-94 can be found at page 37, line 8 of the specification.
`
`Claims 72 and 74-79 are amended to change claim dependencies. No new matter is added.
`
`With respect to claim amendments and cancellation, Applicants have not dedicated or
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`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
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`and/or divisional application(s).
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`Summary of Interview
`
`Applicants thank Examiners Trevor Love and Sharmila Landau for the courtesy in
`
`conducting the in-person interview with inventor Dr. Neil Desai, Applicants' representatives
`
`Catherine Polizzi and Jian Xiao, and Dr. Carla Kuhner from Celgene Corporation on June 22, 20ll.
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`The guidance provided by the Examiners during the interview is greatly appreciated.
`
`During the interview, Dr. Desai discussed the differences between the claimed
`
`composition and those disclosed in the cited references, as well as the structural and stability
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`features of the claimed invention. Possible claim amendments were also discussed.
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`Information Disclosure Statement
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`Applicants hereby submit a Supplemental Information Disclosure Statement and
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`respectfully request that the references submitted therein be considered and entered into record.
`
`Desai in view of Shively
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`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. (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.
`
`Solely in an effort to expedite prosecution and without acquiescing to the Examiner's
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`rejection, claim 66 has been amended to recite "[a] pharmaceutical formulation comprising:
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`paclitaxel at a concentration between 5 mg/ml and 15 mg/ml, wherein the pharmaceutical
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`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 is less than 400 nm." Applicants respectfully submit that the
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`cited references do not render the claims as amended obvious.
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`Applicants hereby submit a 37 C.P.R. § 1.132 Declaration by Dr. Neil Desai (hereinafter
`
`referred to as "the Desai Declaration"). As discussed in the Desai Declaration and below, neither
`
`Shively nor Desai teaches or suggests that the nanoparticle formulations recited in the claims would
`
`be stable at paclitaxel concentration of between 5 mg/ml and 15 mg/ml. Furthermore, the
`
`nanoparticle formulations recited in the amended claims show advantageous stability. In view of
`
`the lack of teachings in the cited references and the advantageous 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.
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`Neither Shively nor Desai teaches or suggests that the claimed nanoparticle formulations would be
`stable at paclitaxel concentration of between 5 mg/ml and 15 mg/ml
`
`As stated in the Desai Declaration, physical stability is a key consideration for ensuring
`
`safety and efficacy of nanoparticle drug products, and the tendency of nanoparticles to precipitate
`and increase in size (for example by aggregation) increases as drug concentration increases. 1
`
`Accordingly, Dr. Desai states that it would have been expected that a nanoparticle formulation
`
`having a solid core of paclitaxel and an albumin coating would be unstable at a high paclitaxel
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`concentration, for example between 5 mg/ml and 15 mg/ml?
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`In finding claims of the present application obvious, the Examiner relies on Shively as
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`allegedly teaching a preferred therapeutic amount of paclitaxel, namely, 5 mg/ml. Specifically,
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`Shively states that "[f]or therapeutic use, emulsions containing between about 0.5 mg/ml and about
`
`5 mg/ml [paclitaxel] are prepared by the foregoing methods and administered orally or
`
`intravenously." Column 9, lines 51-54. Applicants respectfully submit that Shively's teaching
`
`pertains to emulsions, which involve different stability considerations than solid nanoparticle
`
`formulations as recited in the present claims. Shively teaches nothing about paclitaxel in the form
`
`of solid nanoparticles, much less solid paclitaxel nanoparticles at a paclitaxel concentration of 5
`
`mg/ml or even higher.
`
`As explained in the Desai Declaration, in Shively's emulsions, the paclitaxel is dissolved
`
`in oil droplets suspended in an aqueous solution rather than a solid core of albumin-coated
`
`nanoparticles. Such oil droplets are different from solid nanoparticles in terms of composition,
`density, and buoyancy, and involve different stability considerations. 3 Thus, according to Dr. Desai,
`
`Shively's teaching of 5 mg/ml paclitaxel in an oil-in-water emulsion formulation provides no
`
`suggestion that a nanoparticle formulation having a solid core of paclitaxel and an albumin coating
`would be stable at paclitaxel concentration of between 5 mg/ml and 15 mg/ml. 4
`
`1 Paragraphs 6 and 7 of the Desai Declaration.
`2 Paragraph 7 of the Desai Declaration.
`3 Paragraph 9 of the Desai Declaration.
`4 Paragraph 9 of the Desai Declaration.
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`The Examiner further relies on Example 4 of Desai as teaching obtaining "higher loading
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`of drug," and thus allegedly providing a motivation and method for one of ordinary skill in the art to
`
`arrive at 5 mg/ml paclitaxel in Desai's composition. Pages 4 and 6 of the Office Action. However,
`
`as pointed out in the Desai Declaration, the Examiner himself acknowledges that the paclitaxel
`suspension "is taught as being protein walled polymeric shells enclosing an oil/taxol solution."5 As
`
`explained in the Desai Declaration, such oil-containing polymeric shells are different from the solid
`
`nanoparticles in terms of composition, density, and buoyancy, and involve different stability
`
`considerations. Dr. Desai further states that an increase in loading of paclitaxel within the
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`polymeric shells as taught in Desai would be expected to increase the particle size and/or the density
`of the particles, which in tum could increase the tendency of the particles to precipitate. 6 Thus,
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`Applicants respectfully submit that Desai neither teaches nor suggests a nanoparticle composition
`
`comprising solid paclitaxel nanoparticles at a paclitaxel concentration of between 5 mg/ml and 15
`
`mg/ml, much less that such a composition would be stable.
`
`Applicants further submit that the Examiner's reliance on Example 5 of Desai as
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`allegedly teaching that the composition of Desai is stable for 27 days at various temperatures is
`
`misplaced. As explained in the Desai Declaration, Example 5 of Desai refers to the stability of
`polymeric shells containing buoyant soybean oil. No drug was present within the polymeric shel1. 7
`
`Because the oil-containing polymeric shells in Example 5 of Desai and the solid nanoparticles
`
`claimed in the amended claims are different in terms of composition, density, and buoyancy, the
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`stability of the oil-containing polymeric shells discussed in Example 5 of Desai provides no
`
`suggestion that a nanoparticle formulation comprising a solid core of paclitaxel and an albumin
`coating would be stable at paclitaxel concentration of between 5 mg/ml and 15 mg/ml. 8
`
`Furthermore, as stated in the Desai Declaration, the wide size range taught in Desai
`
`would be expected to lead to further instability according to the well-known phenomenon of
`
`5 Paragraph 11 of the Desai Declaration.
`6 Paragraph 11 of the Desai Declaration.
`7 Paragraph 10 of the Desai Declaration.
`8 Paragraph 10 of the Desai Declaration.
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`Ostwald ripening. 9 Dr. Desai states that, given the wide size range of the particles in Desai and the
`
`increased tendency of the particles to precipitate when the paclitaxel concentration increases, one
`
`would not reasonably have expected that the nanoparticle formulation of paclitaxel disclosed in
`
`Desai could be obtained at a concentration between 5 mg/ml and 15 mg/ml, without causing
`precipitation and compromising the stability of the composition. 10
`
`Thus, Applicants respectfully submit that neither Shively nor Desai teaches or suggests
`
`that a nanoparticle formulation comprising a solid core of paclitaxel and an albumin coating as
`
`claimed would be stable at a paclitaxel concentration between 5 mg/ml and 15 mg/ml.
`
`The claimed nanoparticle formulations show advantageous stability
`
`Applicants further submit that the nanoparticle formulations recited in the amended
`
`claims show advantageous stability as demonstrated in the present specification as well as in a
`
`subsequent experiment. Such advantageous stability further supports nonobviousness.
`
`Specifically, as stated in the Desai Declaration, Example 37 of the present application
`
`has shown, unexpectedly, that a pharmaceutical composition 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
`. .
`11
`composition.
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`In his Declaration, Dr. Desai further presents data from a subsequent experiment which
`
`compared the physical stability of two pharmaceutical compositions containing nanoparticles
`
`comprising a solid core of paclitaxel and an albumin coating, namely, Composition 1 and
`Composition 2. 12 Composition 1 contained no detectable percentage of nanoparticles that have a
`
`size above 400 nm, while at least 10% of the nanoparticles in Composition 2 had a particle size that
`
`9 Paragraph 12 of the Desai Declaration.
`10 Paragraph 12 of the Desai Declaration.
`11 Paragraph 14 of the Desai Declaration.
`12 Paragraphs 15-18 of the Desai Declaration.
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`was above 400 nm. 13 Both compositions (Composition 1 and two lots of Composition 2) were
`stored at 40 oc for 24 hours at the paclitaxel concentration of about 5 mg/ml. 14 Upon storage,
`distinctly visible sedimentations were observed in vials containing Composition 2, while no
`sedimentation was observed in the vial containing Composition 1. 15 Microscopic observation of the
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`reconstituted suspensions for Composition 2 revealed large particles upon storage. Such large
`particles were not observed in Composition 1. 16 Furthermore, upon storage, the weight mean
`
`diameter of the nanoparticles in Composition 1 remained unchanged. In Composition 2, by
`contrast, the weight mean diameter of the nanoparticles increased significantly upon storage. 17 The
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`data presented in the Desai Declaration thus further demonstrate that the nanoparticle formulations
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`recited in the present claims are advantageously more stable.
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`In summary, due to the increased tendency of nanoparticles to precipitate and increase in
`
`size as the drug concentration increases, it would not have been expected that a nanoparticle
`
`formulation comprising a solid core of paclitaxel and an albumin coating would be stable at a
`
`paclitaxel concentration of between 5 mg/ml and 15 mg/ml. Shively's teaching of 5 mg/ml
`
`paclitaxel in an oil-in-water emulsion, which involves different stability considerations as solid
`
`nanoparticles, provides no teaching or suggestion that a nanoparticle formulating comprising a solid
`
`core of paclitaxel and an albumin coating would be stable at paclitaxel concentration of between 5
`
`mg/ml and 15 mg/ml. The teachings in Desai the Examiner relies on also relate to oil-containing
`
`polymeric shells which involve different stability considerations than those of the nanoparticles
`
`recited in the present claims. Furthermore, given the wide size range of the particles taught in Desai
`
`and the increased tendency of the particles to precipitate as the paclitaxel concentration increases,
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`one of ordinary skill in the art would not reasonably have expected that the nanoparticle formulation
`
`of paclitaxel disclosed in Desai could be obtained at a concentration between 5 mg/ml to 15 mg/ml,
`
`without causing precipitation and compromising the stability of the composition. It was unexpected
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`13 Paragraph 15 of the Desai Declaration.
`14 As stated in the Desai Declaration, storage at 40 oc for 24 hours is equivalent to storage at room temperature for at
`least three days. Paragraph 16, footnote 2 of the Desai Declaration.
`15 Paragraph 16 of the Desai Declaration.
`16 Paragraph 17 of the Desai Declaration.
`17 Paragraph 18, Table 1 of the Desai Declaration.
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`that a pharmaceutical composition comprising nanoparticles having a size of less than 400 nm and
`
`comprising 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
`
`composition. This is in stark contrast with a composition containing nanoparticles comprising a
`
`solid core of paclitaxel and an albumin coating, wherein at least 10% of the nanoparticles have a
`
`particle size above 400 nm, which showed significant precipitation within 24 hours upon storage at
`
`40°C (equivalent to storage at room temperature for at least three days) at about 5 mg/ml paclitaxel
`
`concentration. Such unexpected and advantageous stability of the composition recited in the present
`
`claims provides further evidence of non-obviousness.
`
`Applicants thus respectfully submit that claims of the present application are nonobvious
`
`over Desai and Shively, and respectfully 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
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`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 66-68 and 70-77, 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, neither Shively nor Desai
`
`teaches or suggests that the nanoparticle formulations recited in the amended claims would be stable
`
`at paclitaxel concentration of between 5 mg/ml and 15 mg/ml. Furthermore, the nanoparticle
`
`formulations with solid nanoparticles less than 400 nm as recited in the amended claims show
`
`advantageous stability. Applicants thus respectfully submit that the claimed nanoparticle
`
`compositions 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
`
`nanoparticle formulation. Nor does Klein teach how an amorphous form of paclitaxel can be
`
`incorporated into an albumin/paclitaxel nanoparticle composition, much less an albumin/paclitaxel
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`Docket No.: 638772000109
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`nanoparticle composition that is stable at paclitaxel concentration of between 5 mg/ml and 15
`
`mg/ml.
`
`Accordingly, Applicants respectfully submit that the claims of the present application are
`
`nonobvious 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 and 70-78 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 rejection be withdrawn.
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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
`
`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
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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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`638772000109. 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: January 27, 2012
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`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-1440434
`
`Actavis - IPR2017-01100, Ex. 1020, p. 15 of 15
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