Docket No.: 638772000301
`(PATENT)
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re Patent Application of:
`Neil P. DESAI et al.
`
`Application No.: 111553,339
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`Confirmation No.: 3605
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`Filed: October 26, 2006
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`For: COMPOSITIONS AND METHODS OF
`DELIVERY OF PHARMACOLOGICAL
`AGENTS
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`Art Unit: 1656
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`Examiner: M. Tsay
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`AMENDMENT IN RESPONSE TO NON-FINAL OFFICE ACTION
`
`MS Amendment
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Dear Sir:
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`INTRODUCTORY COMMENTS
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`This is in response to the non-final Office Action dated April28, 2009 (Paper No.
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`20090415), for which a response was due on July 28, 2009. Filed herewith is a Petition and fee for
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`a three month(s) extension of time, thereby extending the deadline for response to October 28, 2009.
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`Accordingly, this response is timely filed. Reconsideration and allowance of the pending claims, as
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`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 2
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`of this paper.
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`Remarks/ Arguments begin on page 5 of this paper.
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`CIPLA EXHIBIT 1020
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`Application No.: 111553,339
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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
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`claims in the application:
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`Claim 1 (Cancelled)
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`Claim 2 (Currently amended): A pharmaceutical composition comprising a pharmaceutical agent
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`and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier
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`comprises albumin, wherein the albumin and the pharmaceutical agent in the composition are
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`formulated as nanoparticles, and wherein the weight ratio of albumin to pharmaceutical agent in the
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`composition is about 1:1 to about.§..;.!. 9:1.
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`Claim 3 (Previously presented): The pharmaceutical composition of claim 2, wherein the
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`nanoparticles have a mean-diameter of less than about 200 nm.
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`Claim 4 (Previously presented): The pharmaceutical composition of claim 2, wherein the albumin
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`is human serum albumin.
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`Claim 5 (Previously presented): The pharmaceutical composition of claim 2, wherein the
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`pharmaceutical agent is selected from the group consisting of anticancer agents, anesthetics,
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`antimicrotubule agents, agents to treat cardiovascular disorders, antihypertensives, anti(cid:173)
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`inflammatory agents, anti-arthritic agents, antiasthmatics, analgesics, vasoactive agents,
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`immunosuppressive agents, antifungal agents, antiarrhythmic agents, antibiotics, and hormones.
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`Claim 6 (Previously presented): The pharmaceutical composition of claim 5, wherein the
`pharmaceutical agent is an anticancer agent.
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`Claim 7 (Withdrawn): The pharmaceutical composition of claim 5, wherein the pharmaceutical
`agent is an anti-inflammatory agent.
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`Claim 8 (Withdrawn): The pharmaceutical composition of claim 5, wherein the pharmaceutical
`agent is an immunosuppressive agent.
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`Application No.: 111553,339
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`3
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`Docket No.: 638772000301
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`Claim 9 (Withdrawn): The pharmaceutical composition of claim 5, wherein the pharmaceutical
`agent is an antibiotic.
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`Claim 10 (Previously presented): The pharmaceutical composition of claim 2, wherein the
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`pharmaceutical agent is selected from the group consisting of paclitaxel, docetaxel, taxanes,
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`camptothecin, propofol, amiodarone, cyclosporine, rapamycin, amphotericin, liothyronine,
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`epothilones, colchicines, thyroid hormones, vasoactive intestinal peptide, corticosteroids,
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`melatonin, tacrolimus, mycophenolic acids.
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`Claim 11 (Previously presented): The pharmaceutical composition of claim 10, wherein the
`anticancer agent is a taxane.
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`Claim 12 (Previously presented): The pharmaceutical composition of claim 11, wherein the
`pharmaceutical_agent is paclitaxel.
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`Claim 13 (Previously presented): The pharmaceutical composition of claim 12, wherein the
`pharmaceutical composition is free of Cremophor.
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`Claim 14 (Withdrawn): A method of treating a disease comprising administering an effective
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`amount of a pharmaceutical composition of claim 2.
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`Claim 15 (Withdrawn): The method of claim 14, wherein the disease is cancer.
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`Claim 16 (Withdrawn): The method of claim 14, wherein the disease is arthritis.
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`Claim 17 (Withdrawn): The method of claim 14, wherein the disease is cardiovascular disease.
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`Claim 18 (Withdrawn): The method of claim 17, wherein the disease is restenosis.
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`Claim 19 (Withdrawn): The method of claim 14, wherein the composition is administered
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`intravenously, intraarterially, intrapulmonary, orally, by inhalation, intravasicularly,
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`intramuscularly, intra-tracheally, subcutaneously, intraocularly, intrathecally, or transdermally.
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`Application No.: 111553,339
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`4
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`Docket No.: 638772000301
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`Claim 20 (Withdrawn): The method of claim 19, wherein the pharmaceutical composition is
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`administered intravenously.
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`Claim 21 (Withdrawn): The method of claim 19, wherein the pharmaceutical composition is
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`administered orally.
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`Claim 22 (Withdrawn and Currently Amended): A method of preparing a pharmaceutical
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`composition of claim 2, comprising combining a pharmaceutical agent with a pharmaceutically
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`acceptable carrier comprising albumin, wherein the weight ratio of albumin to the pharmaceutical
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`agent in the composition is about 5:1 or less about 1:1 to about 9:1.
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`Claim 23 (Withdrawn): The method of claim 22, further comprising subjecting the combination of
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`the pharmaceutical agent and the pharmaceutically acceptable carrier to high pressure
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`homogenization.
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`Claim 24 (New): The pharmaceutical composition of claim 2, wherein the ratio (w/w) of albumin to
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`the pharmaceutical agent in the pharmaceutical composition is about 1: 1 to about 5: 1.
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`Claim 25 (New): The pharmaceutical composition of claim 2, wherein the ratio (w/w) of albumin to
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`the pharmaceutical agent in the pharmaceutical composition is 1:1 to 9:1.
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`Application No.: 111553,339
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`5
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`Docket No.: 638772000301
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`REMARKS
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`Claims 2-23 are pending in the present application. Claims 7-9 and 14-23 are withdrawn
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`from consideration. By this amendment, pending claims 2 and withdrawn claim 22 are amended.
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`New claims 24 and 25 are added. Upon entry of this amendment, claims 2-6, 10-13, and 24-25 are
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`under examination.
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`Support for the amendment of claim 2 and 22 can be found at page 14, line 21 (Paragraph
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`[0041]) of the specification.
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`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
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`objections made by the Patent Office. Applicants expressly reserve the right to pursue prosecution
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`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
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`Applicants express their gratitude for the telephonic interview between Examiner Marsha M.
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`Tsay and Applicants' representative Jian (Janet) Xiao on May 19, 2009. The time and consideration
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`of the Examiner is greatly appreciated.
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`During the May 19, 2009 interview, the Examiner and Applicants' representatives briefly
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`discussed the 35 U.S.C. § 103(a) rejection cited in the Office Action. Applicants inquired about the
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`possibility of amending the independent claim to recite a ratio of "about 1:1 to about 9:1." The
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`Examiner indicated that such amended claim will be examined.
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`Rejection under 35 U.S.C. § 103(a)
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`Claims 2-6 and 10-13 are rejected under 35 U.S.C. § 103(a) as allegedly being unpatentable
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`over Damascelli et al. ("Damascelli," 2001 Cancer 92(10): 2592-2602) in view of Ibrahim et al.
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`("Ibrahim," 2000 Proc Am Soc Clin Onco 19: abstract 609F). Applicants respectfully traverse this
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`rejection. The response addresses claims as amended, and the arguments presented herein apply
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`equally to the claims prior to the amendment.
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`Application No.: 111553,339
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`6
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`Docket No.: 638772000301
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`The claims as amended are directed to "a pharmaceutical composition comprising a
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`pharmaceutical agent and a pharmaceutically acceptable carrier, wherein the pharmaceutically
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`acceptable carrier comprises albumin, wherein the albumin and the pharmaceutical agent in the
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`composition are formulated as nanoparticles, and wherein the weight ratio of albumin to
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`pharmaceutical agent in the composition is about 1:1 to about 9:1." The present application teaches
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`that a low albumin/pharmaceutical agent ratio, such as the ratios recited in the claims of the present
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`application, allows enhanced cellular binding and transport of the pharmaceutical agent. As stated
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`in paragraph [0041] of the present application,
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`Not to adhere to any one particular theory, it is believed that the ratio of protein, e.g., human
`serum albumin, to pharmaceutical agent in the pharmaceutical composition affects the
`ability of the pharmaceutical agent to bind and transport the pharmaceutical agent to a cell.
`In this regard, higher ratios of protein to pharmaceutical agent generally are associated with
`poor cell binding and transport of the pharmaceutical agent, which possibly is the result of
`competition for receptors at the cell surface. The ratio of protein, e.g., albumin, to active
`pharmaceutical agent must be such that a sufficient amount of pharmaceutical agent binds
`to, or is transported by, the cell.
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`Example 45 demonstrates that increasing amounts of albumin can compete with the binding
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`of a pharmaceutical agent, namely, paclitaxel, to the cell surface, and states that "higher albumin
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`concentration inhibited binding of paclitaxel. Thus, invention compositions having lower amounts
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`of albumin are preferred."
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`The present application further teaches that a low albumin/pharmaceutical agent ratio, such
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`as the ratios recited in claims of the present application, allows formation of stable nanoparticle
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`compositions of the pharmaceutical agent. Specifically, Example 46 states,
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`To investigate if lower amounts of albumin in the composition would affect stability of the
`inventive pharmaceutical composition, albumin-paclitaxel compositions with low amounts
`of albumin were prepared. It was found that these compositions were as stable as
`compositions with higher quantities of albumin when examined for several months at
`different temperatures (2-8 °C, 25 °C, and 40 °C) for potency of paclitaxel, impurity
`formation, particle size, pH and other typical parameters of stability. Thus compositions
`with lower amounts of albumin are preferred as this can greatly reduce cost as well as allow
`increased binding and transport to cells.
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`Application No.: 111553,339
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`7
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`Docket No.: 638772000301
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`Example 48 further demonstrates the production of a nanoparticle pharmaceutical
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`composition with a starting albumin/paclitaxel ratio of 4.5: 1.
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`Thus, a low albumin/pharmaceutical agent ratio, such as the ratios recited in claims of the
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`present application, allows enhanced cellular binding and transport of the pharmaceutical agent
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`while at the same time allowing the formation of stable nanoparticle compositions of the
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`pharmaceutical agent even at the low ratio. Such advantageous result and characteristics were
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`neither taught nor suggested in the cited references.
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`The two references cited by the Examiner, namely, Damascelli and Ibrahim, are silent about
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`the weight ratio of albumin to pharmaceutical agent in the compositions disclosed therein. They
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`neither teach nor suggest the significance of the albumin/pharmaceutical agent ratio on cellular
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`binding and transport. Nor do they teach or suggest that a low albumin/pharmaceutical agent ratio,
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`such as those recited in the claims of the present application, would allow enhanced cellular binding
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`and transport of the pharmaceutical agent while at the same time allowing the formation of stable
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`nanoparticle compositions of the pharmaceutical agent even at low ratio.
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`The Examiner acknowledges that Damascelli does not disclose a specific albumin/paclitaxel
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`ratio, but states that "it would have been obvious to one of ordinary skill in the art at the time the
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`invention was made to modify the teachings of Damascelli by determining the optimum
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`concentration and/or weight ratio of albumin to paclitaxel that will result in a composition that will
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`deliver paclitaxel most effectively in an albumin delivery system." Applicants respectfully
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`disagree.
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`First, Damascelli is completely silent about any need or even desirability to further modify
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`the composition disclosed therein in order to delivery paclitaxel more effectively. According to
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`Damascelli, intraarterial administration of ABI007 has "acceptable toxicity" and at most dose levels
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`"showed considerable antitumor activity (42 assessable patients with 80.9% complete response and
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`partial response)." See Abstract. There is no indication that delivery of paclitaxel needs to or
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`should be further improved.
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`Application No.: 111553,339
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`Docket No.: 638772000301
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`Second, Damascelli provides no direction or basis for adjusting the weight ratio of albumin
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`to paclitaxel in the composition disclosed therein for the purpose of improving the composition, let
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`alone any direction or basis for choosing a low albumin/pharmaceutical agent ratio, such as the
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`ratios recited in the present application.
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`MPEP states,
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`B. Only Result-Effective Variables Can be Optimized
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`A particular parameter must first be recognized as a result-effective variable, i.e., a variable
`which achieves a recognized result, before the determination of the optimum or workable
`range of said variable might be characterized as routine experimentation. In re Antonie, 559
`F.2d 618, 195 USPQ 6 (CCPA 1977)(The claimed waste water treatment device had a tank
`volume to contractor area of 0.12 gal/sq. ft. The prior art did not recognize that treatment
`capacity is a function of the tank volume to contractor ratio, and therefore the parameter
`optimized was not recognized in the art to be a result-effective variable.). See also in re
`Boesch, 617 F.2d 272, 205 (CCPA 1980) (prior art suggested proportional balancing to
`achieve desired results in the formation of an alloy).
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`MPEP §2144.05.II.B.
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`As discussed above, Damascelli is silent about weight ratio of albumin to pharmaceutical
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`agent, namely, paclitaxel, in the composition disclosed therein. Nor does Damascelli teach or
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`suggest the significance of the albumin/pharmaceutical agent ratio on cellular binding and transport.
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`Without a recognition in the art of the significance of albumin/pharmaceutical agent ratio, for
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`example in cellular binding and transport of the pharmaceutical agent, one of ordinary skill would
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`not have been motivated to adjust the albumin/pharmaceutical agent ratio, let alone to choose a low
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`albumin/pharmaceutical agent ratio, such as the ratios recited in the present application, in order to
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`make a composition that will delivery the pharmaceutical agent most effectively in an albumin
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`delivery system.
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`Similarly, Ibrahim neither discloses a weight ratio of albumin to pharmaceutical agent nor
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`teaches the significance of the albumin/pharmaceutical agent ratio on the cellular binding and
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`transport.
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`Application No.: 111553,339
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`9
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`Docket No.: 638772000301
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`Because it has not been established that the weight ratio of albumin to pharmaceutical agent
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`was recognized in the art as a result-effective variable, Applicants respectfully submit that the
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`rejection of the claims should be withdrawn.
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`Applicants further respectfully submit that optimization and/or achieving a desired result do
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`not mean the result is non-inventive. As discussed above, the albumin/pharmaceutical agent ratios
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`recited in claims of the present application allow enhanced cellular binding and transport of the
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`pharmaceutical agent while at the same time allowing the formation of stable nanoparticle
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`compositions of the pharmaceutical agent even at the low ratio. Such advantageous result and
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`characteristics were neither predictable based on the teaching of the cited references nor expected by
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`a person of ordinary skill in the art.
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`Accordingly, Applicants respectfully request that the rejection under 35 U.S.C. §103(a) be
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`withdrawn.
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`Application No.: 111553,339
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`10
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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
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`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, applicant petitions 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: October 27, 2009
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`Respectfully submitted,
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`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
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