IN THE UNITED STATES PATENT AND TRADEMARK OFFICE

Transcription

1 In re Patent Application of: Neil P. DESAI et al. Docket No.: (PATENT) IN THE UNITED STATES PATENT AND TRADEMARK OFFICE Application No.: 11/520,479 Filed: September 12, 2006 For: NOVEL FORMULATIONS OF PHARMACOLOGICAL AGENTS, METHODS FOR THE PREPARATION THEREOF AND METHODS FOR THE USE THEREOF Confirmation No.: 8972 Art Unit: 1611 Examiner: T. Love AMENDMENT AFTER FINAL ACTION UNDER 37 C.F.R MSRCE Commissioner for Patents P.O. Box 1450 Alexandria, VA 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 29, 2010 (Paper No ), for which a response was due on March 29, On June 28, 2011, 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 28, Filed herewith is a Petition and fee for a five months extension of time, thereby extending the deadline for response to January 28, 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. Actavis - IPR , Ex. 1020, p. 1 of 15

2 Application No.: 11/520,479 2 Docket No.: Amendments to the Claims are reflected in the listing of claims which begins on page 3 of this paper. Remarks/Arguments begin on page 7 of this paper. Actavis - IPR , Ex. 1020, p. 2 of 15

3 Application No.: 11/520,479 3 Docket No.: AMENDMENTS TO THE CLAIMS This listing of claims will replace all prior versions, and listings of claims in the application: Claims 1-65 (Cancelled). Claim 66 (Currently amended): A pharmaceutical formulation comprising: paclitaxel at a concentration between 5 mg/ml and 15 mg/ml, wherein the pharmaceutical formulation is an aqueous suspension that is stable for at least 3 days under at least one of room temperature or refrigerated conditions, wherein the pharmaceutical formulation comprises nanoparticles comprising a solid core of paclitaxel and an albumin coating, and wherein the size of the nanoparticles in the composition is less than 400 nm. Claim 67 (Previously presented): The pharmaceutical formulation of claim 66, wherein the pharmaceutical formulation is a stable aqueous suspension reconstituted from a sterile lyophilized powder. Claim 68 (Previously presented): The pharmaceutical formulation of claim 67, wherein the pharmaceutical formulation comprises paclitaxel at a concentration of 5 mg/ml. Claim 69 (Cancelled). Claim 70 (Previously presented): average diameter of the nanoparticles is no greater than 220 nm. The pharmaceutical formulation of claim 67, wherein the Claim 71 (Previously presented): The pharmaceutical formulation of claim 67, wherein there is substantially no precipitation of paclitaxel for at least 3 days under at least one of room temperature or refrigerated conditions. Actavis - IPR , Ex. 1020, p. 3 of 15

4 Application No.: 11/520,479 4 Docket No.: Claim 72 (Currently amended): The pharmaceutical formulation of claim [[70]] 66, wherein the average nanoparticle size does not substantially change for at least 3 days under at least one of room temperature or refrigerated conditions. Claim 73 (Cancelled). Claim 74 (Currently amended): The pharmaceutical formulation of claim [[70]] 66, wherein the nanoparticles have a core and the nanoparticle solid core is substantially free of polymeric material. Claim 75 (Currently amended): The pharmaceutical formulation of claim [[73]] 66, wherein the albumin coating has free albumin associated therewith, and wherein a portion of the paclitaxel is contained within the albumin coating and a portion of the paclitaxel is associated with the free albumin. Claim 76 (Currently amended): least a portion of the albumin is crosslinked by disulfide bonds. The pharmaceutical formulation of claim [[70]] 66, wherein at Claim 77 (Currently amended): the paclitaxel is substantially amorphous. The pharmaceutical formulation of claim [[70]] 66, wherein Claim 78 (Currently amended): the paclitaxel is substantially crystalline. The pharmaceutical formulation of claim [[70]] 66, wherein Claim 79 (Withdrawn, currently amended): A method of treatment, comprising administering an effective amount of the composition of claim [[70]] 66 to a patient to treat a tumor. Actavis - IPR , Ex. 1020, p. 4 of 15

5 Application No.: 11/520,479 5 Docket No.: Claim 80 (Withdrawn): The method of claim 79, wherein the composition is administered parenterally, orally, intravenously, subcutaneously, intraperitoneally, intrathecally, intramuscularly, by inhalation, topically, transdermally, rectally, or vaginally. Claim 81 (Withdrawn): intravenously. The method of claim 80, wherein the composition is administered Claim 82 (Withdrawn): infused, and the infusion volume is no greater than 200 ml. The method of claim 81, wherein the pharmaceutical formulation is Claim 83 (Withdrawn, currently amended): A method of treatment, comprising administering an effective amount of the composition of claim [[70]] 66 to a patient to treat rheumatoid arthritis breast cancer. Claim 84 (Withdrawn): The method of claim 83, wherein the composition is administered parenterally, orally, intravenously, subcutaneously, intraperitoneally, intrathecally, intramuscularly, by inhalation, topically, transdermally, rectally, or vaginally. Claim 85 (New): The pharmaceutical formulation of claim 66, wherein the average diameter of the nanoparticles is no greater than about 200 nm. Claim 86 (New): The pharmaceutical formulation of claim 67, wherein the average diameter of the nanoparticles is no greater than about 200 nm. Claim 87 (New): The pharmaceutical formulation of claim 68, wherein the average diameter of the nanoparticles is no greater than about 200 nm. Claim 88 (New): The pharmaceutical formulation of claim 7 4, wherein the average diameter of the nanoparticles is no greater than about 200 nm. Actavis - IPR , Ex. 1020, p. 5 of 15

6 Application No.: 11/520,479 6 Docket No.: Claim 89 (New): The pharmaceutical formulation of claim 77, wherein the average diameter of the nanoparticles is no greater than about 200 nm. Claim 90 (New): albumin. The pharmaceutical formulation of claim 66, wherein the albumin is human Claim 91 (New): albumin. The pharmaceutical formulation of claim 67, wherein the albumin is human Claim 92 (New): albumin. The pharmaceutical formulation of claim 68, wherein the albumin is human Claim 93 (New): albumin. The pharmaceutical formulation of claim 7 4, wherein the albumin is human Claim 94 (New): albumin. The pharmaceutical formulation of claim 77, wherein the albumin is human Actavis - IPR , Ex. 1020, p. 6 of 15

7 Application No.: 11/520,479 7 Docket No.: REMARKS Claims and were pending in the present application. Claims were withdrawn from consideration. By virtue of this response, claim 73 has been cancelled, claims 66, 72, 74-79, and 83 have been amended, and new claims have been added. Accordingly, claims 66-68, 70-72, 74-78, and are currently under consideration. Support for the amendment of claim 66 can be found at page 37, lines 2-8 and page 59, lines 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 can be found at page 36, lines 4-5 of the specification. Support for new claims can be found at page 37, line 8 of the specification. Claims 72 and are amended to change claim dependencies. No new matter is added. With respect to claim amendments and cancellation, Applicants have not dedicated or abandoned any unclaimed subject matter and moreover have not acquiesced to any rejections and/or objections made by the Patent Office. Applicants expressly reserve the right to pursue prosecution of any presently excluded subject matter or claim embodiments in one or more future continuation and/or divisional application(s). Summary of Interview Applicants thank 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. 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 features of the claimed invention. Possible claim amendments were also discussed. Actavis - IPR , Ex. 1020, p. 7 of 15

8 Application No.: 11/520,479 8 Docket No.: Information Disclosure Statement Applicants hereby submit a Supplemental Information Disclosure Statement and respectfully request that the references submitted therein be considered and entered into record. Claim Rejections- 35 USC 103 Desai in view of Shively Claims and 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 rejection, claim 66 has been amended to recite "[a] pharmaceutical formulation comprising: paclitaxel at a concentration between 5 mg/ml and 15 mg/ml, wherein the pharmaceutical formulation is an aqueous suspension that is stable for at least 3 days under at least one of room temperature or refrigerated conditions, wherein the pharmaceutical formulation comprises nanoparticles comprising a solid core of paclitaxel and an albumin coating, and wherein the size of the nanoparticles in the composition is less than 400 nm." Applicants respectfully submit that the cited references do not render the claims as amended obvious. Applicants hereby submit a 37 C.P.R 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. Actavis - IPR , Ex. 1020, p. 8 of 15

9 Application No.: 11/520,479 9 Docket No.: 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 concentration, for example between 5 mg/ml and 15 mg/ml? In finding claims of the present application obvious, the Examiner relies on Shively as allegedly teaching a preferred therapeutic amount of paclitaxel, namely, 5 mg/ml. Specifically, 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 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. Actavis - IPR , Ex. 1020, p. 9 of 15

10 Application No.: 11/520, Docket No.: The Examiner further relies on Example 4 of Desai as teaching obtaining "higher loading 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 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, 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 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 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. Actavis - IPR , Ex. 1020, p. 10 of 15

11 Application No.: 11/520, Docket No.: 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. 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 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 of the Desai Declaration. Actavis - IPR , Ex. 1020, p. 11 of 15

12 Application No.: 11/520, Docket No.: 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 Microscopic observation of the reconstituted suspensions for Composition 2 revealed large particles upon storage. Such large particles were not observed in Composition 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 data presented in the Desai Declaration thus further demonstrate that the nanoparticle formulations recited in the present claims are advantageously more stable. 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, 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 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. Actavis - IPR , Ex. 1020, p. 12 of 15

13 Application No.: 11/520, Docket No.: 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 and over Desai and Shively be withdrawn. Desai in view of Shively, further in view of Klein Claims and stand rejected under 35 U.S.C. 103(a) as allegedly being unpatentable over Desai in view of Shively as applied to 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 Actavis - IPR , Ex. 1020, p. 13 of 15

14 Application No.: 11/520, Docket No.: 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 and under 35 U.S.C. 103(a) be withdrawn. Double Patenting Claims and 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. Actavis - IPR , Ex. 1020, p. 14 of 15

15 Application No.: 11/520, Docket No.: CONCLUSION In view of the above, each of the presently pending claims in this application is believed to be in immediate condition for allowance. Accordingly, the Examiner is respectfully requested to withdraw the outstanding rejection of the claims and to pass this application to issue. If it is determined that a telephone conference would expedite the prosecution of this application, the Examiner is invited to telephone the undersigned at the number given below. In the event the U.S. Patent and Trademark Office determines that an extension and/or other relief is required, applicants petition for any required relief including extensions of time and authorizes the Commissioner to charge the cost of such petitions and/or other fees due in connection with the filing of this document to Deposit Account No referencing docket no However, the Commissioner is not authorized to charge the cost of the issue fee to the Deposit Account. Dated: January 27, 2012 Respectfully submitted, Electronic signature: /Jian Xiao/ Jian Xiao Registration No.: 55,748 MORRISON & FOERSTER LLP 755 Page Mill Road Palo Alto, California (650) Actavis - IPR , Ex. 1020, p. 15 of 15