Ex Parte Chow et alDownload PDFPatent Trial and Appeal BoardApr 17, 201712220364 (P.T.A.B. Apr. 17, 2017) Copy Citation United States Patent and Trademark Office UNITED STATES DEPARTMENT OF COMMERCE United States Patent and Trademark Office Address: COMMISSIONER FOR PATENTS P.O.Box 1450 Alexandria, Virginia 22313-1450 www.uspto.gov APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO. 12/220,364 07/24/2008 Diana Shu-Lian Chow D6810CIP2 6889 7590 Benjamin Aaron Adler ADLER & ASSOCIATES 8011 Candle Lane Houston, TX 77071 EXAMINER ANDERSON, JAMES D ART UNIT PAPER NUMBER 1629 MAIL DATE DELIVERY MODE 04/17/2017 PAPER Please find below and/or attached an Office communication concerning this application or proceeding. The time period for reply, if any, is set in the attached communication. PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte DIANA SHU-LIAN CHOW, PRANAV GUPTA, YULAN QI, JAYMIN SHAH, and PETER WISNIECKI Appeal 2016-001979 Application 12/220,3641 Technology Center 1600 Before FRANCISCO C. PRATS, TAWEN CHANG, and DEVON ZASTROW NEWMAN, Administrative Patent Judges. PRATS, Administrative Patent Judge. DECISION ON APPEAL This appeal under 35 U.S.C. § 134(a) involves claims to a nano suspension formulation for improving the bioavailability of a benzimidazole derivative in lung tissue. The Examiner rejected the claims for obviousness. We have jurisdiction under 35 U.S.C. § 6(b). We affirm. STATEMENT OF THE CASE The following rejections are before us for review: 1 Appellants identify The University of Houston System as the real party in interest. Br. 3. Appeal 2016-001979 Application 12/220,364 (1) Claims 1, 6—8, 10, and 15—19, under 35 U.S.C. § 103(a), as unpatentable over Van Den Bossche,2 Shah,3 and Deschamps4 (Ans. 3—13); and (2) Claims 1, 6—8, 10, and 15—19, under 35 U.S.C. § 103(a), as unpatentable over Van Den Bossche, Kipp,5 and Deschamps (Ans. 13-24). Claim 1 is representative and reads as follows (App. Br. A-l, A-2): Claim 1: A nanosuspension formulation for improving the bioavailability of a benzimidazole derivative in lung tissue, comprising: a) a benzimidazole derivative having the formula: wherein R1 is OH, Cl, SH, carbamate, or piperidin- 4-yl; R2 is hydrogen, a-methylvinyl, 3-chloropropyl or piperidin-4-yl; R3 is selected from the group consisting of hydrogen, carboxyl (-CO2H), hydroxyl, amino, chloro, difluormethoxy, benzoyl, phenyl-thio, pyridinyl, propyl- thio, diphenyl, 5-methoxy, fluorophenylmethyl-2-chloro, propenyl, chloropropyl, and esters (CO2R4); 2 Hugo Van Den Bossche et al., Mebendazole and Related Anthelmintics, 19 Adv. Pharmacol. Chemother. 67—128 (1982). 3 WO 2006/109177 Al (published Oct. 19, 2006). 4 WO 2007/144362 Al (published Dec. 21, 2007). 5 US 6,884,436 B2 (issued Apr. 26, 2005). 2 Appeal 2016-001979 Application 12/220,364 R4 is selected from the group consisting of alkoxy, haloalkyl, alkenyl, and cycloalkyl, wherein the alkyl groups have from 1 to 8 carbons, or the alkyl groups are CH3CH2(OCH2CH2)n-, or CHsCHsCHsCOCHsCHsCHsjn-, or (CH3)2CH(OCH(CH3)CH2)n-, wherein n is from 1— 3 [,] or the pharmaceutically effective organic or inorganic salts thereof, or mixtures thereof: b) a block copolymer; and c) a surfactant; wherein particle size of the benzimidazole derivative within the nanosuspension is configured as about 167 nm, about 400 nm, about 700 nm, or about 1700 nm to manipulate the release rate and bioavailability of the benzimidazole derivative in the lung tissue. OBVIOUSNESS- VAN DEN BOSSCHE, SHAH, AND DESCHAMPS The Examiner’s Prima Facie Case The Examiner’s position, essentially, is that Shah teaches or suggests a nanosuspension-type composition having all of the features of the formulations recited in claims 1, 6—8, 10, and 15—19, “except for the claimed benzimidazoles (e.g. mebendazole).” Ans. 12. The Examiner finds, however, based on the teachings of Van Den Bossche, that an ordinary artisan would have recognized that mebendazole was “a compound that meets all of the requirements disclosed in Shah et al. for a compound that would benefit from formulation in the nanosuspensions disclosed [in Shah].” Id. The Examiner cited Deschamps as further evidence of the suitability of including benzimidazoles in nanosuspensions that contain surfactants encompassed by the rejected claims. See id. Based on the references’ combined teachings, the Examiner concludes that “[tjaking a well-known water-insoluble, poorly bioavailable compound 3 Appeal 2016-001979 Application 12/220,364 such as mebendazole and applying a well-known method of increasing the water solubility and bioavailability of water-insoluble, poorly bioavailable compounds, i.e., formulation in a nanosuspension, would have been prima facie obvious to one of ordinary skill in the art.” Ans. 13. Analysis As stated in In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992): [T]he examiner bears the initial burden ... of presenting a prima facie case of unpatentability. . . . After evidence or argument is submitted by the applicant in response, patentability is determined on the totality of the record, by a preponderance of evidence with due consideration to persuasiveness of argument. Appellants do not persuade us that the Examiner’s conclusion of obviousness is not supported by a preponderance of the evidence. To the contrary, we adopt as our own the Examiner’s findings as to the scope and content of the prior art, the Examiner’s reasoning as to how and why an ordinary artisan would have combined the cited teachings of the references, and the Examiner’s conclusion, summarized above, that representative claim 1 would have been prima facie obvious over the cited combination of references. We provide the discussion below for emphasis. Representative claim 1 recites a nanosuspension formulation for improving the bioavailability of a benzimidazole derivative in lung tissue, the formulation containing three ingredients: (a) a benzimidazole derivative having a formula that encompasses the compound mebendazole, (b) a block copolymer, and (c) a surfactant. Br. 16—17. Claim 1 requires the particle size of the benzimidazole derivative within the nanosuspension to be either about 167 nm, about 400 nm, about 4 Appeal 2016-001979 Application 12/220,364 700 nm, or about 1700 nm, to manipulate the release rate and bioavailability of the benzimidazole derivative in the lung tissue. Br. 17. Turning to the prior art, Shah discloses a formulation composed of “(1) a low solubility drug or pharmaceutically acceptable salt thereof; (2) a pharmaceutically acceptable carrier; and (3) at least two surface stabilizers.” Shah, 3:22-23. As required by Appellants’ claim 1, one of Shah’s surface stabilizers may be a block copolymer surfactant, such as “Pluronic FI08®.” Id. at 10:2. As also required by Appellants’ claim 1, Shah’s second surface stabilizer may be another surfactant, such as “Tween® 80,” which is combined with the Pluronic FI08 block copolymer. Id. at 17:3—5; see also id. at 27:30-28:26 (Shah’s Examples 6—8 using a combination of Pluronic FI08 (block copolymer) and Tween 80 (surfactant)). As to the particle size requirement of Appellants’ claim 1, Shah discloses that the average particle size of the low solubility compound in its formulations should be less than about 2000 nm (id. at 12:33—36), and more particularly discloses that suitable average particle sizes can be less than about 1500 nm, less than about 1000 nm, less than about 500 nm, and even more particularly in a range from about 120 nm to about 400 nm. Id. at 14:12-19. Shah, thus, differs from representative claim 1 only in that Shah does not expressly include a benzimidazole, such as mebendazole, in its formulations. Nonetheless, Shah broadly discloses that it is advantageous to include a wide variety of drugs having low water solubility in its compositions: 5 Appeal 2016-001979 Application 12/220,364 The compound may be a pharmaceutical, including, without limitation, biologies such as proteins, peptides and nucleic acids or a diagnostic, including, without limitation, contrast agents. In one embodiment, the compound . . . has low water solubility. In another embodiment, the logP of the compound is at least about 3 or greater. . . . A compound having “low water solubility” refers to any compound having a solubility in water, measured at 37°C, not greater than about 10 mg/ml. In another embodiment, the measured solubility is not greater than about 1 mg/ml. In another embodiment, the measured solubility is not greater than about 0.1 mg/ml. A synonymous term is “low aqueous solubility.” Exemplary compounds include, without limitation, compounds from the following classes: . . . anthelminthics .... Shah, 5:3—7:32 (emphasis added). As the Examiner finds, Van Den Bossche discloses that mebendazole, a known anthelminthic, “is almost insoluble in water” and has a logP of 3.1. Van Den Bossche, 76. Thus, given the breadth of compounds taught in Shah as being desirable for inclusion in its formulations, and further given that mebendazole was known in the art to be an anthelminthic meeting the low water solubility and logP value suitability criteria for use in Shah’s formulations, we agree with the Examiner that an ordinary artisan had ample reason for, and a reasonable expectation of success in, including mebendazole in Shah’s formulations, thus yielding the formulation required by Appellants’ claim 1. To that end, we note that Deschamps provides further evidence of the suitability of including mebendazole in surfactant- containing nanoparticulate emulsion formulations, similar to those taught in Shah. See, e.g., Deschamps Abstract (disclosing “a pharmaceutical composition for drinking water administration comprising benzimidazole 6 Appeal 2016-001979 Application 12/220,364 carbamate particles having an effective average particle size of less than 450 nm and a Tween-type surfactant”); id. 149 (well known benzimidazole carbamates include mebendazole). Turning to Appellants’ arguments, we are not persuaded that ziprasidone is “the only drug taught by Shah.” Br. 7. Nor are we persuaded that, because of the asserted differences in solubility between ziprasidone and mebendazole, an ordinary artisan lacked motivation to incorporate mebendazole, a benzimidazole encompassed by claim 1, into Shah’s formulations. See id. at 7—8. It might be true that ziprasidone is the only drug compound used in Shah’s examples. It is well settled, however, that “[a]ll the disclosures in a reference must be evaluated, including nonpreferred embodiments, and a reference is not limited to the disclosure of specific working examples.” In re Mills, 470 F.2d 649, 651 (CCPA 1972) (citations omitted). In the present case, as noted above, Shah broadly discloses that a wide variety of different compounds are useful in its compositions. See Shah, 5:3—7:32 (quoted above). As also noted above, moreover, Van Den Bossche discloses that mebendazole meets a number of the criteria outlined in Shah for suitability for inclusion in its formulations, including low water solubility, a logP value over 3, and its recognition in the art as an anthelminthic. See Van Den Bossche, 76. Given these teachings, we are not persuaded that an ordinary artisan lacked an adequate reason for, or a reasonable expectation of success in, including mebendazole in Shah’s formulations. Moreover, because the reason for including mebendazole in Shah’s formulations would have been derived from the prior art, we are not 7 Appeal 2016-001979 Application 12/220,364 persuaded that the Examiner’s rejection of claim 1 is based on improper hindsight. As to Appellants’ contentions regarding pages 2 and 123 of the Liu reference6 (Br. 8—9), we acknowledge the disclosure in Liu that a “water- insoluble drug” can encompass a variety of solubility ranges. See Liu, 2. We acknowledge also Liu’s disclosure that the “nanosuspension technique usually does not work well for basic compounds with high pH-dependent solubility.” Id. at 123. We acknowledge further Liu’s disclosure that nanosuspensions can experience problems, such as precipitation and agglomeration, and that not all compounds can form nanosuspensions. Id. Appellants do not, however, advance specific evidence showing that mebendazole is a basic compound with high pH-dependent solubility. Nor do Appellants explain adequately why Liu’s definition of a water-insoluble drug would have led an ordinary artisan to ignore Shah’s teachings about the suitability of including drugs with low water solubility in its formulations. Although it might be true that an ordinary artisan knew that not all compounds were amenable to Shah’s nanosuspension technique, it is well settled that “[ojbviousness does not require absolute predictability of success. . . . Lor obviousness under § 103, all that is required is a reasonable expectation of success.” In re Kubin, 561 L.3d 1351, 1360 (Led. Cir. 2009) (quoting In re O’Farrell, 853 L.2d 894, 903-04 (Led. Cir. 1988) (emphasis removed). In the present case, given the wide variety of different compounds taught by Shah as being desirable for inclusion in its formulations, we are not persuaded that an ordinary artisan lacked a 6 Water-Insoluble Drug formulation (Rong Liu ed., 2008). 8 Appeal 2016-001979 Application 12/220,364 reasonable expectation that mebendazole also would have been advantageously included in Shah’s formulations. In sum, for the reasons discussed, Appellants do not persuade us that the Examiner failed to make out a prima facie case of obviousness as to representative claim 1. Because Appellants do not advance specific secondary evidence of nonobviousness, a preponderance of the evidence supports the Examiner’s conclusion that the formulation recited in claim 1 would have been obvious to an ordinary artisan in view of Van Den Bossche, Shah, and Deschamps. We, therefore, affirm the Examiner’s rejection of claim 1 over those references. Claims 6—8, 10, and 15—19 fall with claim 1 because they were not argued separately. See 37 C.F.R. § 41.37(c)(l)(iv). OBVIOUSNESS- VAN DEN BOSSCHE, KIPP, AND DESCHAMPS The Examiner’s Prima Facie Case As to this rejection, the Examiner’s position, essentially, is that Kipp teaches or suggests a nanosuspension-type composition having all of the features of the formulations recited in claims 1, 6—8, 10, and 15—19, “except for the claimed benzimidazoles (e.g. mebendazole).” Ans. 23. The Examiner finds, however, based on the teachings of Van Den Bossche, that an ordinary artisan would have recognized that mebendazole was “a compound that meets all of the requirements disclosed in Kipp et al. for a compound that would benefit from formulation in the nanosuspensions disclosed [in Kipp].” Id. The Examiner cited Deschamps as further evidence of the suitability of including benzimidazoles in nanosuspensions that contain surfactants encompassed by the rejected claims. See id. at 23— 24. 9 Appeal 2016-001979 Application 12/220,364 Based on the references’ combined teachings, the Examiner concludes that “[tjaking a well-known water-insoluble, poorly bioavailable compound such as mebendazole and applying a well-known method of increasing the water solubility and bioavailability of water-insoluble, poorly bioavailable compounds, i.e., formulation in a nanosuspension, would have been prima facie obvious to one of ordinary skill in the art.” Ans. 24. Analysis Appellants do not persuade us that a preponderance of the evidence fails to support the Examiner’s conclusion that claim 1 would have been obvious in view of Van Den Bossche, Kipp, and Deschamps. To the contrary, we adopt as our own the Examiner’s findings as to the scope and content of the prior art, the Examiner’s reasoning as to how and why an ordinary artisan would have combined the cited teachings of the references, and the Examiner’s conclusion, summarized above, that representative claim 1 would have been prima facie obvious over the cited combination of references. We provide the discussion below for emphasis. Similar to Shah, Kipp is directed to addressing difficulties involved in administering drugs with low water solubility. See Kipp, 1:30-36. To address those difficulties, Kipp dissolves the drug in a first solvent, then adds a second solvent to make a “pre-suspension,” and then “add[s] energy to the pre-suspension to form particles having an average effective particle size of less than about 2 pm [2000 nm].” Id. at 3:54—56. As is evident, the particle size range taught in Kipp encompasses the particle sizes recited in claim 1. As required by claim 1, Kipp discloses that the second solution it forms can contain one or more surfactants, one of which can be a block 10 Appeal 2016-001979 Application 12/220,364 copolymer. Id. at 8:1—44; see also id. at 14:8—16:60 (Examples 1—4 using combination of block copolymer (Pluronic F-68) and surfactant (sodium deoxycholate)). Also similar to Shah, Kipp broadly discloses that a wide variety of drugs are amenable to inclusion in its formulations: It should be understood . . . that the process conditions such as choice of surfactants or combination of surfactants, amount of surfactant used, temperature of reaction, rate of mixing of solutions, rate of precipitation and the like can be selected to allow for any drug to be processed under any one of the categories discussed next. . . . An organic compound for use in the process of this invention is any organic chemical entity whose solubility decreases from one solvent to another. This organic compound might be a pharmaceutically active compound from various groups such as, but not limited to: . . . antimicrobials .... Kipp 7:8—23; see also id. at 14:8—26:41 (Kipp’s Examples using four different drug compounds (itraconazole, carbamazepine, prednisolone, nabumetone)). Thus, given the breadth of compounds taught in Kipp as being desirable for inclusion in its formulations, and further given that mebendazole was known in the art to be an antimicrobial with low water solubility and, thus, desirably included in Kipp’s formulations, we agree with the Examiner that an ordinary artisan had ample reason for, and a reasonable expectation of success in, including mebendazole in Kipp’s formulations, thereby yielding the formulation required by Appellants’ claim 1. To that end, we note again that Deschamps provides further evidence of the suitability of including mebendazole in surfactant-containing nanoparticulate emulsion formulations, similar to those taught in Kipp. See, e.g., Deschamps, abstract (disclosing “a pharmaceutical composition for 11 Appeal 2016-001979 Application 12/220,364 drinking water administration comprising benzimidazole carbamate particles having an effective average particle size of less than 450 nm and a Tween- type surfactant”); id. 149 (well known benzimidazole carbamates include mebendazole). Appellants’ arguments, similar to those directed to the rejection discussed above, do not persuade us that the evidence of record fails to support the Examiner’s prima facie case of obviousness. As to Appellants’ contention that Kipp fails to teach or suggest the concentrations of block copolymer and surfactant required in the claims (Br. 12), we note that representative claim 1 does not recite specific concentrations as to those ingredients, see Br. 16—17, and Appellants do not argue any of the remaining claims separately. See Br. generally. As to Appellants’ contention that Kipp’s four exemplified compounds differ in structure from mebendazole (Br. 12—14), as discussed above, a prior art reference is not limited to the teachings in its working examples. See In re Mills, 470 F.2d at 651. Given the breadth of Kipp’s disclosure as to compounds useful in its compositions, and further given Kipp’s exemplification of four compounds of varying structure, we are not persuaded that the Examiner erred in finding that an ordinary artisan had a good reason for, and a reasonable expectation of success in, including mebendazole in Kipp’s formulations. Lastly, as to Appellants’ assertion that an ordinary artisan would have understood from Liu that mebendazole would not work in nanosuspensions of the type described in Liu (Br. 13—14 (citing Liu, 123)), we again note that Appellants have not advanced specific evidence showing that mebendazole is a basic compound with high pH-dependent solubility, the type of 12 Appeal 2016-001979 Application 12/220,364 compound taught in Liu as not being amenable to formulation in nanosuspensions. As noted above, moreover, “[ojbviousness does not require absolute predictability of success. .. . For obviousness under § 103, all that is required is a reasonable expectation of success.” In re Kubin, 561 F.3d at 1360. Given the wide variety of different compounds taught by Kipp as being desirable for inclusion in its formulations, we are not persuaded that an ordinary artisan lacked a reasonable expectation that mebendazole would have been advantageously included in Shah’s formulations. In sum, for the reasons discussed, Appellants do not persuade us that the Examiner failed to make out a prima facie case of obviousness as to representative claim 1. Because Appellants do not advance specific secondary evidence of nonobviousness, a preponderance of the evidence supports the Examiner’s conclusion that the formulation recited in claim 1 would have been obvious to an ordinary artisan in view of Van Den Bossche, Kipp, and Deschamps. We, therefore, affirm the Examiner’s rejection of claim 1 over those references. Claims 6—8, 10, and 15—19 fall with claim 1 because they were not argued separately. See 37 C.F.R. § 41.37(c)(l)(iv). SUMMARY For the reasons discussed, we affirm the Examiner’s rejection of claims 1, 6—8, 10, and 15—19, under 35 U.S.C. § 103(a), as unpatentable over Van Den Bossche, Shah, and Deschamps. For the reasons discussed, we also affirm the Examiner’s rejection of claims 1, 6—8, 10, and 15—19, under 35 U.S.C. § 103(a), as unpatentable over Van Den Bossche, Kipp, and Deschamps. 13 Appeal 2016-001979 Application 12/220,364 TIME PERIOD No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a). AFFIRMED 14 Copy with citationCopy as parenthetical citation