Ex Parte Rashid et alDownload PDFPatent Trial and Appeal BoardDec 12, 201814627589 (P.T.A.B. Dec. 12, 2018) Copy Citation UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE 14/627,589 02/20/2015 29880 7590 12/14/2018 FOX ROTHSCHILD LLP PRINCETON PIKE CORPORATE CENTER 997 LENOX DRIVE BLDG. #3 LAWRENCEVILLE, NJ 08648 FIRST NAMED INVENTOR Abdul Rashid 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 ATTORNEY DOCKET NO. CONFIRMATION NO. 100867.00501 6302 EXAMINER PROSSER, ALISSA J ART UNIT PAPER NUMBER 1619 NOTIFICATION DATE DELIVERY MODE 12/14/2018 ELECTRONIC 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. Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the following e-mail address(es): ipdocket@foxrothschild.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte ABDUL RASHID, DAHAI GUO, MINH TRAN, and ZHANG JULIA ZHANG (APPLICANT: Enspire Group LLC) Appeal2017-008437 Application 14/627 ,589 1 Technology Center 1600 Before DONALD E. ADAMS, DEMETRA J. MILLS, and JAMES A. WORTH, Administrative Patent Judges. ADAMS, Administrative Patent Judge. DECISION ON APPEAL This Appeal under 35 U.S.C. § 134(a) involves claims 1-15, 22, 23, 25, and 30-35 (Final Act. 2 2; Appeal Br. 3 3; Reply Br. 4 3). 5 Examiner entered a rejection under 35 U.S.C. § 103(a). We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. 1 Appellants identify "Enspire Group LLC" as the real party in interest (Appeal Br. 3). 2 Office Action mailed September 9, 2016. 3 Appellants' February 8, 2017 Appeal Brief. 4 Appellants' May 9, 2017 Reply Brief. 5 Appellants' pending claims 16-21 and 24 stand withdrawn from consideration (see Final Act. 2; Appeal Br. 3; Reply Br. 3). Appeal2017-008437 Application 14/627,589 STATEMENT OF THE CASE Appellants' disclosure "relates to bioavailable fill compositions containing [] fexofenadine, soft gelatin capsules filled with the bioavailable fexofenadine fill compositions, and methods of making same" (Spec. ,r 1 ). Claim 1 is representative and reproduced below: 1. A bioavailable liquid softgel fill composition comprising: a) 4-40% by weight of fexofenadine or a fexofenadine salt; b) a matrix comprising: i) 40-80% by weight of a pharmaceutically acceptable poly(alkylene glycol); ii) 5-30% by weight of a pharmaceutically acceptable alkylene glycol; iii) 1-10% by weight of a pharmaceutically acceptable polymeric solubilizing agent; and iv) 0.001- 0.4% by weight of a pharmaceutically acceptable surfactant; and c) 0.001-2% by weight of a pharmaceutically acceptable acidulant; based on the total weight of the composition, provided that said fexofenadine or fexofenadine salt and said pharmaceutically acceptable surfactant are present in a ratio of about 40000: 1 to 30: 1 by weight. (Appeal Br. 18.) Appellants' claims stand rejected as follows: Claims 1-15, 22, 23, 25, and 30-35 stand rejected under 35 U.S.C. § I03(a) as unpatentable over the combination ofVamvakas6 and Wilson. 7 6 Vamvakas et al., US 2015/0108033 Al, published Apr. 23, 2015. 7 Wilson et al., US 6,287,594 B 1, issued Sept. 11, 2001. 2 Appeal2017-008437 Application 14/627,589 ISSUE Does the preponderance of evidence relied upon by Examiner support a conclusion of obviousness? FACTUAL FINDINGS (FF) FF 1. Vamvakas discloses that "[ s ]olubilizing hydrophobic and amphiphilic active drug substances for efficient oral delivery remains a problem ... because of precipitation of the active" (Vamvakas ,r 3; see Appeal Br. 5 ("fexofenadine is ... quite hydrophobic")). FF 2. Vamvakas disclose that "there is an unmet need in the field for soft capsule pharmaceutical formulations that are suitable for poorly soluble active drug substances, which increase bioavailability and inhibit or reduce the affinity of the P-gp transporter for poorly soluble active drug substances" (Vamvakas ,r 7; see id. ,r 4 (Vamvakas discloses that "[s]oft capsules have gained popularity and acceptance over tablets and hard capsules due to their elegant and clear appearance")). FF 3. Vamvakas discloses "pharmaceutical formulations suitable for poorly soluble active drug substances that in some embodiments may inhibit or reduce the affinity of the P-gp transporter for the poorly active drug substances" and "may further increase the permeability of the active drug substances" (Vamvakas ,r 8; see also id. ,r 2 (Vamvakas discloses "pharmaceutical compositions for the delivery of poorly soluble active pharmaceutical ingredients" and "[i]n particular, a substantially clear fexofenadine HCl[sJ solution in a soft gelatin capsule"); see id. ,r 50 ("The 8 See e.g., Appeal Br. 19 ("fexofenadine salt is fexofenadine hydrochloride"). 3 Appeal2017-008437 Application 14/627,589 term 'substantially' as used [in Vamvakas] ... means to a great or significant extent, but not completely")). FF 4. Vamvakas discloses that "pharmaceutical excipients such as surfactants, polyethylene glycols, solubilizing polymers, and classes of lipids can indirectly reduce or inhibit P-gp transporter activity (Vamvakas ,r 70). FF 5. Vamvakas discloses "[i]n one aspect, the solubility enhancing agent comprises polyethylene glycol, propylene glycol, or glycerol. In another aspect, the solubility enhancing agent comprises polyethylene glycol and propylene glycol. In another aspect, polyethylene glycol has a molecular weight of about 200 to about 1000" (Vamvakas ,r 10; see also id. ,r,r 63-64). FF 6. Vamvakas discloses "[i]n one aspect, the surfactant comprises an anionic surfactant," such as "sodium lauryl sulfate, sodium docusate, sodium sterate, or ammonium lauryl sulfate" (Vamvakas ,r 12; see id. ,r 5 (Vamvakas discloses that a surfactant disperses emulsions, generated by the solubilization of an active ingredient in an oil phase, in an aqueous environment); see also id. ,r,r 56-57). 4 Appeal2017-008437 Application 14/627,589 FF 7. Vamvakas exemplifies a matrix fill that comprises: [P]olyethylene glycol 400[9J comprises about 59% of the matrix fill mass, propylene glycol[lOJ comprises about 15% of the matrix fill mass, Povidone[llJ K 90 comprises about 3.3% of the matrix fill mass, citric acid comprises about 1 % of the matrix fill mass, sodium lauryl sulfate comprises about 4.2% of the matrix fill mass, the active pharmaceutical ingredient comprises about 15% of the matrix fill mass, and water comprises about 2.5% of the matrix fill mass. (Vamvakas ,r 81; see id. ,r 51 ("The term 'about' as used [ in Vamvakas] ... refers to any value that is within a variation of up to ± 10% of the value modified by the term 'about'"); id. ,r 9 (V amvakas' matrix fill comprises about 40-85% solubility enhancing agent, about 1-10% viscosity enhancing agent, about 1-7% surfactant, about 1-3% pH-modifying agent, and about 5- 33% pharmaceutical ingredient); see Final Act. 5 (Examiner finds that "[t]he ratio of the active pharmaceutical ingredient ( fexofenadine) to the matrix as instantly claimed is 15/(59+15+3.3+4.2) = 15/81.5 which is equivalent to a weight ratio of 1 :5.4); see also Final Act. 4---6 and 8.) FF 8. Examiner finds that "Vamvakas do[es] not specifically teach or exemplify [a composition] ... comprising 0.001 to 0.4 wt% of a surfactant 9 See e.g., Appeal Br. 19 ("pharmaceutically acceptable poly(alkylene glycol) is selected from the group consisting of PEG 200 to PEG 8000, and mixtures thereof'); see also Spec. ,r,r 9 and 12. 10 See e.g., Appeal Br. 19 ("pharmaceutically acceptable alkylene glycol is propylene glycol"); see also Spec. ,r,r 9 and 12. 11 Examiner finds that "provodone" is otherwise known in the art as "polyvinylpyrrolidone or PVP" (Final Act. 6); see also Appeal Br. 19 (pharmaceutically acceptable polymeric solubilizing agent is a polyvinylpyrrolidone (PVP)); Spec. ,r 9 ("polyvinylpyrrolidone (povidone)"); Spec. ,r 12 ("PVP is selected from the group consisting of ... PVP K90")). 5 Appeal2017-008437 Application 14/627,589 as required by [Appellants'] claim 1" and relies on Wilson to make up for this deficiency in Vamvakas (Final Act. 6-7). FF 9. Wilson "relates to pharmaceutically elegant compositions for oral administrations," wherein such "compositions ... include at least one pharmaceutically active agent having at least one acid moiety, preferably a carboxylic acid moiety," such as "fexofenadine" (Wilson 1: 11--47; id. at 3:45-54 ("Active Ingredients for [Wilson's] compositions ... [include] fexofenadine"); id. at 4:37-39 (Wilson discloses the use of an Active Ingredient at a concentration range "from about 5 percent to about 25 percent (w/w)); see Appeal Br. 14 ("fexofenadine contains a free carboxylic acid group"); see Final Act. 7). FF 10. Wilson discloses: soft gelatin capsules ... comprising: one or more pharmaceutically active agents wherein said pharmaceutically active agent is selected from the group consisting of said agents wherein at least one of said agents having at least one acid moiety, and at least one of said agents having at least one ester group or other chemically active moiety in which the terminal moiety to said ester group or other chemically active moiety is hydrolyzed or otherwise removed in situ or in vivo forming at least one acid moiety; and wherein said pharmaceutically active agent is soluble in acid at a ratio of about 3: 1 ( acid to solute) to about 10,000: 1 ( acid to solute) or a pharmaceutically acceptable salt thereof (hereinafter, the "Active Ingredient"); at least one dispersing agent; and at least one solubilizing agent; and, optionally, at least one surfactant; and, further optionally, at least one plasticizing agent. 6 Appeal2017-008437 Application 14/627,589 The present invention further relates to the use of the compositions of the present invention for improving adsorption of the Active Ingredients. (Wilson 2:33-55; see Final Act. 7.) FF 11. Wilson discloses the PVP is a dispersing agent within the scope of its invention and exemplified the use of PVP at a concentration of 4%, 6.3%, 10%, and 15% (w/w) (Wilson 4:40-50; 12: 1-13; 12:40-50; 13: 10-20; 10:48-59; see Final Act. 7). FF 12. Wilson discloses that "[d]ispersing polymers generally are selected to ensure appropriate uniformity using viscosity while providing a pharmaceutically elegant appearance to the resulting solution" (Wilson 4:60-63; see Final Act. 7). FF 13. Wilson discloses that "polyethylene glycols (PEG) having molecular weights from about 200 to about 8,000" are solubilizing agents within the scope of its invention and are used in a concentration "from about O percent (Oust greater than zero) to about 99 percent (w/w)" (Wilson 5:16-46; id. at 20:1-16; see Final Act. 7). FF 14. Wilson discloses the "propylene glycol" is a plasticizing agent within the scope of its invention and are used in a concentration "from about zero percent [(]Oust greater than zero) to about 25% (w/w)" (Wilson 5:50- 63; id. at 20:1-16; see Final Act. 7). FF 15. Wilson discloses the use of surfactants "well known in the pharmaceutical formulation art" in a "concentration ranging from about zero percent to about 10 percent (w/w) of the total composition" (Wilson 6:7-17; id. at 20: 1-16; see Final Act. 7 and 9). FF 16. Wilson discloses the use of reagents to maintain the composition at a proper pH (see Wilson 6:24--54). 7 Appeal2017-008437 Application 14/627,589 ANALYSIS Based on the combination of V amvakas and Wilson, Examiner concludes that, at the time Appellants' invention was made, it would have been prima facie obvious to modify the amount of surfactant or sodium lauryl sulfate [ (SLS)] in the soft capsule matrix fill compositions of Vamvakas ... because Wilson teach[ es] it is known in the art to formulate soft matrix fills comprising fexofenadine, PVP, PEG 400, propylene glycol and water in combination with ( optionally) at least one surfactant from zero to about 10%. (Final Act. 8-9; see FF 1-16). In addition, Examiner reasons that Appellants' claimed ratio of ratio of fexofenadine to surfactant/SLS of about 40000:1 to 30:1, about 40000:1 to 30:1, because the combined teaching of Vamvakas in view of Wilson render obvious compositions comprising 5 to 25 wt% fexofenadine HCl and surfactants inclusive of SLS from O to 10 wt%, the combine teachings of the prior art render obvious a ratio of about infinity ( dividing either 5 or 25 wt% fexofenadine by zero) to about 0.5 which overlaps [Appellants'] ... claimed range(s). (Final Act. 9.) Appellants contend that "[t]he mere fact that Wilson describes oral liquid compositions with a surfactant about zero percent to about 10% does not provide the necessary motivation for one of ordinary skill in the art to us 0.001-[] 0. 4 % surfactant in the context of the V amvakas composition" (Appeal Br. 9; Reply Br. 3--4 and 6-8). In this regard, Appellants contend that Vamvakas and Wilson address different problems relating to pharmaceutical formulations (Appeal Br. 9-10; Reply Br. 4). We are not persuaded. 8 Appeal2017-008437 Application 14/627,589 As Examiner explains, the logic of the rejection does not hinge on the mere fact that Wilson describes oral liquid compositions comprising about 0 to about 10% surfactant. Rather, the rejection is predicated on the fact that Wilson, like Vamvakas, render obvious a pharmaceutical composition comprising an active agent such as fexofenadine, at least one dispersing agent such as PVP, at least one solubilizing agent such as PEG 400 and water, at least one surfactant, and at least one plasticizing agent such as propylene glycol. (Ans. 3.) Thus, notwithstanding Appellants' contentions to the contrary, Vamvakas and Wilson both related to pharmaceutically elegant soft gel capsules comprising fexofenadine, polyethylene glycol, propylene glycol, PVP, and a surfactant (see FF 1-16). Therefore, a person of ordinary skill in this art would have had a reason and motivation to consider Vamvakas and Wilson in combination when preparing pharmaceutically elegant soft gel capsule formulations comprising the foregoing ingredients (see Ans. 3 ("Wilson is indisputably analogous to Vamvakas")). We are not persuaded by Appellants' contention that a person of ordinary skill in this art would not have been motivated to reduce the amount of surfactant disclosed by Vamvakas, because Vamvakas discloses that surfactant is important in solubilizing fexofenadine and "can indirectly reduce or inhibit P-gp transporter activity" (Appeal Br. 10-12). Vamvakas discloses that "pharmaceutical excipients such as surfactants, polyethylene glycols, solubilizing polymers, and classes of lipids can indirectly reduce or inhibit P-gp transporter activity" (FF 4; see Ans. 5-6; cf Appeal Br. 12 ("there is no teaching from the cited art that an increase in PEGs or PVPs (if any) could offset the decrease in surfactant at the same magnitude in terms of the P-gp transporter inhibiting activity")). Thus, notwithstanding 9 Appeal2017-008437 Application 14/627,589 Appellants' contentions to the contrary, Vamvakas expressly discloses that, inter alia, PEG can be used to indirectly reduce or inhibit P-gp transporter activity. Thus, we find no err in Examiner's reasoning, as quoted by Appellants, that "any loss on the P-gp transporter inhibiting activity due to decrease in surfactant's percentage of the Vamvakas composition would be offset by PEGs" (Appeal Br. 12; see Ans. 12 6). Consistent with Vamvakas' disclosure, Wilson discloses a soft gel capsule comprising fexofenadine, wherein the concentration ranges of PEG, propylene glycol, PVP, and surfactant overlap and are broader than those disclosed in Vamvakas (see FF 10-15; cf FF 7). Included in Wilson's disclosed ranges is a range of surfactant "from about zero percent to about 10 percent" (FF 15). As discussed above, Examiner explains that a person of ordinary skill in this art would have recognized from Vamvakas that when the concentration of surfactant is reduced, "any loss on the P-gp transporter inhibiting activity due to [a] decrease in [the] surfactant's percentage" would be offset by an increase in the concentration of PEG and PVP within the ranges disclosed by Vamvakas and Wilson (see Appeal Br. 12; FF 4, 7, and 10-15). See Iron Grip Barbell Co. v. USA Sports, Inc., 392 F.3d 1317, 1322 (Fed. Cir. 2004) ("[W]here there is a range disclosed in the prior art, and the claimed invention falls within that range, there is a presumption of obviousness."); see also In re Aller, 220 F.2d 454, 456 (CCPA 1955) ("[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation."). Thus, we are not are not persuaded by Appellants' 12 Examiner's March 22, 2017 Answer. 10 Appeal2017-008437 Application 14/627,589 contentions regarding In re Patel, 566 Fed. Appx. 1005 (Fed. Cir. 2014) (Appeal Br. 13-14; Reply Br. 9). We are not persuaded by Appellants' contention that increasing the relative amounts of components, such as PEG and PVP, would necessarily result in an increase in the relative amount of fexofenadine (Reply Br. 8). As discussed above, Vamvakas discloses that "pharmaceutical excipients such as surfactants, polyethylene glycols, solubilizing polymers, and classes of lipids can indirectly reduce or inhibit P-gp transporter activity" (FF 4; see also Ans. 5-6). Thus, notwithstanding Appellants' contention to the contrary, a person of ordinary skill in this art would have found it prima facie obvious, in view of the combination of Vamvakas and Wilson, to increase the amount of PEG relative to surfactant without increasing the amount of fexofenadine in the composition (see Ans. 6-7; see also FF 1- 16). There is no requirement in Appellants' claimed invention that the claimed composition is clear (see Appeal Br. 18; see also Reply Br. 4--5). In this regard, Appellants do not identify, and we do not find, a disclosure in Appellants' Specification relating to a clear composition. Thus, we are not persuaded by Appellants' contentions or Zhang's statements relating to a clear composition (see Appeal Br. 14--15; Zhang Dec. 13 ,r 5). See In re Greenfield, 571 F.2d 1185, 1189 (CCPA 1978) (In order to establish unexpected results for a claimed invention, objective evidence of non- obviousness must be commensurate in scope with the claims which the evidence is offered to support.). 13 March 2, 2016 Declaration of Zhang Julia Zhang. 11 Appeal2017-008437 Application 14/627,589 We are not persuaded by Zhang' s statement: It was unexpected that the specific combination of poly(alkylene glycol) ... , propylene glycol, a solubilizing polyer (such as polyvinylpyrrolidone), water, and acidulant (such as citric acid), in the presently claimed proportions by weight, provided a solubilizing matrix that is useful for dissolving fexofenadine HCl with only a low wt% (0.001 %- 0.5%) of a surfactant (such as sodium lauryl sulfate). (Zhang Dec. ,r 9; cf FF 1-16.) As discussed above, Wilson discloses solubilizing fexofenadine in a composition comprising PEG, propylene glycol, and PVP in concentrations encompassing Appellants' claimed range, with surfactant at a concentration "from about zero percent to about 10 percent (w/w)" (FF 10-15). Thus, as discussed above, the combination of Vamvakas and Wilson makes obvious the solubilization of fexofenadine in a composition falling with the scope of Appellants' claimed invention (see FF 1-16). Therefore, we are not persuaded by Zhang's assertion that such a result would have been unexpected on this record (see Zhang Dec. ,r 9; see also Reply Br. 5-7 and 9-10). We are not persuaded by Zhang's reliance on Patel, 14 which does not address compositions comprising PEG, propylene glycol and PVP (see Zhang Dec. ,r 5). In this regard, we note that Vamvakas discloses that "surfactant disperses emulsions, generated by the solublization of an active ingredient in an oil phase, in an aqueous environment" (FF 6) and Wilson discloses the use of PVP as a dispersing agent "to ensure appropriate uniformity using viscosity while providing a pharmaceutically elegant appearance to the resulting solution" (FF 11-12). 14 Patel et al., Preparation and evaluation of self microemulsifying drug delivery system for fexofenadine hydrochloride, 3 J. DRUG DELIVERY & THERAPEUTICS 26-32 (2013). 12 Appeal2017-008437 Application 14/627,589 For the foregoing reasons we are not persuaded by Appellants' contentions that Examiner's rejection is based in improper hindsight (Reply Br. 10-11). Arguments made, for the first time, in Appellants' Reply Brief are not timely filed and were not included in our deliberations (see e.g. Reply Br. 5- 6 (citing Savjani 15)). See Ex parte Borden, 93 USPQ2d 1473, 1474 (BPAI 2010) (informative) (Appellant fails to "explain what 'good cause' there might be to consider the new argument. On this record, Appellant's new argument is belated."). CONCLUSION The preponderance of evidence relied upon by Examiner supports a conclusion of obviousness. The rejection of claim 1 under 35 U.S.C. § 103(a) as unpatentable over the combination of Vamvakas and Wilson is affirmed. Claims 2-15, 22, 23, 25, and 30-35 are not separately argued and fall with claim 1. TIME PERIOD FOR RESPONSE 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 15 Savjani et al., Drug Solubility: Importance and Enhancement Techniques, ISRN PHARMACEUTICS (2012). 13 Copy with citationCopy as parenthetical citation