Ex Parte Betageri

Patent Trial and Appeal BoardNov 1, 2012

10999831 (P.T.A.B. Nov. 1, 2012)

UNITED STATES PATENT AND TRADEMARK OFFICE __________ BEFORE THE PATENT TRIAL AND APPEAL BOARD __________ Ex parte GURU V. BETAGERI __________ Appeal 2011-012356 Application 10/999,831 Technology Center 1600 __________ Before DEMETRA J. MILLS, ERIC GRIMES, and JEFFREY N. FREDMAN, Administrative Patent Judges. FREDMAN, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. § 134 involving claims to a method of making a formulation for administration to patients. The Examiner rejected the claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We reverse. Appeal 2011-012356 Application 10/999,831 2 Statement of the Case Background “[T]he invention relates to coated proliposomal formulations for poorly water soluble drugs” (Spec. 1 ¶ 0002). According to the Specification, “when a coating . . . is combined with a proliposomal formulation . . . drug delivery is enhanced. . . . this novel and unexpected enhancement, which results from the unique combination of a coating and a proliposomal formulation, relates to increased drug absorption, stability and bioavailability.” (Spec. 2 ¶ 0006). The Claims Claims 1 and 3-27 are on appeal. Claim 1 is representative and is reproduced below: 1. A method of making a formulation suitable for administration to a patient, consisting essentially of: providing one or more phospholipids; providing one or more biologically active agents; providing one or more surfactants; mixing said one or more biologically active agents, said one or more surfactants, and at least a portion of said one or more phospholipids with a non-aqueous solvent without exposure to an aqueous phase; removing said non-aqueous solvent, thereby making a dry powder, wherein said dry powder comprises said one or more phospholipids, said one or more surfactants, and said one or more biologically active agents; and coating said dry powder with one or more coatings selected from the group consisting of a cellulose-based agent, povidone and polyethylene, thereby making coated particles. Appeal 2011-012356 Application 10/999,831 3 The Issues A. The Examiner rejected claims 1, 3-14, and 17-27 under 35 U.S.C. § 103(a) as obvious over Ganter,1 Boulikas,2 Barchfeld,3 Huang,4 Mehta,5 and Szente6 (Ans. 5-6). B. The Examiner rejected claim 8 under 35 U.S.C. § 103(a) as obvious over Ganter, Boulikas, Barchfeld, Huang, Mehta, Szente, and Lee7 (Ans. 6- 7). C. The Examiner rejected claim 9 under 35 U.S.C. § 103(a) as obvious over Ganter, Boulikas, Barchfeld, Huang, Mehta, Szente, and Fraser8 (Ans. 7). D. The Examiner rejected claim 15 and 16 under 35 U.S.C. § 103(a) as obvious over Ganter, Boulikas, Barchfeld, Huang, Mehta, Szente, and Desai9 (Ans. 7-8). E. The Examiner rejected claims 1 and 3-27 on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-25 of U.S. Patent No. 6,849,269 (Ans. 8). 1 Ganter et al., US 5,635,206, issued Jun. 3, 1997. 2 Boulikas, T., US 6,511,676 B1, issued Jan. 28, 2003. 3 Barchfeld et al., US 5,709,879, issued Jan. 20, 1998. 4 Huang et al., US 6,133,026, issued Oct. 17, 2000. 5 Mehta et al., US 5,811,119, issued Sep. 22, 1998. 6 Szente et al., US 6,432,928 B1, issued Aug. 13, 2002. 7 Lee et al., US 5,643,599, issued Jul. 1, 1997. 8 Fraser et al., US 6,180,604 B1, issued Jan. 30, 2001. 9 Desai, A., US 5,206,219, issued Apr. 27, 1993. Appeal 2011-012356 Application 10/999,831 4 A. 35 U.S.C. § 103(a) over Ganter, Boulikas, Barchfeld, Huang, Mehta, and Szente The Examiner finds that Ganter “teaches that a mixture suitable for the preparation of liposomes can be made by mixing lecithin (phospholipid), solubilizer (alcohol) and/or lipophilic and hydrophilic active agents and preparing a dry powders without the addition of water” (Ans. 5). The Examiner finds that “Boulikas, Barchfield [sic] and Huang teach that liposomes can be coated with a hydrophilic polymer such as hydroxyethylcellulose or polyethylene glycol” (Ans. 5). The Examiner finds that “Mehta while disclosing preliposomal formulations teaches that intercalation promoter agents such as polysorbates can be included” (Ans. 5). The Examiner finds that “Szente teaches that proliposomal compositions containing taxol wherein the taxol is dissolved in mixed micelles system containing bile acid salt and phospholipids which form liposomes spontaneously is known” (Ans. 6). The Examiner finds it obvious to coat Ganter’s particles since “Boulikas, Barchfield [sic] and Huang teach hydroxyethylcellulose as routine coating compounds of the phospholipid containing compositions” (Ans. 6). Appellant “submits that Ganter does not teach the claim element of independent claim 1 directed at ‘removing said non-aqueous solvent, thereby making a dry powder’” (App. Br. 14). Appellant “submits that the Office has not provided a reason for why one of ordinary skill in the art would, after reading Ganter and Mehta, or any of the other cited references, add the Appeal 2011-012356 Application 10/999,831 5 additional step of removing non-aqueous solvent to the method of making a proliposomal formulation.” (App. Br. 15-16). Appellant “submits that the Examiner’s question ‘if there is only 0 % water in Ganter’s method, how can the structure be a larmellar structure’ actually reveals the Office’s recognition of the fact that the Ganter formulations contain an aqueous phase” (App. Br. 16-17). Appellant contends that “unexpected improvements of the claimed proliposornal formulations are achieved by preparing a proliposomal dry powder without exposure to an aqueous phase and removing the nonaqueous solvent” (App. Br. 17). Appellant contends that “the mere teaching that liposomal compositions can be coated using hydroxyethylcellulose or polyethylene glycol does not mean that one of skill in the art would have looked to the references for coating proliposomal compositions” (App. Br. 20). The issues with respect to this rejection are: (i) Does the evidence of record support the Examiner’s conclusion that the cited prior art renders claim 1 obvious? (ii) If so, has Appellant presented evidence of secondary considerations that, when weighed with the evidence of obviousness, is sufficient to support a conclusion of non-obviousness? Findings of Fact 1. Ganter teaches “a process for the preparation of liposomes or proliposomes in which a mixture suitable for their preparation is milled in an agitator-ball mill” (Ganter, col. 1, ll. 13-15). Appeal 2011-012356 Application 10/999,831 6 2. Ganter teaches that “[l]ecithins of various origin, for example, egg lecithin or soya lecithin are used in mixtures which can be used to prepare liposomes or proliposomes” (Ganter, col. 2, ll. 8-10). 3. Ganter teaches that “[s]uitable compounds which can be incorporated are lipophilic or hydrophilic substances, such as, lipophilic or hydrophilic vitamins, pharmaceuticals, as well as, flavorants and odorants” (Ganter, col. 2, ll. 15-18). 4. Ganter teaches that “[s]olubilizers which can be used are polar organic solvents, for example, alcohols, such as, ethanol, iso-propanol and the like” (Ganter, col. 2, ll. 12-14). 5. Ganter teaches that “[p]roliposomal formulations preparations [sic, prepared?] by the process of the invention are distinguished by a very regular, long lamellar structure” (Ganter, col. 2, ll. 60-62). 6. Example 1 of Ganter teaches preparation of a proliposomal solution with the formula of 120 g of lecithin (= 60% wt./wt.), 24 g of tocopherol acetate (= 12% wt./wt.), 42 g of ethanol (= 21% wt./wt.), and remainder to (“ad”) 200 g of distilled water (= 7% wt./wt.) (Ganter, col. 3, ll. 40-52). 7. Boulikas teaches “liposomes provide the outer lipid bilayer surfaces that are coated with the hydrophilic polymer, PEG. . . . Other hydrophilic polymers include hyaluronic acid, polyvinylpyrrolidone, DSPE, hydroxyethylcellulose” (Boulikas, col. 17, ll. 32-37). 8. Barchfeld teaches that “viscosity enhancers are also added to some formulations [of liposomes] generally believed that these polymeric substances coat the particles and prevent contact which otherwise would Appeal 2011-012356 Application 10/999,831 7 result in aggregation, fusion or coalescence. Polymers used include polyethylene glycol” (Barchfeld, col. 31, ll. 35-40). 9. Huang teaches “liposomes having a surface coating of hydrophilic polymer chains, effective to extend the blood circulation time of the plasmid/liposome complexes. Suitable hydrophilic polymers include polyethylene glycol” (Huang, col. 5, ll. 35-39). 10. Mehta teaches that a “suitable intercalation promoter agent will permit the high molar ratio of carotenoid to lipid that is desired for the present invention, without substantial crystallization from the liposomes after they are reconstituted in aqueous solution” (Mehta, col. 7, ll. 1-5). 11. Mehta teaches that prior “to lyophilization, the carotenoid, lipids, and intercalation promoter agent can be dissolved in an organic solvent, such as t-butanol. Lyophilization to form a preliposomal powder can be performed using commercial apparatus which is known to persons skilled in this field” (Mehta, col. 7, ll. 14-18). 12. Szente teaches that “[t]axol is dissolved in a mixed micelle system containing bile acid salt and phospholipide [sic] and the spontaneously formed liposomes are diluted. The solubility of Taxol can be increased only to 0.8 mg/ml even by using various bile acid salts” (Szente, col. 2, ll. 58-62). 13. Tables 4 and 5 of the Specification are reproduced below: Appeal 2011-012356 Application 10/999,831 8 Tables 4 and 5 show comparative results between the method of Ganter in U.S. Patent 5,635,206 and the method of the Specification (see Spec. 18-19 ¶ 0078). Principles of Law The Examiner has the initial burden of establishing a prima facie case obviousness under 35 U.S.C. § 103. In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992). “The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield Appeal 2011-012356 Application 10/999,831 9 predictable results.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007). Prima facie obviousness can be rebutted by presenting evidence of secondary considerations and when such evidence is submitted, all of the evidence must be considered anew. In re Piasecki, 745 F.2d 1468, 1472- 1473 (Fed. Cir. 1984). Secondary considerations include: long-felt but unsolved needs, failure of others, unexpected results, commercial success, copying, licensing, and praise. In re Rouffet, 149 F.3d 1350, 1355 (Fed. Cir. 1998). Analysis We adopt the Examiner’s findings regarding the scope and content of the prior art (Ans. 5-8) and agree with the conclusion that the method of making a proliposomal formulation would have been prima facie obvious in view of the cited references. Appellant presents arguments disputing the prima facie case of obviousness, but we do not find it necessary to address these arguments since, as discussed below, we conclude that the evidence of unexpected results has successfully rebutted the prima facie case of obviousness. We agree with Appellant that the evidence of unexpected results presented in the Specification is sufficient to rebut the prima facie case of obviousness over the Ganter and the other cited references. As Appellant points out, the texture, yield, and particle size resulting from Appellant’s method significantly exceeds the same values for Ganter’s (see Spec. 18-19, tables 4-5; FF 13). Appeal 2011-012356 Application 10/999,831 10 We note that the Specification actually compared controls which are closer to the claimed invention than the closest example in Ganter, where Example 1 teaches the inclusion of 7% water (FF 6). In tables 4 and 5, the comparison with Ganter used either 5% water or 0% water to compare to the method of the Specification using 0 % water (FF 13). The Specification showed that the yield for the inventive method was 97.8%, compared to 55- 69% for the control method, and the particle size was substantially larger than the control method of Ganter using either 0% or 5% water (FF 13). The Specification states that the larger particle size is “advantageous for ease of coating and increased stability and absorption in the gastrointestinal tract” (Spec. 20, ¶ 0079). The Examiner finds that: When the solvent is removed totally from the phospholipid, Glyburide mixture, one would expect the hydrophobic Glyburide to exist as an intimate mixture with the phospholipid and when hydrated, sequester into the phospholipid bilayer. If the solvent is present part of Glyburide will still be in a solution form. Therefore, the Examiner does not consider this finding as unexpected (Ans. 12). We are not persuaded since the Examiner seems to be making some sort of expectation argument, but provides no logic which would suggest that the inclusion of Appellant’s “removing the non-aqueous solvent” step would have the property of increasing yields or particle size. If the Examiner intends to argue that the claims are not commensurate in scope by this argument, we are not persuaded since two different drugs were compared. See In re Kao, 639 F.3d 1057, 1068 (Fed. Cir. 2011) (“If an Appeal 2011-012356 Application 10/999,831 11 applicant demonstrates that an embodiment has an unexpected result and provides an adequate basis to support the conclusion that other embodiments falling within the claim will behave in the same manner, this will generally establish that the evidence is commensurate with [the] scope of the claims.”). Conclusions of Law (i) The evidence of record supports the Examiner’s conclusion that the cited prior art renders claim 1 obvious. (ii) Appellant has presented evidence of secondary considerations that, when weighed with the evidence of obviousness, is sufficient to support a conclusion of non-obviousness. B.-D. 35 U.S.C. § 103(a) Each of these rejections relies upon the underlying obviousness rejection including Ganter. Having reversed the rejection of claim 1 over Ganter, Boulikas, Barchfeld, Huang, Mehta, and Szente, we necessarily reverse these obviousness rejections, which do not overcome the unexpected result demonstrated in Appellant’s Specification (FF 13). E. Double Patenting The rejection of claims 1 and 3-27 on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-25 of U.S. Patent No. 6,849,269 is moot in view of the terminal disclaimer filed June 27, 2011 and accepted on August 5, 2011. Appeal 2011-012356 Application 10/999,831 12 SUMMARY In summary, we reverse the rejection of claims 1, 3-14, and 17-27 under 35 U.S.C. § 103(a) as obvious over Ganter, Boulikas, Barchfeld, Huang, Mehta, and Szente. We reverse the rejection of claim 8 under 35 U.S.C. § 103(a) as obvious over Ganter, Boulikas, Barchfeld, Huang, Mehta, Szente, and Lee. We reverse the rejection of claim 9 under 35 U.S.C. § 103(a) as obvious over Ganter, Boulikas, Barchfeld, Huang, Mehta, Szente, and Fraser. We reverse the rejection of claims 15 and 16 under 35 U.S.C. § 103(a) as obvious over Ganter, Boulikas, Barchfeld, Huang, Mehta, Szente, and Desai. REVERSED lp