Ex Parte Gao et al

Patent Trial and Appeal BoardNov 5, 2012

11418338 (P.T.A.B. Nov. 5, 2012)

UNITED STATES PATENT AND TRADEMARK OFFICE __________ BEFORE THE PATENT TRIAL AND APPEAL BOARD __________ Ex parte JULIA ZH GAO and RAJESHWAR MOTHERAM __________ Appeal 2011-006428 Application 11/418,338 Technology Center 1600 __________ Before ERIC GRIMES, FRANCISCO C. PRATS, and STEPHEN WALSH, Administrative Patent Judges. PRATS, Administrative Patent Judge. DECISION ON APPEAL This appeal under 35 U.S.C. § 134 involves claims to a pharmaceutical composition. The Examiner entered rejections for obviousness and obviousness-type double patenting. We have jurisdiction under 35 U.S.C. § 6(b). We affirm. STATEMENT OF THE CASE Claims 1, 2, 4-6, 14, and 15 stand rejected and appealed (App. Br. 1). The claims have not been argued separately and therefore stand or fall together. See 37 C.F.R. § 41.37(c)(1)(vii). Claim 1 is representative and reads as follows: Appeal 2011-006428 Application 11/418,338 2 1. A pharmaceutical composition for oral administration comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I), monohydrate, or pharmaceutically acceptable salt thereof and a non-reactive coating, wherein the non-reactive coating is a coating having polyethylene glycol as plasticizer, and wherein the non-reactive coating does not cause decomposition of the compound of formula (I). The following rejections are before us for review: 1 (1) Claims 1, 2, 14, and 15, on the ground of nonstatutory obviousness-type double patenting over claims 43 and 46 of Das 2 in view of Niazi 3 (Ans. 4-5); (2) Claims 4-6, on the ground of nonstatutory obviousness-type double patenting over claims 43 and 46 of Das in view of Niazi, Li, 4 and Bolhuis 5 (Ans. 5-7); 1 The Examiner withdrew the rejection of claim 14 under 35 U.S.C. § 112, first paragraph (Ans. 3). 2 U.S. Patent No. 6,596,746 B1 (issued July 22, 2003). 3 SARFARAZ K. NIAZI, HANDBOOK OF PHARMACEUTICAL MANUFACTURING FORMULATIONS, COMPRESSED SOLID PRODUCTS, 267, 269 (vol. 1 2004). 4 Jason Z. Li et al., The Role of Intra- and Extragranular Microcrystalline Cellulose in Tablet Dissolution, 1 PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY 343-355 (1996). 5 G.K. Bolhuis et al., Improvement of dissolution of poorly soluble drugs by solid deposition on a super disintegrant. II. The choice of super Appeal 2011-006428 Application 11/418,338 3 (3) Claims 1, 2, 14, and 15, under 35 U.S.C. § 103(a) obvious over Das and Niazi (Ans. 7-9); and (4) Claims 4-6, under 35 U.S.C. § 103(a) as obvious over Das, Niazi, Li, and Bolhuis (Ans. 9-11). OBVIOUSNESS In rejecting claims 1, 2, 14, and 15 as obvious under 35 U.S.C. § 103(a), the Examiner cited Das as describing a pharmaceutical composition that contained salts of dasatinib, 6 the compound of formula (I) (Ans. 7). The Examiner conceded, however, that Das did not describe “compositions of dasatinib with a non-reactive coating” (id. at 8). To address this deficiency, the Examiner cited Niazi as teaching that “pharmaceutical dosage forms are often coated to hide surface defects, enhance aesthetic appeal by adding colors, provide protection from the environment, and accomplish other goals” (id.). The Examiner also cited Niazi as teaching that “film coatings generally include a polymer such as hydroxypropyl methylcellulose, a solvent such as water, and a plasticizer, and that coating choice is dependent upon the purpose of the coating” (id.). The Examiner further found, as required by claim 1, that Niazi described a number of different exemplary coatings that included polyethylene glycol (PEG) as a plasticizer (id.). Based on the ingredients included in those coatings, the Examiner reasoned that “[t]here is no reason disintegrants and effect of granulation, 5 EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES 63-69 (1997). 6 “The compound of formula (I) is also known as „dasatinib,‟ and is now sold in the United States under the tradename Sprycel ®” (App. Br. 2). Appeal 2011-006428 Application 11/418,338 4 to believe that these coatings will react with dasatinib, thus they are considered to be non-reactive toward dasatinib” (id.). In view of the references‟ teachings, the Examiner further reasoned that an ordinary artisan would have considered it obvious to “combine the teachings of Das and Niazi to create oral pharmaceutical compositions of salts, monohydrates, or solvates of dasatinib, a pharmaceutically acceptable carrier, and a non-reactive coating” (id.). The Examiner found that the artisan would have been prompted to provide Das‟ pharmaceutical compositions with a PEG-containing non-reactive coating, such as that described by Niazi, “to hide surface defects, enhance aesthetic appeal, or provide protection from the environment since Niazi teaches that these goals can be accomplished by film coatings” (id.). 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‟ arguments do not persuade us that a preponderance of the evidence fails to support the Examiner‟s conclusion that claim 1 would have been prima facie obvious to an ordinary artisan, nor are we persuaded that the evidence of unexpected results advanced by Appellants is sufficient to overcome the Examiner‟s prima facie case. Specifically, Appellants contend that, before their invention, an ordinary artisan “would not have used a coating containing PEG as plasticizer on a composition containing the compound of formula (I) because Appeal 2011-006428 Application 11/418,338 5 the art teaches that PEG can degrade oxidatively sensitive drugs, such as the compound of formula (I)” (App. Br. 6). Therefore, Appellants argue, “the art teaches away from using PEG as the plasticizer in a coating for a pharmaceutical composition for a compound of formula (I)” (id.; see also Reply Br. 2-3). We are not persuaded. It may be true, as Appellants argue, that dasatinib contains several nitrogen atoms that an ordinary artisan would have recognized as being oxidizable by peroxides (see App. Br. 6; see also Gao Declaration 7 ¶ 7). Despite dasatinib‟s allegedly art-recognized capacity to undergo oxidation, however, Das explicitly teaches that oral formulations of its compounds, which include dasatinib, can contain PEG as an excipient (see Das, col. 26, ll. 4-6 (“Also included in such formulations may be high molecular weight excipients such as celluloses (avicel) or polyethylene glycols (PEG).”)). Thus, the prior art disclosure most directly relevant to the suitable formulations of the specific compound at issue here amply suggests that the compound of claim 1 was acceptably combined with PEG. We acknowledge the disclosure in Wade 8 pointed to by Appellants, that all grades of PEG used as a pharmaceutical excipient “can exhibit some oxidizing activity due to the presence of peroxide impurities and secondary products formed by autoxidation,” as well as the disclosure that “[m]igration of polyethylene glycol can occur from tablet film coatings, leading to 7 Declaration of Julia (Zhihui) Gao Pursuant to 37 C.F.R. § 1.132 (Declaration executed August 13, 2009). 8 HANDBOOK OF PHARMACEUTICAL EXCIPIENTS 359 (Ainley Wade and Paul J. Weller eds., 1994). Appeal 2011-006428 Application 11/418,338 6 interaction with core components” (Wade 359). However, while Wade may indicate that using PEG as an excipient can have certain drawbacks, Appellants do not point to any specific teaching in Wade stating that PEG should not be used as the plasticizer component of a protective coating for a tablet, nor do Appellants point to any specific teaching in Wade that singles out dasatinib, or similar compounds, as being incompatible with PEG. We also acknowledge Wasylaschuk‟s 9 disclosure that oxidative degradation can have deleterious effects on drug formulations, and can stymie development of marketable drug formulations, and that therefore, “[e]xcipient chemical impurity profiles can be very important in influencing the long-term chemical stability performance of the formulated drug product, particularly if an oxidatively sensitive drug is being formulated” (Wasylaschuk 106). We first note, however, that Appellants have not clearly explained how or why Wasylaschuk can properly be considered indicative of the state of the art at the time the claimed subject matter was invented, given Wasylaschuk‟s 2007 publication date as compared to Appellants‟ May 5, 2005 priority date (see Spec. 1). We note that Wasylaschuk discloses the concentrations of oxidizing hydroperoxide (HPO) contaminants in a number of excipients, including PEG (see Wasylaschuk 109 (Table 1)). However, Appellants point to no specific teaching in Wasylaschuk that singles out dasatinib as being incompatible with PEG, nor do Appellants point to any specific statement suggesting that PEG is necessarily undesirable in coatings of oxidatively sensitive drugs. Rather, Wasylaschuk notes the presence of considerable 9 Walter R. Wasylaschuk et al., Evaluation of Hydroperoxides in Common Pharmaceutical Excipients, 96 J. PHARM. SCI. 106-117 (2007). Appeal 2011-006428 Application 11/418,338 7 variation in HPO contamination across different batches and vendors, and thus proposes “active monitoring and control of HPOs by the suppliers” as well as “selection of excipients and manufacturing processes that minimize HPO concentration and enhance product stability” as tactics for addressing the contamination issue (id. at 115). Thus, while both Wade and Wasylaschuk suggest that PEG can possess undesirable oxidative contaminants that must be taken into account when preparing pharmaceutical formulations, neither reference is specifically directed to formulating the compound recited in claim 1, and neither reference specifically teaches that PEG would have been considered undesirable as a plasticizer in a coating, even if that coating were used with an oxidatively sensitive drug. Moreover, the disclosures in Wade and Wasylaschuk must be viewed in light of Das‟ explicit teaching of the compatibility of dasatinib and PEG, as well as Niazi‟s undisputed teaching that PEG was known to be a useful plasticizer in tablet coatings. Indeed, Appellants‟ own disclosure demonstrates that Appellants‟ preferred PEG-containing coating, Opadry ® White, was a commercially available product (see Spec. 7; see also Gao Declaration ¶ 11). Therefore, despite the teachings in Wade and Wasylaschuk, we agree with the Examiner that an ordinary artisan, recognizing from Niazi the advantages of providing an orally administered dosage formulation with a protective coating, would have been prompted to coat an orally administered formulation of dasatinib with an available prior art PEG-containing protective coating. Accordingly, we are not persuaded that a preponderance Appeal 2011-006428 Application 11/418,338 8 of the evidence fails to support the Examiner‟s prima facie case that claim 1 would have been obvious to an ordinary artisan. We are also not persuaded that Appellants have advanced evidence of unexpected results sufficient to outweigh the Examiner‟s prima facie case. As Appellants argue, although “[e]vidence of secondary considerations must be reasonably commensurate with the scope of the claims[,] . . . . [t]his does not mean that an applicant is required to test every embodiment within the scope of his or her claims.” In re Kao, 639 F.3d 1057, 1068 (Fed. Cir. 2011). Nonetheless, “[m]ere improvement in properties does not always suffice to show unexpected results. . . . [W]hen an applicant demonstrates substantially improved results . . . and states that the results were unexpected, this should suffice to establish unexpected results in the absence of evidence to the contrary.” In re Soni, 54 F.3d 746, 751 (Fed. Cir. 1995). Here, we acknowledge Dr. Gao‟s statement that dasatinib could form an N-oxide contaminant in the presence of oxidizing agents, such as peroxides, and that preparation of dasatinib as a drug produced less than 0.1% of the N-oxide as an impurity (Gao Declaration ¶ 7). We also note Dr. Gao‟s statement that the Opadry ® White coating, which contains 9.0 % w/w PEG 400, was unexpectedly found to not measurably increase the level of the N-oxide contaminant under a variety of tested conditions, despite the fact that PEG 400 was known to contain low levels of peroxide impurities (see id. at ¶¶ 9-12). As the Examiner points out, however, claim 1 encompasses the use of PEG of any molecular weight or grade, at any concentration, in combination with any number and type of other co-ingredients, whereas the showing Appeal 2011-006428 Application 11/418,338 9 advanced by Appellants is only with respect to a single coating containing a single type and concentration of PEG. Thus, we are not persuaded that the evidence advanced by Appellants to show unexpected results is commensurate in scope with the subject matter encompassed by claim 1. Moreover, Appellants have not explained how the secondary evidence advanced to show non-obviousness demonstrates a substantial improvement over the prior art, particularly given the close results obtained using the Opadry ® White coating as compared to the coating that uses triacetin as the plasticizer (see Gao Declaration ¶ 12 (Table 1)). In sum, for the reasons discussed, we are not persuaded that a preponderance of the evidence, including the evidence of secondary considerations of non-obviousness, fails to support the Examiner‟s ultimate conclusion that claim 1 would have been obvious to an ordinary artisan. We therefore affirm the Examiner‟s rejection of claim 1 as obvious over Das and Niazi. As they were not argued separately, claims 2, 14, and 15 fall with claim 1. See 37 C.F.R. § 41.37(c)(1)(vii). The Examiner also rejected claims 4-6 under 35 U.S.C. § 103(a) as obvious over Das, Niazi, Li, and Bolhuis (Ans. 9-11). The Examiner reasoned that while the combination of Das and Niazi did not teach or suggest the excipients recited in claims 4-6 in a coated formulation of dasatinib, an ordinary artisan would nonetheless have considered it obvious to include the claimed excipients based on the teachings of Li and Bolhuis (see id.). As Appellants do not direct any specific argument to this ground of rejection, or identify any specific deficiency in the Examiner‟s reasoning as to claims 4-6, and as we detect none, we affirm this rejection as well. Appeal 2011-006428 Application 11/418,338 10 OBVIOUSNESS-TYPE DOUBLE PATENTING The Examiner‟s rationale for rejecting claims 1, 2, 14, and 15 on the ground of obviousness-type double patenting over claims 43 and 46 of Das in view of Niazi is essentially the same rationale as that discussed above for rejecting the same claims as being obvious in view of Das and Niazi (see Ans. 4-5). Appellants advance the arguments discussed above with respect to the obviousness-type double patenting rejection (see App. Br. 4-8; Reply Br. 1-7). For the reasons discussed above, we are not persuaded that the Wade and Wasylaschuk references would have taught away from the composition of claim 1, such that an ordinary artisan would have failed to consider the composition of claim 1 prima facie obvious in view of Das and Niazi. As to Appellants‟ evidence of unexpected results, there is some question as to the applicability of secondary considerations to the doctrine of obviousness-type double patenting. See Geneva Pharms., Inc. v. GlaxoSmithKline PLC, 349 F.3d 1373, 1378 n.1 (Fed. Cir. 2003) (“Obviousness requires inquiry into objective criteria suggesting non- obviousness; nonstatutory double patenting does not.”); compare, however, Eli Lilly and Co. v. Teva Parenteral Medicines, Inc., 689 F.3d 1368, 1381 (Fed. Cir. 2012) (“When offered, such evidence [of objective indicia of nonobviousness] should be considered” when evaluating claims under the doctrine of obviousness-type double patenting.). Even if applicable, however, we do not find Appellants‟ arguments sufficient to overcome the Examiner‟s prima facie case of obviousness as to claim 1, for the reasons discussed above. We therefore affirm the Examiner‟s obviousness-type double patenting rejection of claim 1 over Appeal 2011-006428 Application 11/418,338 11 claims 43 and 46 of Das in view of Niazi. As they were not argued separately, claims 2, 14, and 15 fall with claim 1. See 37 C.F.R. § 41.37(c)(1)(vii). For the reasons discussed above, we also affirm the Examiner‟s obviousness-type double patenting rejection of claims 4-6 over claims 43 and 46 Das, in view of Niazi, Li, and Bolhuis (see Ans. 5-7), which applied essentially the same rationale as that applied in rejecting claims 4-6 as obvious over those references (see id. at 9-11). SUMMARY We affirm the Examiner‟s obviousness-type double patenting rejection of claims 1, 2, 14, and 15 over claims 43 and 46 of Das in view of Niazi. We also affirm the Examiner‟s obviousness-type double patenting rejection of claims 4-6 over claims 43 and 46 of Das in view of Niazi, Li, and Bolhuis. We also affirm the Examiner‟s obviousness rejection of claims 1, 2, 14, and 15 over Das and Niazi. We also affirm the Examiner‟s obviousness rejection of claims 4-6 over Das, Niazi, Li, and Bolhuis. 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 cdc