Ex Parte Leonard

Patent Trial and Appeal BoardNov 16, 2012

11757764 (P.T.A.B. Nov. 16, 2012)

UNITED STATES PATENT AND TRADEMARKOFFICE 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. 11/757,764 06/04/2007 Thomas W. Leonard 9448-50CT2 3265 20792 7590 11/19/2012 MYERS BIGEL SIBLEY & SAJOVEC PO BOX 37428 RALEIGH, NC 27627 EXAMINER BADIO, BARBARA P ART UNIT PAPER NUMBER 1628 MAIL DATE DELIVERY MODE 11/19/2012 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 THOMAS W. LEONARD __________ Appeal 2011-012726 Application 11/757,764 Technology Center 1600 __________ Before DONALD E. ADAMS, DEMETRA J. MILLS, and JEFFREY N. FREDMAN, Administrative Patent Judges. FREDMAN, Administrative Patent Judge. DECISION ON APPEAL This appeal under 35 U.S.C. § 134 involves claims to a method of produce a stable composition comprising sulfated estrogens. The Examiner rejected the claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm. Appeal 2011-012726 Application 11/757,764 2 Statement of the Case Background “The present invention relates to a process for the synthesis of a mixture of sulfated estrogens which may comprise sulfated 8,9- dehydroestrone, estrone, equilin, and derivatives thereof” (Spec. 1 ¶ 0002). The Claims Claims 1, 3-7, 9-13, 15, 17, 18, and 20 are on appeal. Claim 1 is representative and reads as follows: 1. A process for the production of a stable composition comprising a mixture of sulfated estrogens, the process comprising the steps of: a) reacting a sulfur trioxide complex with a mixture of alkali metal salts of estrogens to provide a mixture of sulfated alkali metal salts of estrogens, wherein the estrogens are selected from the group consisting of 8,9- dehydroestrone and estrone; b) adding a stabilizing amount of tris(hydroxymethyl)aminomethane; and c) recovering the stable composition comprising the mixture of sulfated estrogens and tris(hydroxymethyl)aminomethane, wherein the mixture of sulfated estrogens is produced in about the same ratio as that of the starting estrogenic compounds. The Issue The Examiner rejected claims 1, 3-7, 9-13, 15, 17, 18, and 20 under 35 U.S.C. § 103(a) as obvious over Raijmakers,1 Simoons,2 Raveendranath,3 Shah,4 Bender,5 and Kong6 (Ans. 4-6). 1 Raijmakers et al., US 5,998,639, issued Dec. 7, 1999. 2 Simoons, J., US 4,154,820, issued May 15, 1979. Appeal 2011-012726 Application 11/757,764 3 The Examiner finds that “Raijmakers et al. teaches sulfation of estrogen mixtures” (Ans. 4). The Examiner finds that “Simoons teaches a stabilized composition of estrogens utilizing Tris” (Ans. 5). The Examiner finds that Raveendranath teaches “a process for the production of alkali metal 8,9-dehydroestrone sulfate esters and the production of a stabilized composition with Tris . . . The reference teaches mixture of 8,9- dehydroestrone with sodium hydride, reaction with trimethylamine-sulfur trioxide and addition of Tris” (Ans. 5). The Examiner finds that Shah, Bender, and Kong teach “the production of sulfate esters of estrogens by reacting said estrogens in tetrahydrofuran with a sulfur trioxide complex, such as trimethylamine-sulfur trioxide or triethylamine-sulfur trioxide” (Ans. 5). The Examiner finds it obvious “to make a stabilized composition comprising sulfated estrogens . . . based on the knowledge in the art that compositions comprising a mixture of estrogenic sulfate esters are useful in hormone replacement therapy” (Ans. 6). The Examiner finds it obvious that “the amount of each sulfated estrogen in the end product would be depended on several factors, such the composition of the starting material and the reaction condition” (Ans. 6). The issues with respect to this rejection are: (i) Does the evidence of record support the Examiner’s conclusion that Raijmakers, Simoons, Raveendranath, Shah, Bender, and Kong render Claim 1 obvious? 3 Raveendranath et al., US 5,288,717, issued Feb. 22, 1994. 4 Shah et al., US 6,525,039 B1, issued Feb. 25, 2003. 5 Bender et al., US 5,998,638, issued Dec. 7, 1999. 6 Kong et al., US 6,458,778 B1, issued Oct. 1, 2002. Appeal 2011-012726 Application 11/757,764 4 (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. Raijmakers teaches “the first easy and inexpensive method of production of sulfated steroid mixtures containing delta(8,9)DHE through sulfatation of an estrogen mixture containing delta(8,9)DHE or derivatives thereof” (Raijmakers, col. 2, ll. 14-18). 2. Raijmakers teaches that it “has surprisingly been found that although the estrogens present in the natural conjugated estrogen preparations have different physical properties . . . the ratio of sulfated products in the sulfatation reaction mixture reflects the amounts of the input components” (Raijmakers, col. 1, l. 64 to col. 2, l. 2). 3. Raijmakers teaches in Example 13 that: a mixture of delta(8,9)-dehydro estrone (12.5 g) and equilin (12.5 gram) were sulfated with sulfuric acid/acetic anhydride/pyridine. The mixture of crude pyridine sulfates was saponified and converted to the corresponding mixture of sodium sulfates with sodium hydroxide in methanol as described in example 12, yielding 27.5 g of a 1:1 mixture of delta(8,9)-dehydro estrone sodium sulfate and equilin sodium sulfate. GLC analysis indicated full recovery of the steroids charged. (Raijmakers, col. 7, ll. 10-20). 4. Simoons teaches that the “estrogen conjugates are prepared synthetically and the ‘Tris’ functions as an initial stabilizer temporarily” (Simoons, col. 7, ll. 38-39). Appeal 2011-012726 Application 11/757,764 5 5. Raveendranath teaches “the initial production of an alkali metal salt of 8,9-dehydroestrone followed by sulfation with trimethylaminesulfurtrioxide under mild conditions in a polar, aprotic solvent such as tetrahydrofuran with simultaneous or subsequent addition of tris (hydroxymethyl)aminomethane as a stabilizer” (Raveendranath, col. 1, ll. 54-59). 6. Raveendranath teaches that “in the absence of stabilization, the sulfate ester rapidly degrades while tris(hydroxymethyl)aminomethane provides protection from hydrolytic degradation . . . thereby demonstrating better product control than obtained in the absence of tris(hydroxymethyl)aminomethane” (Raveendranath, col. 4, ll. 22-29). 7. Shah teaches the production of sulfate esters of estrogens, specifically teaching that to “a solution of 3-hydroxy-5,7,9-estratriene-17- one (0.58 g, 2.1 mmol) in THF (15 mL) at RT, under nitrogen, was added triethylamine-sulfur trioxide complex . . . The precipitate formed was . . . dried to provide 3 -hydroxy-5(10),6, 8-estrtriene-17-one-3- triethylammonium sulfate” (Shah, col. 6, ll. 15-22). 8. Bender teaches the production of sulfate esters of estrogens, specifically teaching that “5-Pregn-16-en-3-ol-20-one . . . was dissolved in 50 ml of tetrahydrofuran. Sulfur trioxide triethylamine complex (1.2 g, 6.6 mmol) was added. The mixture was stirred at room temperature for 20 hours. After addition of 50 ml of ether, the precipitate was collected on a Buchner funnel, washed with ether and dried” (Bender, col. 4, ll. 23-28). Appeal 2011-012726 Application 11/757,764 6 9. Kong teaches the production of sulfate esters of estrogens, specifically teaching that to “the alcohols 12 (1.34 g, 2.6 mmol) in DMSO (20 mL) containing triethylamine (11 eq, 4.0 mL, 28.7 mmol) was added trimethylamine-sulfur trioxide complex” (Kong, col. 14, ll. 65-67). 10. The Specification teaches that Table 1 “provides ratios at each time indicated comparing each individual compound to the combination of estrogens prepared as taught herein. These relative ratios show the distinct differences in the results of the individual processes versus the combined process” (Spec. 8-9 0027). Principles of Law “In proceedings before the Patent and Trademark Office, the Examiner bears the burden of establishing a prima facie case of obviousness based upon the prior art.” In re Fritch, 972 F.2d 1260, 1265 (Fed. Cir. 1992). “The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007). “If a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability.” Id. at 417. Moreover, an “[e]xpress suggestion to substitute one equivalent for another need not be present to render such substitution obvious.” In re Fout, 675 F.2d 297, 301 (CCPA 1982). As noted by the Court in KSR, “[a] person of ordinary skill is also a person of ordinary creativity, not an automaton.” 550 U.S. at 421. Appeal 2011-012726 Application 11/757,764 7 Analysis Raijmakers teaches a process for the production of sulfated estrogens comprising reacting a sulfuric acid composition with delta(8,9)-dehydro estrone and equilin and recovering the composition in a 1:1 ratio with the starting compounds (FF 3). Raijmakers teaches that it “has surprisingly been found that although the estrogens present in the natural conjugated estrogen preparations have different physical properties . . . the ratio of sulfated products in the sulfatation reaction mixture reflects the amounts of the input components” (Raijmakers, col. 1, l. 64 to col. 2, l. 2; FF 3). Simoons and Raveendranath teach the use of tris in the sulfation of 8,9 dehydroestrone, where Raveendranath teaches that “in the absence of stabilization, the sulfate ester rapidly degrades while tris(hydroxymethyl)- aminomethane provides protection from hydrolytic degradation . . . thereby demonstrating better product control than obtained in the absence of tris(hydroxymethyl)aminomethane” (Raveendranath, col. 4, ll. 22-29; FF 6). Shah, Bender, and Kong teach the use of a sulfur trioxide complex for sulfation of estrogen based compounds (FF 7-9). Applying the KSR standard of obviousness to the findings of fact, we conclude that the person of ordinary creativity would have predictably added Tris as a stabilizer after Raijmakers sulfation reaction (FF 1-3) to protect from degradation as taught by Simoons and Raveendranath (FF 4-6) and substituted the sulfur trioxide complex for sulfation as suggested by Shah, Bender and Kong (FF 7-9). Such a combination is merely a “predictable use of prior art elements according to their established functions.” KSR, 550 U.S. at 417. Appeal 2011-012726 Application 11/757,764 8 Appellant contends that “the cited references do not teach or suggest the recited method wherein the mixture of sulfated 8,9-dehydroestrone and estrone is produced in about the same ratio as that of the reactant 8,9- dehydroestrone and estrone” (App. Br. 4). Appellant contends that “Raijmakers et al. found it surprising that their process could produce a ratio of sulfated products in the sulfated reaction mixture that reflects the amount of the input components” (App. Br. 5). Appellant contends that “Raijmakers supports Appellant’s argument that it is surprising and nonobvious that the presently claimed processes would result in a mixture of sulfated estrogens that is produced in about the same ratio as that of the starting estrogenic compounds” (App. Br. 5). We are not persuaded. Raijmakers teaches that it “has surprisingly been found that although the estrogens present in the natural conjugated estrogen preparations have different physical properties . . . the ratio of sulfated products in the sulfation reaction mixture reflects the amounts of the input components” (Raijmakers, col. 1, l. 64 to col. 2, l. 2; FF 2). Issued three years prior to Appellants filing, Raijmakers teaches that the ratio of product reflects the starting material (FF 2) and Raijmakers shows in Example 13 that sulfation of a mixture of delta(8,9)- dehydroestrone and equilin resulted in a 1:1 mixture and full recovery of the starting components. Consequently, after Raijmakers states and experimentally demonstrates that the sulfated estrogen products produced after the sulfation reaction are in the same ratio as that of the starting estrogen products (FF 2-3), Appellant’s position that this result is surprising is untenable. Based upon the Raijmakers, the only evidence available regarding the state of the prior art for ratios of estrogen products before and Appeal 2011-012726 Application 11/757,764 9 after sulfation, the ordinary artisan would have expected a 1:1 ratio of starting estrogen materials to sulfated product after a sulfation reaction (FF 3). See In re Skoner, 517 F.2d 947, 950 (CCPA 1975) (“Expected beneficial results are evidence of obviousness of a claimed invention. Just as unexpected beneficial results are evidence of unobviousness.”) Unexpected Results Appellant, relying upon table 1 of the Specification, contends that “additional by-products are forming when estrone, equilin and Delta-8,9 are reacted together” (App. Br. 6). Appellant also contends that “product ratios change when estrone, equilin or Delta-8,9 are reacted together” (App. Br. 6). We are not persuaded. We note that the Specification in describing Example 4 does not provide specific details on how the sulfation reactions were performed nor does the Specification clearly indicate what other reagents were present in the reaction (see Spec. 8-9). While Appellant contends that the same process was used (see App. Br. 8), there is no evidence to support this argument. More significantly, the Specification compares the results of the sulfation of individual estrogens with the sulfation of all three estrogens, estrone, equilin and delta 8,9 together. This comparison is not commensurate in scope with claim 1, since claim 1 requires the use of only two estrogens, delta 8,9, and estrone, not three estrogens. See In re Harris, 409 F.3d 1339, 1344 (Fed. Cir. 2005) (Unexpected results must also be “commensurate in scope with the degree of protection sought by the claimed subject matter.”). Appeal 2011-012726 Application 11/757,764 10 Finally, the comparison shown in Table 1 is not closer than the closest prior art of Raijmakers, in which two estrogens were used, as required by claim 1, rather than three estrogens as in the Example in Table 1. Therefore, Table 1 does not represent the closest prior art which is Raijmakers. See In re Baxter Travenol Labs., 952 F.2d 388, 392 (Fed. Cir. 1991) (“[W]hen unexpected results are used as evidence of nonobviousness, the results must be shown to be unexpected compared with the closest prior art.”). Appellant has provided no comparison with Raijmakers. Conclusion of Law (i) The evidence of record supports the Examiner’s conclusion that Raijmakers, Simoons, Raveendranath, Shah, Bender, and Kong render Claim 1 obvious. (ii) Appellant has not presented evidence of secondary considerations, that when weighed with the evidence of obviousness, is sufficient to support a conclusion of non-obviousness. SUMMARY In summary, we affirm the rejection of claim 1 under 35 U.S.C. § 103(a) as obvious over Borsig and Kawashima. Pursuant to 37 C.F.R. § 41.37(c)(1), we also affirm the rejection of claims 3-7, 9-13, 15, 17, 18, and 20, as these claims were not argued separately. Appeal 2011-012726 Application 11/757,764 11 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 dm