Ex Parte IngvoldstadDownload PDFBoard of Patent Appeals and InterferencesFeb 28, 201212566038 (B.P.A.I. Feb. 28, 2012) Copy Citation UNITED STATES PATENT AND TRADEMARK OFFICE __________ BEFORE THE BOARD OF PATENT APPEALS AND INTERFERENCES __________ Ex parte ODD EINAR INGVOLDSTAD __________ Appeal 2012-000663 Application 12/566,038 Technology Center 1600 __________ Before DONALD E. ADAMS, LORA M. GREEN, and JACQUELINE WRIGHT BONILLA, Administrative Patent Judges. BONILLA, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. § 134 involving a claim directed to a process for crystallizing a non-ionic X-ray contrast agent. The Examiner has rejected the claim as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm. Appeal 2012-000663 Application 12/566,038 2 STATEMENT OF THE CASE Claim 1 is the only claim on appeal. Claim 1 reads as follows (emphasis added): 1. A process for crystallizing 5-amino-N, N'-bis(2,3- dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide (Compound B) to increase its crystallization yield comprising the steps: (a) reacting 5-amino-N,N' -bis-(2,3-dihydroxypropyl) isophthalamide with iodine chloride in an aqueous medium to form a crude product comprising Compound B; (b) quenching excess iodine chloride from step (a) with sodium bisulphate and forming low molecular weight salts; (c) crystallizing Compound B from said crude product by adding seeds of Compound B to form a crystallization suspension comprising said Compound B and said low molecular weight salts; (d) filtering the mother liquor of said crystallization suspension of step (c) through a nanomembrane whereby said Compound B is retained on the retentate side of the nanomembrane while said low molecular weight salts pass through the nanomembrane; (e) returning the retentate containing enriched concentration of Compound B to said crystallization suspension of step (c); and (f) repeating steps (d) and (e). Claim 1 stands rejected under 35 U.S.C. § 103(a) as being obvious over the combined teachings of Thieking et al (U.S. Pat. No. 6,137,006, issued Oct. 24, 2000), Viscardi et al. (U.S. Pat. No. 5,447,635, issued Sep. 5, 1995), and Cervenka et al. (U.S. Publ. No. 2008/0214867 A1, Sep. 4, 2008). Appeal 2012-000663 Application 12/566,038 3 Issue Issues regarding claim 1 are (1) whether it would have been prima facie obvious to one of skill in the art to engage in the process recited in claim 1 by modifying the process of Thieking in light of teachings in Viscardi and Cervenka, and if so, (2) whether the record presents evidence of secondary considerations, such as unexpected results, that when weighed with the evidence of obviousness, are sufficient to rebut the prima facie case. Findings of Fact 1. Claim 1 recites a process for crystallizing a non-ionic X-ray contrast agent, Compound B. (Spec. 3, ll. 5-14.) The process comprises reacting a specific starting compound with iodine chloride, quenching excess iodine chloride with sodium bisulfate and forming low molecular weight salts, and crystalizing Compound B by adding seeds of Compound B to form an initial crystallization suspension comprising Compound B and the low molecular weight salts. (See also Spec. 3, 6.) 2. The process of claim 1 also comprises filtering the “mother liquor” of the crystallization suspension through a nanomembrane. The nanofiltering step retains Compound B and some of the mother liquor on the retentate side of the membrane and allows the salts in liquid to pass through. (Claim 1; Spec. 3.) The process further involves returning the retentate (containing Compound B and mother liquid) to the crystallization suspension, and then repeating the steps of nanofiltering and returning the retentate to the crystallization suspension. (Claim 1; Spec. 3-4.) Appeal 2012-000663 Application 12/566,038 4 3. The instant Specification states that the inventors “have surprisingly found that in the instant process the solubility of Compound B depends on the salt concentration.” (Spec. 4, ll. 6-15.) 4. Examples in the Specification describe the production of Compound B via methods disclosed in Example 1 (comparative), Example 2 and Example 3. 5. Example 2 is similar to Example 1, but differs in that the “seeded mixture is slowly cooled to 35ºC” (rather than 32ºC as disclosed in Example 1) and then “subjected to nanofiltration followed by diafiltration with water.” (Spec. 5, ll. 2-4.) In addition, “[t]he mother liquor is decanted from the slurry and concentrated in the nanofiltration unit to about 60 % of its original volume before it is returned to the crystallization vessel” where crystal growth proceeds for 12 hours before filtering and washing the filter cake with water. (Id. at ll. 4-7.) 6. Example 3 is similar to Example 2, except that the procedure of nanofiltering, diafiltering with water, concentrating and returning to the crystallization vessel is repeated twice before proceeding with final crystal growth for 12 hours. (Id. at ll. 16-21.) 7. The Specification states that yields of Compound B via the processes of Example 2 and 3 are about 3.5% higher and about 4% higher, respectively, than via the process of comparative Example 1. (Id. at ll. 7-8, 21.) 8. Thieking discloses “a process for the preparation of compounds containing triiodinated benzene rings, e.g., iodinated X-ray contrast agents.” (Thieking, col. 1, ll. 11-18.) Appeal 2012-000663 Application 12/566,038 5 9. Thieking teaches that the “2,4,6-unsubstituted starting reagent for the triiodination is preferably a 5-amino-benzamide,” such as 5-amino-N,N’bis- (2,3-dihydroxypropyl)-isophthalamide, which is “[e]specially prefer[red].” (Id. at col. 2, ll. 47-65.) 10. Thieking teaches a process that comprises (a) reacting the 5-amino- benzamide with iodine halide, such as iodine chloride, to yield a triiodinated product (id. at col. 1, ll. 49-61; col. 2, ll. 64-65; col. 3, ll. 4-5, 39-42); (b) quenching excess iodine chloride with sodium bisulphate (id. at col. 3, ll. 44- 45; col. 4, l. 9); and (c) crystallizing the triiodinated product using seed crystals of the compound, thereby creating a “reaction mixture” (id. at col. 4, ll. 19-31). 11. Thieking also describes filtering the reaction mixture, which generates a “cake” of the triiodinated product. Thieking further states that “[g]iven the high initial salt content of the reaction medium following addition of the aqueous base … it is very surprising that such low salt contents can be achieved with such little washing and without requiring recrystallization.” (Id. at col. 4, ll. 57-61.) In other words, Thieking discloses that the filtering membrane retains the triiodinated product, and salts in the initial reaction mixture pass through the membrane. 12. Viscardi teaches a method of concentrating and purifying iodinated X- ray contrast agents via nanofiltration. (Viscardi, col. 1, ll. 5-22, col. 3, ll. 42- 56.) Viscardi states that the nanofiltration “process of this invention has provided excellent and fully unexpected degrees of purification and recovery of the desired products.” (Id. at col. 3, ll. 49-57.) Appeal 2012-000663 Application 12/566,038 6 13. Viscardi also discloses that “[i]t is known that organic impurities with low relative mass and/or inorganic salts can be removed from aqueous dilute solutions through tangential filtration processes by using ultrafiltration (U.F.) or nanofiltration (N.F.) membranes.” (Id. at col. 2, ll. 17-21.) In this context, Viscardi teaches that: “Water, salts, organic compounds at relative mass lower than 200 and solvents, if any, permeate through the membranes and the retentate, partially concentrated and purified as to the contrast agent, is recycled at the first stage after dilution with a little amount of deionized make-up water.” (Id. at col. 4, ll. 57-62.) 14. Cervenka discloses a process for purifying iodinated X-ray contrast agents by continuous crystallization. (Cervenka, 1, [0009] – [0010].) Cervenka states that the process “allows for purification in an efficient and safe manner at a low cost.” (Id. at [0001].) 15. As disclosed by Cervenka, “[b]y performing the crystallisation process as a continuous crystallisation process the yield per volume and time unit of the equipment is increased while the purity level of the crystallised iodinated compounds are maintained and may even be increased.” (Id. at [0010].) 16. Cervenka also teaches the concept of seeding, or preloading, with crystals before repeated crystallization, and states that the “use of seed crystals will enhance the initial crystallisation process and promote the establishment of steady state conditions.” (Id. at 2, [0027].) 17. Cervenka further describes a filtering step between the repeated crystallization steps when it teaches that “crystallisers will usually be coupled in series, optionally with partial recycling of the product stream and Appeal 2012-000663 Application 12/566,038 7 mother liquor or crystals after filtration from a crystalliser to a previous crystalliser in the series.” (Id. at 3, [0032].) Principles of Law “An examiner bears the initial burden of presenting a prima facie case of obviousness.” In re Huai-Hung Kao, 639 F.3d 1057, 1066 (Fed. Cir. 2011). “Once the examiner establishes a prima facie case of obviousness, the burden shifts to the applicant to rebut that case.” Id. If the applicant presents rebuttal evidence, such as unexpected results or that the prior art teaches away from the claimed invention, the Examiner must consider the totality of the evidence to determine whether the obviousness rejection should stand. Id. Analysis We agree with the Examiner that it would have been prima facie obvious to one of skill in the art to engage in the process recited in claim 1 by modifying the process of Thieking to include nanofiltration as taught by Viscardi as well as continuous crystallization as taught by Cervenka. (Ans. 5.) Thieking taught a process for crystallizing a 5-amino-benzamide compound comprising (a) reacting 5-amino-N,N’bis-(2,3-dihydroxypropyl)- isophthalamide with iodine chloride to form the compound; (b) quenching excess iodine chloride with sodium bisulphate (and thereby forming low molecular weight salts); (c) crystallizing the compound by adding seed compounds to form a crystallization suspension comprising the compound and salts; and (d) filtering the crystallization suspension. (FF 10, 11.) Thus, Appeal 2012-000663 Application 12/566,038 8 as noted by the Examiner (Ans. 5), the difference between the Thieking and the process of claim 1 is that Thieking does not teach nanofiltering or continuous crystallization by returning the retentate from the nanofiltering step to the crystallization suspension for crystallization, and then repeating the nanofiltering and returning steps. Viscardi and Cervenka both provided clear motivation to add such steps to the process described in Thieking. Both references, similarly to Thieking, describe methods for purifying non-ionic iodinated X-ray contrast agents. Viscardi teaches that nanofiltration “provided excellent and fully unexpected degrees of purification and recovery of the desired products.” (FF 12.) Cervenka teaches that continuous crystallization “allows for purification in an efficient and safe manner at a low cost,” and “the yield … is increased while the purity level … are maintained and may even be increased.” (FF 14, 15.) Thus, as stated by the Examiner, “absent evidence to the contrary” (Ans. 5), it would have been obvious to modify the Thieking process to include nanofiltration and continuous (repeated) crystallization to increase yield and purity. The question then becomes whether the record before us presents evidence of secondary considerations, such as unexpected results, that when weighed with the evidence of obviousness, are sufficient to rebut the prima facie case. In the first instance, Appellant asserts that Thieking, Viscardi, and Cervenka do not teach or suggest that use of nanofiltration and continuous crystallization would increase the yield of Compound B. (App. Br. 4, 8.) For the reasons discussed above, however, we conclude otherwise. Appeal 2012-000663 Application 12/566,038 9 Viscardi and Cervenka expressly teach that nanofiltration and continuous crystallization, respectively, would increase yield. Appellant also argues (App. Br. 4), as also stated in the instant Specification (Spec. 4, ll. 6-15), that they “have surprisingly found that in the instant process the solubility of Compound B depends on the salt concentration.” (FF 3.) In response to the Examiner’s assertion that “it is well known in the chemical art that the solubility of a compound increases in the salt form” (Ans. 6), Appellant “submit[s] that it is not always the case” and “it is not common knowledge that the solubility of a large molecule like Compound B would decrease with lower salt concentration or increase in the presence of salts” (App. Br. 5 (emphasis in original).) In support, Appellant provides attorney argument, but no evidence of what one skilled in the art would have known or expected regarding the solubility of Compound B in relation to salt concentration. In any event, the issue here is whether a skilled artisan would have been motivated to modify the Thieking process to include the steps of nanofiltration as taught by Viscardi and continuous crystallization as taught by Cervenka. Regardless of the salt solubility issue, Viscardi and Cervenka taught that such steps would increase yield, as discussed above. Appellant also argues unexpected or surprising results. In support, Appellant presents Table 1, which “compares side by side, Comparative Example 1 against Example 2 and Example 3.” (App. Br. 6-7.) Appellant states that “the increased yield of 3.5% and 4% recited in Example 2 and Example 3, respectively, reflects that 3.5% and 4% more Compound B was isolated when using nanofiltration and repeated crystallization … than when Appeal 2012-000663 Application 12/566,038 10 only a single crystallization step without nanofiltration was performed ….” (Id. at 7.) Appellant asserts that these increases in yield are “unexpected results.” (Id.) In light of the fact that Viscardi and Cervenka taught that nanofiltration and continuous crystallization would increase yield (as discussed above), we agree with the Examiner that “an increase of 3 to 4% yield is definitely not [] unexpected and one of ordinary skill in the art would expect much more higher yield” than the yields presented in the instant Specification and Table 1. (Ans. 6.) Appellant has not provided persuasive evidence or reasoning to refute the Examiner’s conclusion. In sum, Appellant has not shown sufficient evidence of unexpected results or any other secondary considerations in support of non-obviousness. Conclusion of Law We agree with the Examiner that, based on the cited references, it would have been prima facie obvious to combine the teachings of Thieking with those of Viscardi and Cervenka to engage in the process recited in claim 1. We also conclude that the record before us does not provide sufficient evidence of secondary considerations, when weighed with the evidence of obviousness, to rebut the prima facie case. SUMMARY We affirm the rejection of claim 1 under 35 U.S.C. §103(a) as unpatentable over the combined teachings of Thieking, Viscardi, and Cervenka. Appeal 2012-000663 Application 12/566,038 11 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)(1)(iv). AFFIRMED cdc Copy with citationCopy as parenthetical citation