Ex Parte Chait et alDownload PDFBoard of Patent Appeals and InterferencesApr 30, 200910393190 (B.P.A.I. Apr. 30, 2009) Copy Citation UNITED STATES PATENT AND TRADEMARK OFFICE ____________ BEFORE THE BOARD OF PATENT APPEALS AND INTERFERENCES ____________ Ex parte EDWARD M. CHAIT and SEUNG-YONG CHOI ____________ Appeal 2009-0718 Application 10/393,190 Technology Center 1600 ____________ Decided:1 April 30, 2009 ____________ Before DONALD E. ADAMS, RICHARD M. LEBOVITZ, and MELANIE L. McCOLLUM, Administrative Patent Judges. LEBOVITZ, Administrative Patent Judge. DECISION ON APPEAL 1 The two-month time period for filing an appeal or commencing a civil action, as provided for in 37 C.F.R. § 1.304, begins to run from the decided date shown on this page of the decision. The time period does not run from the Mail Date (paper delivery) or Notification Date (electronic delivery). Appeal 2009-0718 Application 10/393,190 This is a decision on appeal from the Examiner’s final rejection of claims 2, 3, and 6-35 as obvious over prior art. Jurisdiction for this appeal is under 35 U.S.C. § 6(b). The rejection is affirmed. STATEMENT OF THE CASE The claims are directed to methods of synthesizing a diacyl cyclic nucleotide salt known as N6,2'-O-diacyl-adenosine-3',5'-cyclic monophosphate salt. Adenosine 3',5'-cyclic monophosphate (cAMP), a cyclic nucleotide, is an intracellular mediator of the action of a large number of extracellular mammalian hormones (Spec. 1: 9-11). Because of their physiological activity, cyclic nucleotides and cyclic nucleotide derivatives are potential pharmacological targets (id. at 12-14). For instance, the cyclic nucleotide derivative dibutyryl-adenosine- 3',5'-cyclic monophosphate sodium salt (db-cAMP-Na) can be used for organ preservation and maintenance (id. at 14-17). Claims 2, 3, and 6-35 are pending and stand rejected by the Examiner under 35 U.S.C. § 103(a) as obvious in view of Posternak (38 METHODS OF ENZYMOLOGY 399-409 (1974)) and Yamaji (US 4,458,067, Jul. 3, 1984) (Ans. 3). Appellants did not provide separate arguments for the patentability of any individual claim. Therefore, we select claim 20 as representative for the purpose of deciding the issues in this appeal. 37 C.F.R. § 41.37(c)(1)(vii). Claim 20 reads as follows: 20. A method for synthesizing a N6, 2’-O-diacyl-adenosine-3’,5’- cyclic monophosphate salt comprising: a) adding an alkyl acid anhydride or an alkyl acid halide to a solution 2 Appeal 2009-0718 Application 10/393,190 3 comprising an ammonium salt of adenosine-3’,5’-cyclic monophosphate and a pyridine solvent to produce a reaction mixture comprising a N6,2’-O-diacyl-adenosine-3’,5’-cyclic monophosphate salt, b) concentrating the reaction mixture by evaporating the pyridine solvent, c) adding a dialkyl ether to the reaction mixture to produce an organic solution, d) adding a water solution to the organic solution to produce a two phase system, e) extracting the N6,2’-O-diacyl-adenosine-3’,5’-cyclic monophosphate salt from the organic solution to produce an aqueous solution of the a N6, 2’-O-diacyl-adenosine-3’,5’- cyclic monophosphate salt, and f) removing the aqueous solution of the a N6, 2’-O-diacyl-adenosine- 3’,5’-cyclic monophosphate salt from the organic solution, wherein steps d), e) and f) are accomplished before complete hydrolysis of any alkyl acid halide or alkyl carboxylic acid anhydride. ISSUE ON APPEAL There is one obviousness rejection on appeal. The rejection is based on descriptions by Posternak and Yamaji of methods for synthesizing diacyl cyclic nucleotides. The issue in this appeal is whether persons of ordinary skill in the art would have had reason to combine the teachings of Posternak and Yamaji to have made the claimed method for synthesizing a N6,2'-O- diacyl-adenosine-3',5'-cyclic monophosphate salt. PRINCIPLES OF LAW The question of obviousness is resolved on the basis of underlying factual determinations including: (1) the scope and content of the prior art; (2) the level of ordinary skill in the art; (3) the differences between the claimed invention and the prior art; and (4) secondary considerations of Appeal 2009-0718 Application 10/393,190 4 nonobviousness, if any. Graham v. John Deere Co., 383 U.S. 1, 17-18 (1966). FINDINGS OF FACT Scope and content of the prior art In making an obviousness determination, we must first ascertain the scope and content of the prior art. Graham, 383 U.S. at 17. The following numbered findings of fact (“FF”) summarize the prior art relied upon by the Examiner in setting forth the basis of the rejection (Ans. 3-4): Posternak 1. Posternak describes methods of preparing derivatives of cyclic nucleotides, such as by treating a cyclic nucleotide (cAMP or cGMP) salt with anhydrous pyridine and an acid anhydride (401-402). 2. In one method of preparing a dibutyryl-cGMP derivative, Posternak describes starting with ten grams of a cGMP free acid and converting it to an ammonium salt (406-407). 3. The salt was treated with pyridine and butyric anhydride, an acid anhydride (407). 4. After reflux, the solvent was removed by vacuum and, after addition of water, the residue was re-evaporated to dryness (407). 5. Water was added to the residue (“taken up in . . . distilled water) and extracted with ether (407). 6. “The organic phase was discarded” to leave an aqueous solution (“water layer”) (407). 7. The aqueous solution was treated, filtered through a Dowex-50 column, and freeze dried (407). Appeal 2009-0718 Application 10/393,190 5 8. Posternak also describes preparing an acyl derivative of cUMP by the pyridine/acid anhydride method followed by addition of water and ether extraction (407). Yamaji patent 9. Yamaji states that it was known to produce diacyl-cAMP salts by reacting a cAMP triethylamine salt with n-butyric anhydride, an akyl acid anhydride, in a pyridine solvent, adding water, and then extracting with ether (col. 1, ll. 29-39). 10. Yamaji describes a method of producing diacyl-cAMP by method which uses a carboxylic anhydride, but does not require a solvent such as pyridine (col. 1, l. 54 to col. 2, l. 52). 11. After the reaction, the resulting diacyl-cAMP can be separated and purified “in a usual way” (col. 3, ll. 16-17). For example, Yamaji describes adding diethyl ether to the rejection mixture and extracting with water (id. at col. 4, ll. 33-36; see also col. 3, ll. 17-20). Claim 20 12. Claim 20 is a method of synthesizing “a N6, 2'-O-diacyl-adenosine- 3'-,5'-cyclic monophosphate salt” comprising, inter alia, the following steps: 13. a) adding an alkyl acid anhydride or halide to an ammonium salt of cAMP and pyridine solvent; 14. b) evaporating the pyridine solvent; 15. c) adding dialkyl ether to produce an organic solution; 16. d) adding water to the organic solution to produce a two phase system; Appeal 2009-0718 Application 10/393,190 6 17. e) extracting the diacyl salt from the organic solution to produce an aqueous solution of the diacyl salt; and 18. f) removing the aqueous solution of the diacyl salt from the organic solution. Differences between the prior art and the claimed invention Once the scope and content of the prior art has been determined, the next step is to identify the differences between the prior art and the claimed invention. Graham, 383 U.S. at 17. The following numbered findings of fact are pertinent to this issue: 19. Both Posternak and Yamaji teach that it was conventional to produce diacyl cAMP by reacting a cAMP salt with an alkyl acid anhydride (such as n-butyric anhydride) with pyridine (FF1, 3, & 9) as in step a) of claim 20 (FF13). 20. Posternak further describes a method of synthesizing a diacyl cGMP salt comprising removing the pyridine solvent (FF4), the same step as in b) of claim 20 (FF14). 21. The resulting residue is taken up in water by Posternak and ether is added (FF5) which correspond to steps c) and d) of claim 20 (FF15 & 16), but in the opposite order. 22. Posternak’s diacyl cGMP salt is extracted into the water or aqueous layer as in claim 20’s step e) and the aqueous layer is removed, meeting the limitation of step f) of claim 20 (FF6, 7, 17, & 18). 23. Posternak does not describe an example of synthesizing a diacyl-cAMP salt following the claimed steps b) through f) as in claim 20, but rather Posternak synthesizes a diacyl-cGMP salt (FF1 & 2) following these steps. Appeal 2009-0718 Application 10/393,190 7 ANALYSIS Posternak describes a method of synthesizing a diacyl-cyclic nucleotide which incorporates steps a) through f) of claim 20, but adds the water and ether in a different order than claimed (FF21) and produces a diacyl-cGMP, rather than a diacyl-cAMP as claimed (FF23). The Examiner finds that Yamaji teaches that “diacyl cAMP’s are the ones that are useful in pharmaceutical and biochemical research (Yamaji, col. 1, lines 6-15). . . . The process of Posternak, which is similar to the instant method, uses an ammonium salt [of a cGMP], gives good yield” (Ans. 7), providing reason to have applied Posternak’s method to an ammonium salt of cAMP as recited in claim 20. Appellants contend that the Examiner erred in combining Yamaji and Posternak. Appellants argue: 1) lack of motivation to combine Yamaji and Posternak (App. Br. 13); and 2) modifying Yamaji with Posternak would render Yamaji unsatisfactory for its intended purpose (App. Br. 16). As to the motivation argument, Appellants focus on the incompatibility of the two references because Posternak is said to utilize pyridine as a solvent in the production of diacyl nucleotide, while Yamaji is said to teach that pyridine should not be used as a solvent in the synthetic method (App. Br. 14). It is correct that Yamaji teaches a method for synthesizing diacyl- cAMP which does not require a pyridine solvent (FF10). However, Yamaji recognizes that diacyl-cAMP derivatives were conventionally synthesized with alkyl acid anhydride and pyridine solvent (FF9) as in step a) of claim 20. Yamaji also teaches that it was conventional to purify a diacyl-cAMP derivative by water/ether extraction as in claim 20, steps c) through of e), Appeal 2009-0718 Application 10/393,190 8 whether produced in the presence (FF9) or absence of pyridine (FF10-11). Yamaji performs the extraction by first adding the dialkyl ether and then adding water (FF11), the same order recited in claim 20 (FF15 & 16). In addition to distinguishing Yamaji because of its teaching of an alternative synthesis method that leaves out pyridine, Appellants also contend that it is incompatible with Posternak because the reaction temperatures used in the two references are different (App. Br. 14). However, Yamaji’s teaching about carrying out the reaction above 70°C as cited by Appellants (App. Br. 15) is with respect to the synthesis method which omits pyridine, not the more conventional method which includes it (FF9). Yamaji’s teaching is therefore not incompatible with Posternak. Finally, Appellants point to differences between Posternak and Yamaji in how a sodium salt is prepared from the diacyl cyclic nucleotide derivative, stating that the former uses a Dowex exchange column while the latter specifically indicates that columns can be dispensed (App. Br. 16; Reply Br. 7). First, we note the claim 20 is not limited to a particular salt type, nor does the claim exclude column chromatography. Second, once again, Yamaji’s discussion about columns relates to the pyridine-free synthetic methods, not the more general conventional synthesis methods which use pyridine. Appellants have focused their arguments on Yamaji’s apparent pyridine-free synthetic method. However, while the Examiner referred to this method in the Answer, the Examiner did not rely on it exclusively to reach the principal manipulation steps of claim 20, but rather quite clearly cited Posternak for teaching substantially all the claimed method steps Appeal 2009-0718 Application 10/393,190 9 (paragraph spanning pages 3-4 of the Answer; Ans. 7: 3-10). The Examiner also recognized that Posternak differed from the claimed process because it used a cGMP derivative, and cited Yamaji for its teaching of cAMP derivatives as cited in claim 20 (Ans. 3). Thus, the Examiner did not ignore this difference as asserted by Appellants (Reply Br. 6). In sum, Yamaji’s teachings are not incongruous with Posternak since, despite its teaching that pyridine may be omitted from the synthesis method, it describes a more conventional synthesis method for diacyl cAMP which incorporates many of the same steps as in claim 20. Appellants also contend that the combination of Yamaji and Posternak “would render the prior art invention being modified unsatisfactory for its intended purpose” (App. Br. 16). Appellants argue that adding pyridine to the reaction mixture would frustrate Yamaji’s goal in providing an alternative pyridine free synthetic method (id. at 17). For the reasons already discussed, this argument is not persuasive since this portion of Yamaji is unnecessary to reach the conclusion that claim 20 would have been obvious to persons of ordinary skill in the art. Appellants also argue that Yamaji “is unlikely to suggest to one of ordinary skill in the art that a process for preparing and/or separating cAMP can be efficiently performed using pyridine as a solvent” (Reply Br. 7). This argument is not supported by the evidence. Both Posternak and Yamaji teach that it was conventional to produce diacyl cAMP with a pyridine solvent (FF19). Claim 20 does not require a particular degree of efficiency or cAMP yield. Appellants also argue that Posternak “only discloses processes for separating non-cAMP based compounds that are salts of tetrabutyl Appeal 2009-0718 Application 10/393,190 10 ammonium hydroxide, compounds IV-VI, using pyridine and ether/water” (Reply Br. 7). Again, this argument is not persuasive. Yamaji clearly teaches that it was known to make and separate cAMP derivatives using pyridine (FF9) followed by water/ether extraction (FF9, 11), the same order specified in claim 20 (FF15 & 16). Based on these teachings, persons of ordinary skill in the art would have reasonably expected that Posternak’s cGMP synthesis method using the same pyridine and water/ether extraction steps would also work for cAMP. Appellants have not provided adequate evidence to rebut this reasonable expectation. CONCLUSION OF LAW Persons of ordinary skill in the art would have had reason to combine the teachings of Posternak and Yamaji to have made the claimed synthesis method. The rejection of claim 20 as obvious in view of Posternak and Yamaji is therefore affirmed. Claim 2, 3, 6-19, and 21-35 fall with claim 20 because separate reasons for their patentability were not provided. 37 C.F.R. § 41.37(c)(1)(vii). 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 Appeal 2009-0718 Application 10/393,190 11 cdc Charles W. Calkins, Esq. Kilpatrick Stockton LLP 1001 West Fourth Street Winston-Salem NC 27101-2400 Copy with citationCopy as parenthetical citation