DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Application Status
The Amendment filed on 1/08/2026 is acknowledged and has been entered. Claims 26 and 28 are currently pending and under consideration.
Information Disclosure Statement
The information disclosure statements filed on 11/12/2025 and 1/07/2026 are acknowledged and have been considered unless lined through.
Rejections/Objections withdrawn in view of Amendments:
The objection to the specification for using the term “Trim-N-butyl-amine” which appears to be misspelled and should be Tri-N-butyl amine is withdrawn in view of Applicants amendment.
The rejection of Claim(s) 1-2 and 4-5 under 35 U.S.C. 102(a)(1) as being anticipated by Akbarzadeh et al. (Current Science, (2002), Vol. 83, No. 1) is withdrawn in view of cancellation of the claims.
The rejection of Claim(s) 1 under 35 U.S.C. 102(a)(1) as being anticipated by Akbarzadeh et al. (Asian J. Biochem., (2007), 2(1): 58-65) referred to here as Akbarzadeh 2 is withdrawn in view of cancellation of claim 1.
The rejection of Claim(s) 2, 4-5, 7, 9-12, 30-33 under 35 U.S.C. 103 as being unpatentable over Akbarzadeh et al. (Asian J. Biochem., (2007), 2(1): 58-65) referred to here as Akbarzadeh 2, as applied above to claim 1, in view of Akbarzadeh et al. (Current Science, (2002), Vol. 83, No. 1) and Torres et al. (Anal Bioanal Chem (2014) 406, 5927-5937) is withdrawn in view of cancellation of the claims.
Rejections Maintained but modified in view of Applicants amendments
Claim(s) 26 and 28 is/are rejected under 35 U.S.C. 103 as being unpatentable over Akbarzadeh et al. (Biotechnol. Appl. Biochem (1999) 30, 139-145) referred to here as Akbarzadeh 3 in view of Wainer et al. (Science (1972, Vol. 176, 1143-1144) and Torres et al. (Anal Bioanal Chem (2014) 406, 5927-5937).
Akbarzadeh 3 teach the design and synthesis of a morphine-6-succinyl-bovine serum albumin hapten for vaccine development (Title). In particular, the reference teaches first preparing morphine-6-succinate by refluxing morphine with excess succinic anhydride in dry benzene leads to the selective succinylation of the 6-hydroxy group (page 139, Synthesis of M-6-S). The reference further teaches the coupling of M-6-S to BSA in an aqueous solution in the presence of water-soluble carbodi-imide (EDAC)(page 141, Coupling of M-6-S to BSA).
Akbarzadeh 3 does not teach that the coupling of M-6-S to BSA occurs in the presence of tributylamine, dioxane, and isobutyl chloroformate, wherein the reaction excludes EDAC.
Torres et al. teach that the carbodiimide reaction (e.g. use of EDAC) is a popular conjugation strategy for introducing haptens on carriers because surface lysines are ubiquitous in proteins. However, Torres et al. teach that Carbodiimide chemistry is prone to oligomerization due to intermolecular reactions of surface lysines and glutamate/aspartate groups, wherein protein oligomers are usually insoluble in aqueous solutions and are difficult to characterize (page 5928, 1st column, 1st full paragraph). Moreover, Torres et al. teach that in general, the chemical structure of the hapten and hapten density (number of covalently attached haptens per molecule carrier) are critical for the generation of effective antibody titers (page 5928, 1st column, 2nd full paragraph)
Wainer et al. teach the preparation of morphine-3-succinyl-bovine serum albumin, morphine-3-succinate (M-3-HS) was conjugated to BSA by the mixed anhydride method. For example, the reference teaches that a mixture of dioxane, M-3-HS, isobutyl chloroformate and tributylamine w was added to a mixture of BSA in water and dioxane (pH adjusted with sodium hydroxide) (page 1143, 3rd column, 1st full paragraph).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to substitute the conjugation reaction conditions of Akbarzadeh 3 with those of Wainer et al. in view of the teachings of Torres et al.. One of ordinary skill in the art would have been motivated to make such a substitution, with a reasonable expectation of success, because:
-Torres teaches that carbodiimide chemistry used in conjugations are prone to generating protein oligomers which are insoluble in aqueous solutions and difficult to characterize.
While the combination does not specifically teach that the morphine-6-succinyl-BSA so formed has an average ratio of morphine-6-succinyl moieties to BSA of at least 8.2, the claimed limitation does not appear to result in a when following the procedures of the prior art combination since Torres teaches using dry benzene as the solvent because it leads to the selective succinylation of the 6-hydroxy group and Wainer’s mixed anhydride methods appears to be substantially identical to that taught in the instant specification (Example 3). It is also important to note that the specification does not appear to provide an actual calculation of the average ratio similar to that provided by Wainer et al. or Akbarzadeh 3. Accordingly, it is unclear of whether the process disclosed by Applicants creates an average ratio as claimed and how this method, which appears to be substantially similar (for example, mmol’s of reactant used) is advantageous or different from the prior art.
In response to this rejection, Applicants first notes that Akbarzadeh 3 teaches the coupling of M-6-S to BSA in an aqueous solution in the presence of water-soluble carbodi-imide (EDAC) and does not teach that the coupling of M-6-S to BSA occurs in the presence of tributylamine, dioxane, and isobutyl chloroformate. Moreover, Applicants assert that Akbarzadeh 3 teaches a ratio of morphine-6-succinyl moieties to BSA of only 6.5 rather than the surprising high ratio of at least 8.2 seen with the claimed invention. Accordingly, Applicants contend that Akbarzadeh 3 teaches away from the claimed invention. Applicants further contend that while the Examiner cites Torres as teaching that the carbodiimide reaction is a popular conjugation strategy and notes certain issues with this reaction mentioned by Torres, Torres does not teach or suggest that this ‘popular” carbodiimide reaction is to be avoided when making protein-hapten conjugates. Regarding Wainer, Applicants notes that Wainer teaches a ratio of only 6.5 and fails to teach or suggest the surprisingly high morphine-6-succinyl to BSA ratio of at least 8.2. Applicants also notes a subsequent publication by Wainer et al. (Science (1972); 178: 647-648) correcting certain misstatements of fact in the cited Wainer reference. In view of this, Applicants contend that one of ordinary skill would not have envisioned, or reasonably expected success for, the claimed invention.
These arguments have been carefully considered but are not found persuasive.
In response to applicant's arguments of each of the references with what appears to be individually, the Examiner recognizes that the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). As noted above, while Torres discusses the popularity of Carbodiimide chemistry in conjugating haptens to carrier proteins, Torres realizes the potential pitfalls. Wainer, on the other hand, provides an alternative conjugation method haptens to carrier proteins, specifically morphine succinate to BSA which does not involve Carbodiimide chemistry. It is noted that the examiner has reviewed the Wainer et al. Science paper pointed out by the Applicants. The paper seems to be clarifying that the succinate was added to the 6 position vs. the originally reported 4 position of morphine and does not comment on the mixed anhydride coupling step of morphine succinate to BSA. Regarding Applicants arguments pertaining to morphine-6-succinyl-BSA so formed has an average ratio of morphine-6-succinyl moieties to BSA of at least 8.2, the claimed limitation does not appear to result in a when following the procedures of the prior art combination since Torres teaches using dry benzene as the solvent because it leads to the selective succinylation of the 6-hydroxy group and Wainer’s mixed anhydride methods appears to be substantially identical to that taught in the instant specification (Example 3). It is also important to note that the specification does not appear to provide an actual calculation of the average ratio similar to that provided by Wainer et al. or Akbarzadeh 3. Accordingly, it is unclear of whether the process disclosed by Applicants creates an average ratio as claimed and how this method, which appears to be substantially similar (for example, mmol’s of reactant used) is advantageous or different from the prior art.
Conclusion
Therefore, No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRANDON J FETTEROLF whose telephone number is (571)272-2919. The examiner can normally be reached M-F 6AM-4PM.
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/BRANDON J FETTEROLF/Primary Examiner, Art Unit 1626