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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 8/10/2026 has been entered.
Claims 26 and 28 are currently pending and under consideration.
Response to Amendment
The declaration by Babak Behnam under 37 CFR 1.132 filed on 8/10/2026 is insufficient to overcome the rejection of claims 26 and 28 based upon the rejection 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) as set forth in the last Office action for the following reasons:
-The declaration provides experimental studies in Exhibit 1 of three independently synthesized batches of morphine-6-succinyl-BSA prepared according to the method of claim 26, wherein the calculated hapten-to-BSA ratio for the three batches were 8.202, 8.242 and 8.316.
In response to this, the Examiner appreciates Declarants studies and does not dispute that the calculated hapten-to-BSA ratio for the three batches as reported. However, while the declarant asserts that the batches were prepared according to the methods of claim 26 (not example 3 of the specification), it is unclear what the actual reaction condition were and/or how these reaction conditions differ to those taught or suggested by the combination. As the Declarant is aware, 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 was added to a mixture of BSA in water and dioxane (pH adjusted with sodium hydroxide) (page 1143, 3rd column, 1st full paragraph). Moreover, as brought to the attention of the Examiner by Applicant in the 1/08/2026 response, Wainer et al. discovered, after the fact, that the attachment of the succinoyl moiety to morphine is through the 6- rather than the 3-hydroxy as reported. As noted in the prior office action, Wainer’s mixed anhydride methods appears to be substantially identical to that taught in the instant specification (Example 3). Yet, 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.
-Lastly, the Declarant provides an opinion that achieving an average hapten-to-BSA ratio of at least 8.2 was unexpected at the time of the invention, wherein known method of making morphine-succinyl-BSA conjugates, whether using EDAC (Akbarzadeh) or mixed anhydride on the succinyl isomer (Wainer), consistently produced hapten-to-BSA ratios of only approximately 6.5.
In response, the Examiner acknowledges Declarants opinion. However, the Examiner reiterates, as set forth above, that it is unclear what conditions where used in order to achieve the above asserted results.
Rejections Maintained
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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 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 summarizes the Declaration under 37 CFR 1.132 by Dr. Babak Behnam. Application further stresses 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.
The Benham Declaration has been considered, not found persuasive for the reasons set forth above. The majority of Applicants arguments mirror those from the Final Office Action and recreated herein. 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 for 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 3 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.
New Rejections:
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 28 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wainer et al. (Science (1972, Vol. 176, 1143-1144) as evidenced by Wainer et al. (Science (1972); 178: 647-648, IDS) referred to as Wainer 2.
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 was added to a mixture of BSA in water and dioxane (pH adjusted with sodium hydroxide) (page 1143, 3rd column, 1st full paragraph). Thus, while the prior art teaches the preparation of morphine-3-succinyl, as evidenced by Wainer 2 in a correction to the initial paper, Wainer 2 teaches that we now have chemical evidence that the attachment of the succinoyl moiety to morphine is through the 6- rather than the 3-hydroxy group (see page 647, 1st column, 1st full paragraph). Note: While the Examiner acknowledged that Wainer et al. teach that 6.5 mophinie moieties per BSA which is not 8.2 as claimed, the Examiner has reviewed the instant specification 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.
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
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