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 .
DETAILED ACTION
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 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.
Status of the claims
Claims 1, 4-13, 16-23 and 25-31 are pending and claims 1, 4-11, 13 and 16-23 are examined on merits in this office action.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Root et al. (US 2004/0248222A1).
Rott discloses Norbuprenorphine glucuronide having the structure
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, which is very similar to the compound of formula 1 and formula 2 with the following selections:
For formula 1, when R2 is glucuronic acid, R1 is -Y-Z wherein Y is –(CH2)n-, n is 1 and Z is hydrogen; and for Formula 2, when R1 is -Y-Z, wherein Y is –(CH2)n-, n is 1 and Z is hydrogen
With the above selections, the compounds of Formula 1 and Formula 2 differ from above structure of Rott by having a methyl group (Z-Y: -CH2-H) in place of H at nitrogen 17 position of norbuprenorphine glucuronide and thus the compounds are very similar with a substitution of the N17 hydrogen with a methyl group. However, it was well established that the substitution of methyl for hydrogen on a known compound is not a patentable modification, absent unexpected or unobvious results or that hydrogen and methyl are deemed obvious variants. In In re Wood, 582 F.2d 638, 199 USPQ 137 (CCPA 1978).
Claims 1, 4-11, 13 and 16-23 are rejected under 35 U.S.C. 103 as being unpatentable over Root et al. (US 2004/0248222A1).
Root discloses a norbuprenorphine conjugate having the structure:
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, wherein Y can be O, X can be 0-10 carbon atoms or heteroatoms and Z can be a protein, polysaccharide or a label (claim 13). Root specifically discloses compounds
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,
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, and
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, which read on Formula 1 with the following limitations R2 is H, R1 is -Y-Z, wherein Y is a linking group –(CH2)nCO- and Z is an immunogenic carrier, a protein, a label or an activated carboxyl (NHS).
Root, as described above, discloses immunogenic conjugate comprising norbuprenorphine conjugated to an immunogenic carrier (BSA or HAS).
Root is directed to developing antibody that specifically binds to buprenorphine drug (Abstract and para [0001]) (
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) and its metabolites. Root discloses immunizing mice with buprenorphine-KHL and buprenorphine-BSA conjugate (para [0131]) for providing monoclonal antibody recognizing buprenorphine with high specificity compared to buprenorphine metabolites (Fig.5). Root teaches that the antibody BUP 2.2 and BUP23.1 require the hydroxyl group at C3 and N-methyl-cyclopropane at C9 for binding and may additionally require the tert-butyl region at C22 (para [0145]). Root discloses an antibody BUP 83.1 developed from buprenorphine KHL conjugate that binds to metabolite norbuprenorphine but show low cross-reactivity to norbuprenorphine glucuronide metabolite (para [0151]). Root discloses preparing antibodies using buprenorphine conjugated to BSA or KHL as immunogen having variable degrees of binding to buprenorphine and/or one or more metabolites (para [0144]).
Root however, does not disclose metabolite of norbuprenorphine (as for example, norbuprenorphine glucuronide) as an immunogen for developing antibody. Root does not disclose generating specific antibody against specific metabolites by conjugating the metabolite with an immunogenic protein, as for example, norbuprenorphine glucuronide conjugated to BSA or KHL for generating antibody that specifically recognizing glucuronide containing metabolites.
However, Root teaches that parent drug buprenorphine completely metabolized to norbuprenorphine, norbuprenorphine glucuronide and buprenorphine glucuronide and is consequently present in urine (para [0004]). Root teaches that buprenorphine metabolite or conjugate thereof can be used as an immunogen to generate monoclonal antibodies that specifically bind to buprenorphine and/or one or more buprenorphine metabolites. In one embodiment, the immunogen is a buprenorphine metabolite-hapten carrier conjugate (see para [0074]) for example, a buprenorphine glucuronide conjugate (para [0074]).
Therefore, given the fact that norbuprenorphine glucuronide and buprenorphine glucuronide are metabolites of the drug buprenorphine and are present in urine, one of ordinary skilled in the art can easily envisage developing specific antibodies against the glucuronide metabolites, including the metabolite nonbuprenorphine glucuronide, by conjugating the metabolite to BSA or KHL. From the description in mind of BSA and KHL conjugates of norbuprenorphine, wherein BSA and KHL is conjugated at N17 position with a linker, one of ordinary skilled in the art can easily envisage providing conjugates of norbuprenorphine glucuronide with BSA or KHL at the similar position (N17) of norbuprenorphine glucuronide
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, with the expectation of providing immunogenic conjugate with the expectation of generating specific antibody that specifically recognizes norbuprenorphine glucuronide and/or buprenorphine glucuronide metabolite with a reasonable expectation of success. Root teaches that the antibody BUP 2.2 and BUP23.1 require the hydroxyl group at C3 and tert-butyl region at C22 (para [0145]) for binding that are further away from the linker immunogen at position N17, one of ordinary skilled in the art can expect the antibody produced from norbuprenorphine conjugate of KHL at N17 position would provide antibody having recognition specificity involving glucuronide groups as the groups are free and are further away from the linker-immunogen.
In regards to claims 16-18 and 20, Root as described above, discloses BSA, which reads on albumin and which is a protein and also can be considered a protein label.
In regards to claim 19, as described above, Root teaches that Z can be a polysaccharide (see claim 13).
In regards to claims 10-11 and 20-23, Root teaches that Z can be a label and label can be an enzyme (para [0041]) and discloses various enzyme labels including enzyme HRP (para [0105], [0137], 0159], [0062]). Thus, various commonly utilized enzyme labels such as HRP or G6PD are obvious to one of ordinary skilled in the art and are within the purview of one of ordinary skilled in the art except showing of unexpected advantages with a particular enzyme conjugate.
Response to argument
Applicants’ arguments and amendments filed 08/27/2026 have been fully considered and are persuasive to overcome the rejections under 35 USC 112(d) and 35 USC 102(a)(1) in view of the amendments. However, Applicant’s arguments have been rendered moot in view of the new grounds of modified rejections as described in this office action that are necessitated by Applicants’ amendments. However, some of the Applicant’s arguments regarding 35 USC 103 rejection will be addressed below:
Applicant argued that Root teaches away synthesizing buprenorphine and norbuprenorphine glucuronide metabolites conjugated to immunogenic carriers. The argument is based on Root’s teaching of difficulty in synthesizing conjugates with metabolites. Applicant argued that since Root discloses antibodies binding to one or more metabolites, thereby eliminating the need to use the metabolite in the preparation of immunogen.
The above arguments have fully been considered but are not found persuasive because difficulty cannot be equated to teaching away because Root’s teaching on the other hand provides motivation to generate antibody utilizing metabolites as immunogens. Root teaches that parent drug buprenorphine completely metabolized to norbuprenorphine, norbuprenorphine glucuronide and buprenorphine glucuronide and is consequently present in urine (para [0004]). Root teaches that buprenorphine metabolite or conjugate thereof can be used as an immunogen to generate monoclonal antibodies. Root in paragraph [0074] teaches that in one embodiment, the immunogen is a buprenorphine metabolite-hapten carrier conjugate, for example, a buprenorphine glucuronide conjugate. Therefore, contrary to Applicants’ assertion, the disclosure of Root provides strong motivation to generate antibody utilizing metabolites conjugated to immunogenic carrier proteins as immunogens for generating specific antibody against the specific metabolites of glucuronide. Root discloses an antibody BUP 83.1 developed from buprenorphine KHL conjugate that binds to metabolite norbuprenorphine but show low cross-reactivity to norbuprenorphine glucuronide metabolite (para [0151]). Root discloses preparing antibodies using buprenorphine conjugated to BSA or KHL as immunogen having variable degrees of binding to buprenorphine and/or one or more metabolites (para [0144]). Therefore, from the disclosure of Root, one of ordinary skilled in the art understand that utilizing buprenorphine or norbuprenorphine conjugate as immunogen provides antibody highly specific to buprenorphine or norbuprenorphine but low or variable cross-reactivity to their metabolites of glucuronides. Therefore, one of ordinary skilled in the art from the teaching of Root of utilizing buprenorphine glucuronide conjugate and from the disclosure of low reactivity with antibody generated from buprenorphine or norbuprenorphine, would be highly motivated to utilizing the glucuronide metabolites of norbuprenorphine for conjugating with an immunogenic carrier from generation highly specific antibody with a reasonable expectation of success. Moreover, contrary to Applicant’s assertion difficulty and teaching teaching away of synthesizing conjugates with glucuronide metabolites, Root clearly teaches norbuprenorphine glucuronide-KHL and norbuprenorphine glucuronide-BSA as screening agent (col. 18, lines 27-28).
Conclusion
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). Applicants are reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for replying 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 SHAFIQUL HAQ whose telephone number is (571)272-6103. The examiner can normally be reached on Mon-Fri 8-4:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bao-Thuy Nguyen can be reached on 571-272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SHAFIQUL HAQ/Primary Examiner, Art Unit 1678
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