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 .
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.
DETAILED ACTION
The amendments filed on 10/3/2025 which claims 28-29 were amended is acknowledged.
Claims 1-11, 18, and 24-29 are pending in the instant application.
Priority
This application is a 371 of PCT/US2021/013300, filed on 1/13/2021 which claims priority to the provisional application 62960187 filed on 1/13/2020.
Withdrawn Objections
The objection to the specification has been withdrawn; applicant removed the hyperlink.
Withdrawn Rejections
The rejection of claim 29 under § 112(b) is withdrawn in light of the amendments; the claim now recites the active step of “administering to”.
The rejection of claims 1-6, 8, 18, 25-26, and 29 under § 102(a)(1) has been withdrawn in light of the arguments; while the reference of McConnell refers to thiol linkages, thiocarboxylate linkages are shown in the exemplary structures, wherein applicant has excluded thiocarboxylate linkages for variable R4 in Formula (I).
Claim Rejections – 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 28-29 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 28
Claim 28 is drawn to the immunoconjugate being “embedded in” the adjuvant. Applicant did not supply a definition of “embedded in”. “Embedded in” is a relative term that makes it unclear when a molecule is merely associated or to an undetermined degree, encapsulated by another molecule. Furthermore, as there is no defined binding pocket of some of the exemplary adjuvants such (e.g. aluminum hydroxide, aluminum phosphate, or alum described in claim 27) in which to encapsulate the immunoconjugate. One artisan may interpret this to imply a non-covalent interaction of the adjuvant and the immunoconjugate (e.g. the pair are bound to each other such as an antibody and antigen interaction) wherein at least some of the molecule components are overlapped in a 3-D projection, whereas another artisan may interpret this to mean the one molecule is inside the other entirely, such as being contained by a micelle. Because of these multiple interpretations, this claim is rendered indefinite.
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, 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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-11, 18, and 24-29 are rejected under 35 U.S.C. 103 as being unpatentable over McConnell (US20030170728) in view of Pravetoni (doi: 10.1021/jm3013745).
*Claim 1-6, 8, 18
Regarding claims 1-6, 8, and 18, McConnell teaches a fentanyl hapten comprising the structure below,
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wherein Z1 is hydrogen, and Z4 is the structure below (claim 1).
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McConnell teaches Z2 is a crosslinker of the structure (NH)a-(CO)b-Xc-(CH2)d-Se-CO-R, wherein a = 1, b = 1, c = 0, d = 2, e = 1, and R = OH or C1-5 alkyl (claim 5). In sum, McConnell teaches the structural elements below.
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The teachings of McConnell described above satisfy the limitations of R4 = R5 = C1-C6 alkyl (instant claim 1); R3 = CH3 (instant claim 2); n =1 (instant claim 3); x = 1 (instant claim 4); z = 0 (instant claim 5); and y = 0 (instant claim 6). By satisfying instant claims 2-4, McConnell has also satisfied instant claim 8. McConnell teaches that a thiol group on the antigenic material may be used to conjugate it to the linker of the fentanyl-containing unit (pg 7, para 0078). Thus satisfying the limitations of claim 18 specifying the immunogenic carrier is covalently bound to the linker of the hapten.
The structures of McConnell are vague regarding the linker containing a thiol (pg 7, para 0078) as opposed to the explicitly described thiocarboxylate group shown above.
Pravetoni teaches generating an immunogenic hapten of hydrocodone using a thiol-based linker for attaching to the immunogen, KLH (abstract; pg 916, col 1, para 1; Figure 1, reproduced below).
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It would have been obvious to combine the teachings of McConnell and Pravetoni because (1) McConnell teaches that the linker can comprise thiol and functions well with the related thiocarboxylate linkage; and (2) Pravetoni teaches that thiol groups are able to be attached to immunogenic peptides such as KLH in order to generate a functional hapten targeting an opioid compound comprising a thioether linkage. One of skill in the art would have had a reasonable expectation of success because both inventions are directed towards opioid-based haptens known to generate an immunogenic response against the tethered drugs. The art is clear in showing that the particular sulfur-containing functional group can be thiocarboxylate or a thioether without deleteriously affecting the function of the hapten.
Claim 7, 9-11, 24
Regarding claims 7, 9-11, and 24, McConnell teaches the structural elements below, where R = C1-C6 alkyl (i.e. instant variable R4), as discussed above. McConnell teaches that a thiol group on the antigenic material may be used to conjugate it to the linker of the fentanyl-containing unit (pg 7, para 0078).
McConnell does not teach instant variable R4 = H (i.e. McConnell’s variable R). McConnell doesn’t teach the antigenic carrier is KLH.
Pravetoni teaches generating an immunogenic hapten of hydrocodone using a thiol-based linker for attaching to the immunogen, KLH (abstract; pg 916, col 1, para 1; Figure 1, reproduced below).
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Claim 25
Regarding claim 25, McConnell teaches a composition comprising the hapten and saline, thus satisfying the limitation of a composition comprising the hapten and a vehicle (pg 11, para 0161).
Claim 26
Regarding claim 26, McConnell teaches combining the hapten with an adjuvant (pg 11, para 0172).
*claim 27-28
Regarding claims 27-28, McConnell teaches the Adjuvant is Freund’s Complete Adjuvant (FCA) or Freund’s Incomplete Adjuvant (FIA), that forms an emulsion (pg 11, para 0172). While McConnell does not use the term “embedded” this emulsion nonetheless is understood to contain both the adjuvant and the hapten, thus satisfying the limitation of claim 28 of the immunoconjugate being “embedded” and/or “associated with” the adjuvant using the interpretation that the immunoconjugate and adjuvant are in contact with one another in solution.
McConnell does not teach the adjuvant is alum.
Pravetoni teaches the adjuvant is alum (pg 918, col 2, para 3).
Claim 29
Regarding claim 29, McConnell teaches a method of generating an anti-fentanyl immune response in a subject via administering the haptens of the invention to the subject (pg 6, para 0065).
Allowable Subject Matter
McConnell teaches that the antigenicity-conferring material can be attached to any of the indicated positions:
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McConnell does not teach that the antigenicity-conferring material can be attached to the central piperidinyl moiety. Absent the teachings of the instant application, one of skill in the art would not be motivated to link the fentanyl unit to the central piperidinyl moiety given that linkages on the periphery were known to be functional, and it is unclear if linkage to the central piperidinyl unit would have conferred the desired immunogenicity towards fentanyl. Collins (doi: 10.1007/978-3-319-23150-1_18) teaches
“The structure of the target drug must inevitably be modified by the attachment of the linker that covalently connects it to the requisite carrier protein or peptide. As discussed above, modification of the structure should ideally be achieved without significantly impacting the antibody recognition of the drug, thus avoiding generation of antibodies that may have high affinity for the hapten but poor affinity to the soluble drug. This is theoretically achieved by the strategic position of the linker at a distal location on the drug to the optimal epitope, although in practice, the latter is difficult to predict and define. Given that antibody binding is a result of multiple molecular interactions with polar and hydrophobic surfaces, multiple attachment points may need to be tested in order to identify the optimal linker location. Furthermore, the synthetic complexity must also be considered; if the resulting hapten is fairly intractable to synthesis, it may preclude its therapeutic use even if it demonstrates high efficacy.”
In light of this unpredictability, compounds of Formula (II) which use a central attachment as opposed to a distal attachment are rendered allowable over the prior art.
Response to Arguments
Applicant’s arguments filed on 10/3/2025 have been fully considered but they are not persuasive.
112(b); pg 8, para 3
Applicant argues they have addressed the 112(b) issue of “associated with” by replacing it with “embedded in”. No rationale was provided for why this amendment addressed the rejection.
Examiner disagrees as it is unclear what applicant means by “embedded in”. As there is no obvious binding pocket of the exemplary adjuvants such (e.g. aluminum hydroxide described in claim 27) in which to encapsulate the immunoconjugate. It appears applicant is merely referring to adjuvant merely being a component of the composition, one that is not necessarily bound. As claims 26-27 already state the adjuvant is a component that exists in solution with the immunoconjugate (i.e. encompassing detatched adjuvant), claim 28 can only provide the alternative binary selection of the adjuvant being attached. Examiner recommends deleting the language “embedded in or” from claim 28. If desired, Applicant could generate a new claim specifying “The composition according to claim 25, wherein the immunoconjugate is encapsulated by a liposome.”
102; pg 10, para 2
Applicant argues that McConnell does not teach all the limitation of formula (I), because formula (I) specifically excludes R4 being a thiocarboxylate group.
This argument was found convincing. While McConnell teaches “The thus-modified labelling agent or carrier material, can then be conjugated via the thiol groups on haptens in which e is 1, such as haptens A and C” (pg 7, para 0078); it is appreciated that the formulas featured display a thiocarboxylate and not a thiol despite the language, nor does McConnell give an explicit description of the protein-hapten conjugates to make a clear determination if such thiol linkages were or were not envisaged.
103; pg 11, para 6
Applicant argues that McConnell does not teach all the limitation of formula (I), because formula (I) specifically excludes R4 being a thiocarboxylate group. Applicant argues the 103 rejection was only applied to claims 7, 9-11, and 24, thus base claim 1 was not rejected under § 103.
This is an improper interpretation of the 103 header, which clearly stated that all the claims were rejected under 103: “Claims 1-11, 18, and 24-29 are rejected under 35 U.S.C. 103 as being unpatentable over McConnell (US20030170728) as applied to claims 1-6, 8, 18, 25-26, and 29 above, and further in view of Pravetoni (doi: 10.1021/jm3013745).” The issue regarding the sulfide has been addressed in the modified 103 rejection above.
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). 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.
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/L.A.E./
Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
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