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 2-14 are pending and 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 2-14 are rejected under 35 U.S.C. 103 as obvious over Illy et al (Biomacromolecules 2012; Cited in IDS of 8/26/2024, Cite# 46) in view of Blackman et al (J. Am. Chem. Soc. 2008; Cited in IDS of 8/26/2024, Cite# 31) or Devaraj et al (PNAS 2012; Cited in IDS of 8/26/2024, Cite# 38) and further in view of Seitchik et al (Am. Chem. Soc 2012; Cited in IDS of 8/26/2024, Cite# 60).
In regards to claim 2, Illy discloses a linked structure having the structure:
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. The above structure is a mass-tagged specific binding pair member comprising a specific binding pair member (SBP) conjugated to a mass tag which comprises a polymer comprises a plurality of metal chelating moieties loaded with metal isotopes (Abstract). Illy discloses that the SBP is joined to the mas tag by a covalent linker through a covalent bond. Illy discloses that the antibody is loaded with saturating amount of metal isotope (page 2366, last line of 1st column to 1st line of 2nd column) specifically teaches each distinct antibody is labeled with multiple copies of a unique metal isotope (page 2360, lines 4-5 of 1st column; and Table S2).
Illy however, does not disclose click chemistry mediated cycloaddition reaction utilizing clickable linking moieties for conjugation of the polymer to the antibody, as for example, a tetrazine and an alkene (trams-cyclooctene), wherein the tetrazine is methyl substituted as claimed.
Blackman teaches biorthogonal reaction that proceeds with unusually fast reaction without the need for catalysis: the cycloaddition reaction of s-tetrazine and trans-cyclooctyne derivatives. Blackman teaches that the reactions tolerate a broad range of functionality and proceed in high yield in organic solvents, water, cell media, or cell lysate. (Introduction). Blackman discloses bioconjugation of protein functionalized with trans-cyclooctene derivative (TRX-trans-cyclooctene) with tetrazine derivative wherein the bioconjugation was complete within 5 minutes:
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, which demonstrated that the tetrazine ligation was fast and high yielding (page 13519, 1st paragraph).
Devaraj discloses selective biorthogonal reactions or “click” chemistry based on the vary fast and catalyst-free [4+2] tetrazine/trans-cyclooctene cycloaddition (Abstract). Devaraj teaches that the most popular biorthogonal reactions being the Staudinger ligation and the [3 + 2] cycloaddition “click” reaction between azides and alkynes and the latter click reaction involves copper(I) catalyzed coupling of an azide and terminal alkyne to generate a stable triazole. Devaraj teaches that the necessity of the copper catalyst of this reaction in biological systems is of concerns due to toxicity. Devaraj teaches that the cycloaddition between tetrazine (Tz) and trans-cyclooctene (TCO) can proceed orders of magnitude faster than previously studied azide and alkyne click reactions and importantly does not require the action of a catalyst. Devaraj discloses tetrazine and trans-cyclooctene bases bioconjugation:
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(Fig.1). Devaraj teaches that TCO/Tz reaction is an ideal biorthogonal chemical system for in vivo use given its fast reaction kinetics.
Seitchik teaches site-specific biorthogonal ligation utilizing providing protein with tetrazine containing amino acid for conjugation to trans-cyclooatene (Abstract and Fig.1). Seitchik teaches that monoaryl-s-tetrazines,are stable in biological milieu but display slow background reactivity that would be incompatible with cellular growth conditions. Seitchik teaches that adding an electron-donating methyl on the tetrazine improve its stability against nucleophilic attack (page 2898, 2nd col.). Seitchik teaches that amino acid comprising methyl substituted tetrazine and strained trans-cyclooacetne (s-TCO) is a good combination for bioconjugation as it displays relative rates that are significantly faster (page 2899, 1st col.).
Therefore, given the teaching that conjugation utilizing biorthogonal clickable moieties is a useful process for bioconjugation and given the fact that TCO/Tz is art recognized alternative biorthogonal reactive group for alkyne and azide and given the fact that the reaction is fast and can be carried out without toxic copper catalyst (Blackman and Devaraj), it would be obvious to one of ordinary skilled in the art before the effective filing dated to the claimed invention, to easily envisage providing TCO and Tz biorthogonal reactive group for linking the antibody with the polymer with the expectation of providing the linked structure of Illy by a click chemistry, which is fast and which does not require a toxic copper catalyst with a reasonable expectation of success. Moreover, from the teaching in mind of Seitchik, it would be obvious to one of ordinary skilled in the art to easily envisage considering methyl substitution on tetrazine for conjugation with TCO containing antibody for the bioconjugation process that were found to be obvious in view of Illy, Blackman and Devaraj because Seitchik teaches that methyl and amine substitution on tetrazine stabilizes tetrazine and the reaction of methyl and amine substituted tetrazine with s-TCO provides significantly higher rate of reaction.
In regards to claims 3-4, Illy teaches various spacers linking the mass tag (see scheme) including C5 non-cyclic alkyl spacer (see scheme 1). Illy also teaches various backbone polymers including polyglycerol spacer (age 2359). Thus various covalent linker comprising various spacer including polyglycerol would be obvious to one of ordinary skilled in the art.
In regards to claim 5, Illy in view of Blackman or Devaraj et al (PNAS 2012) and Seitchik do not teach providing the contrast agents in a kit, but however, since the method and method components for the process is obvious from the combination of the references, one or ordinary skilled in the art can easily envisage providing the contrast agent in a kit for ease and convenience in an assay performance.
In regards to claim 6, as disclosed above, Blackman and Devaraj discloses reacting alkene containing biomolecule with a tetrazine containing biomolecule for the bioconjugate reaction and the reaction product (i.e. the covalent linker) does not comprise a sulfhydryl group.
In regards to claim 7, Illy discloses that MCPs for mass cytometry were copolymers of N,N-dimethyl acrylamide with a functional acrylamide bearing DOTA pendant groups (page 2358, 1st col.).
In regards to claim 8, Devaraj disclosed trans-cyclooctyne attached to antibody (SBP) and since the combination of the references makes obvious of utilizing trans-cyclooctyne and methyl-substituted tetrazine, attachment of the reactive groups either to SBP or to mass tag would be obvious and would be within the purview of one of ordinary skilled in the art.
In regards to claims 9-12 and 14, Illy teaches specific binding pair member (SBP) conjugated to a mass tag which comprises a polymer comprises a plurality of metal chelating moieties loaded with metal isotopes. Illy discloses that the antibody is loaded with saturating amount of metal isotope (page 2366, last line of 1st column to 1st line of 2nd column) specifically teaches each distinct antibody is labeled with multiple copies of a unique metal isotope (page 2360, lines 4-5 of 1st column; and Table S2). Thus, various number of labeling atoms would be obvious to one of ordinary skilled in the art for optimization and tuning of the mass tag conjugates with a reasonable expectation of success.
In regards to claim 13, Illy discloses antibody (i.e. a SBP) linked to polymer comprising lanthanide ion.
Conclusion
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/SHAFIQUL HAQ/Primary Examiner, Art Unit 1678
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