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 .
The following is a new ground of rejection, which was necessitude by Applicant’s amendments:
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 1-22 and 24-27 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.
The claims have been amended to recite adding a modified linker to the second peptide mixture to obtain a modified peptide mixture, wherein the modified linker labels an unconjugated conjugation site of the partially conjugated antibody or antibody fragment corresponding to the conjugation site of the at least one attachment, and the modified linker is modified to have a molecular weight that is distinguishable from the corresponding cleaved linker using mass analysis.
However, it is unclear how an unconjugated conjugation site can correspond to site that is conjugated. Therefore, the structure of the peptides of the modified peptide mixture is unclear.
The following is a new ground of rejection, which was necessitude by Applicant’s amendments:
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.
Claims 1-4, 6, 12, 19-22, 24-27 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2017/151892 (WO 892) in view of:
Beck et al., Expert Rev Proteomics. 2019 Apr;16(4):337-362 (Beck); and
Chen et al., Anal. Chem. 2013, 85, 1699−1704 (Chen); and
Janin-Bussat et al., J. Chromatogr. B 981–982 (2015) 9–13 (Janin-Bussat);
Hernandez-Alba et al., J. Am. Soc. Mass Spectrom. (2019) (Hernandez-Alba); and
Adamo et al., Journal of Chromatography A, Volume 1481, 2017, Pages 44-52 (Adamo) in further view of:
Beck et al., Anal.Chem.2013,85,715−736 (Beck II); and
Arsène-Ploetze et al., Environ Sci Pollut Res Int. 2014 Dec 5;22(18):13599–13612 (Arsène-Ploetze).
WO 892 teaches the recited quantification methods of conjugated antibodies. Specifically, WO 892 discloses a method for quantifying or characterizing conjugation of at least one attachment linked to at least one specific conjugation site of a partially conjugated protein in a sample, comprising:
cleaving the protein with two proteolytic enzymes to generate a mixture of peptides containing the linked attachment;
subjecting the sample to mass spectrometry to identify the peptides containing the linked attachment and the corresponding peptides having unconjugated conjugation sites.
See claim 6:
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See page 15, line 25 to page 17, line 23
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See figure 8:
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Figure 3 teaches conjugates.
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The applied references also combine protease digestion and mass spec, see Beck:
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See Chen:
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See Janin-Bussat
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See Hernandez-Alba:
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The difference between WO 892 and the claimed inventions is that WO does not teach the invention with particularity so as to amount to anticipation (See M.P.E.P. § 2131: "[t]he identical invention must be shown in as complete detail as is contained in the ... claim." Richardson v. Suzuki Motor Co., 868 F.2d 1226, 1236, 9 USPQ2d 1913, 1920 (Fed. Cir. 1989). The elements must be arranged as required by the claim, but this is not an ipsissimis verbis test, i.e., identity of terminology is not required. In re Bond, 910 F.2d 831, 15 USPQ2d 1566 (Fed. Cir. 1990).). In particular, the use of enzymatic digestion and mass analysis was commonplace to characterize antibody-drug conjugates. In this regard, the secondary references teach the elements of the this analysis method with sufficient guidance, particularity, and with a reasonable expectation of success, that the invention would be prima facie obvious to one of ordinary skill (the prior art reference teaches or suggests all the claim limitations with a reasonable expectation of success. See M.P.E.P. § 2143).
The claims have been amended to require subjecting the first peptide mixture to a second protease to obtain a second peptide mixture, wherein the first peptide mixture includes a digested peptide. In this regard, Applicant argues that Chen 2017 (applied herein as “WO 892”) does not disclose subjecting a first peptide mixture including a digested peptide to a second protease to obtain a second peptide mixture. At most, Chen 2017 discloses subjecting one portion of undigested sample to digestion with trypsin, and a second portion of undigested sample to digestion with Asp-N protease, and then combining spectra obtained from each portion. Chen 2017, p. 15, lines 26-27, and p. 16, lines 12-14. Applicant then argues that the remaining cited references do not cure the deficiencies of Chen 2017 and do not provide a motivation for one of ordinary skill in the art to modify the methods of Chen 2017 to arrive at the claimed methods.
However, Adamo teaches that quantitation of the DAR for random lysine conjugated ADCs was developed. It focuses on the analysis of an antibody drug conjugate that employs a random lysine conjugation process for attachment of a tubulysin analogue to a human IgG1 antibody through a peptidic, hydrolytically stable cathepsin-B cleavable linker.
This method utilizes cleavage at the hinge region of the mAb and mild reduction prior to cathepsin B cleavage and overcomes the aforementioned limitations in other existing methods.
Significantly, the ADC is first treated with Immunoglobulin G-degrading enzyme of S. pyogenes (IdeS) to cleave the molecule into Fabʹ and Fc fragments followed by 2-mercaptoethylamine treatment to mildly reduce to Fdʹ, Fc and Lc fragments (Fig. 1). By using IdeS instead of another protease such as Trypsin, the ADC is cleaved into smaller fragments but without creating a large number of peptides that would likely interfere with the quantitation of the drug. The use of 2-mercaptoethylamine (2-MEA) serves a dual purpose for reduction and also as an activator of the cathepsin B enzyme [16]. Following IdeS cleavage and 2-MEA reduction the sample is treated with cathepsin B enzyme to release the drug from the antibody fragments (Fig. 1):
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In this way, those of ordinary skill could have applied dual digestion in the manner required and in a predictable fashion. Specifically, Adamo teaches that the technique of using the recited protein digestion with a first and second protease was recognized as part of the ordinary capabilities of one skilled in the art. In particular, Adamo teaches that the method is free of interference from the protein and affords a universal method that can be used for ADCs that employ a cathepsin B cleavable linker irrespective of the conjugation chemistry, see page 45. In this manner, those of ordinary skill would have recognized that applying the known technique would have yielded predictable results. Accordingly, using the recited protein digestion with a first and second protease would have been prima facie obvious. See also Beck II, below.
The claims have been amended to require adding a modified linker to the second peptide mixture to obtain a modified peptide mixture, wherein the modified linker labels an unconjugated conjugation site of the partially conjugated antibody or antibody fragment corresponding to the conjugation site of the at least one attachment, and the modified linker is modified to have a molecular weight that is distinguishable from the corresponding cleaved linker using mass analysis.
In this regard, Beck II teaches top-down, middle-down and-up, bottom-up characterization of therapeutic antibodies that also use a multiple protein digestion:
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Using bottom-up peptide level analysis, tandem mass spectrometry is usually performed in order to sequence peptides, to finely locate PTMs, such as glycosylation sites, disulfide bridges, and other potential modifications. In order to quantitatively assess the effect of an induced stress on protein therapeutics, a stable isotope-tagged reference standard can be spiked to the experiments and serve as reference for comparability studies, see page 720. In these techniques, several tags can be used that contain four regions, namely a mass reporter region, a cleavable linker region, a mass normalization region, and a protein reactive group. The chemical structures of all the tags are identical but each contains isotopes substituted at various positions in such a way that the mass reporter and mass normalization regions have different molecular masses in each tag, see Arsène-Ploetze at page 13605.
In this manner, using labels for mass analysis to identify sites in an antibody, such as conjugated or unconjugated sites, was well within the purview of those of ordinary skill, and therefore, prima facie obvious.
Claims 5, 7-11, 13-18 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2017/151892 (WO 892) in view of Adamo et al., Journal of Chromatography A, Volume 1481, 2017, Pages 44-52 (Adamo), in further view of:
Beck et al., Anal.Chem.2013,85,715−736 (Beck II); and
Arsène-Ploetze et al., Environ Sci Pollut Res Int. 2014 Dec 5;22(18):13599–13612 (Arsène-Ploetze), as applied to claim 1, in further view of Jain et al., Pharm Res (2015) 32:3526–3540 (Jain).
WO 892 may fail to explicitly teach the recite conjugates. However, it is for that proposition that the examiner joins Jain. Specifically, Jain demonstrates that the recited conjugates were ubiquitous at the time of the invention:
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In this way, those of ordinary skill could have applied the recite quantification to those conjugates recited in the rejected claims in the manner required and in a predictable fashion. As outlined above, WO 892 teaches the recited quantification methods of conjugated antibodies. Jain is added for the proposition that this process is applicable to the recited antibodies. Specifically, WO 892 teaches that the recited technique of quantifying and characterizing conjugated antibodies was recognized as part of the ordinary capabilities of one skilled in the art. In this manner, those of ordinary skill would have recognized that applying the known technique to other antibody conjugates, such as those taught by Jain, would have yielded predictable results. Accordingly, using the recited method to quantify and characterize the recited antibody conjugates would have been prima facie obvious.
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.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KARL J PUTTLITZ whose telephone number is (571)272-0645. The examiner can normally be reached on Monday to Friday from 9 a.m. to 5 p.m.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Gregory Emch, can be reached at telephone number 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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/KARL J PUTTLITZ/ Primary Examiner, Art Unit 1646
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