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 .
Applicant’s remarks regarding Sequence compliance is noted.
The rejection under obvious double patenting is withdrawn in view of the Terminal Disclaimer filed in connection with this ground of rejection and Applicant’s remarks that the conflicting claims do not recite that all cytotoxic agent groups are conjugated to lysine residues of the same peptide segment of the light chain of the anti-ErbB2 antibody.
The rejection under section 112(b) is withdrawn in favor of the following new grounds of rejection under this section, which was necessitated by Applicant’s amendments: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, 2, 4-7, 11, 28 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 recite that the method produces an ADC composition that has an increased percentage of an ADC relative to the mixture, and is amended to recite ADC’s with different definitions of L. It is unclear what ADC is increased relative to the mixture.
The rejection under section 103 is maintained:
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, 2, 4-7, 11, 28 remain rejected under 35 U.S.C. 103 as being unpatentable over:
Baek et al., Analysis of Monoclonal Antibodies and Antibody-Drug Conjugates Using New Hydrophobic Interaction Chromatography (HIC) Columns, 2015, Thermo Scientific, downloaded 8 May 2026 from https://documents.thermofisher.com/TFS-Assets/CMD/posters/PN-21218-HPLC-Monoclonal-Antibodies-HIC-PN21218-EN-Rev1.pdf (Baek) in view of:
US 10,590,165 (US 165), or its counterpart, WO 2016123412; and
Behrens, Mabs, 01 Jan 2014, 6(1):46-53 (Behrens); and
Bhat et al., The Next Step in Homogenous Bioconjugate Development: Optimizing Payload Placement and Conjugate Composition, 2014, downloaded 23 March 2022 from https://bioprocessintl.com/manufacturing/monoclonal-antibodies/next-step-homogenous-bioconjugate-development-optimizing-payload-placement-conjugate-composition/ (Bhat I); and
U.S. Patent No. 8,741,291 to Bhat et al. (Bhat II); and
Panowski et al., mAbs, 2014, 6:1, 34-45 (Panowski).
Claims 1-7, separation of ADC’s: Baek teaches the recited HIC columns and mobile phases for ADC separation. Specifically, Baek teaches hydrophobic interaction chromatography (HIC) is a technique for separation of proteins and has been widely used as an orthogonal method to size exclusion chromatography and ion exchange chromatography for the characterization of mAb variants.
Baek teaches family of HIC columns designed for the analysis of mAbs and related biologics. Three different ligand chemistries-polyamide, amide and butyl-were developed for the analysis of a wide range of mAb samples. Separation of mAb aggregates, mAb fragments, oxidized mAbs, and antibody-drug conjugates were successfully carried out with excellent efficiency and high recovery.
Baek teaches the recited HIC separation techniques:
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Claims 1, 8-11, structure of the antibody: US 165 teaches the following ADC’s:
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The patent teaches that trastuzumab is recognized as ubiquitous in the art.
US 165 fails to explicitly teach conjugation via light chains.
Bhat discloses site-specific labeling of native mAbs at lysine residues in the kappa light chain constant domain of human mAbs by employing pentafluorophenyl esters as the active ester species for the conjugation:
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As Applicant notes, Bhat discloses that a drug can be conjugated on one light chain. See also description bridging columns 36 and 37.
Bhatt teaches how to conjugate in this manner:
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Therefore, conjugation to the light chains was within the purview of those of ordinary skill, and therefore, prima facie obvious.
Moreover, the references at least provide motivation to conjugate via lysine on the antibody light chain. Specifically:
at time of the invention, there had been a recognized problem of conjugating payloads to antibodies;
there had been a finite number of identified, predictable potential solutions to the recognized conjugation problem;
one of ordinary skill in the art could have pursued the known potential solutions, including lysine conjugation on the antibody light chain, with a reasonable expectation of success.
In this case, there had been a recognized problem of conjugating payloads to antibodies; there are a finite number of identified, predictable potential solutions to the recognized conjugation problem; and one of ordinary skill in the art could have pursued the known potential solutions, including lysine conjugation on the antibody light chain, with a reasonable expectation of success, as demonstrated by Behrens, above.
In this connection, it would have been obvious to one of ordinary skill in the art at the time the invention was made to choose from this finite number of conjugation options with a reasonable expectation of success of producing a functional ADC.
With regard to any unpredictability associated with different conjugation, the notion that unpredictability confers patentability in cases of different conjugation should be disregarded since a rule of law equating unpredictability to patentability, applied in this case, would mean that any new ADC based on a different conjugation would be separately patentable, simply because the formation and properties of each ADC must be verified through testing.
Here, the references provide the reasonable expectation of success, as outlined above. Namely, the references demonstrate the reasonable expectation of success since the references sufficiently characterize the instant ADC’s with a conjugation at a single light chain. Again, the expectation of success need only be reasonable, as it is here, and not absolute, (“obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g., In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988).”).
Moreover, as explained previously, the claims only require that all the cytotoxic agent groups are conjugated to the lysine residues of the same peptide segment of the light chain of the antibody.
Specifically, US 165 teaches the following lysine conjugated ADC’s:
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The references teach that the product of this conjugation results in a heterogenous product mixture, which includes the instant light-chain conjugate, see Behrens:
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See also Panowski:
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The claims do not require a percentage of the product mixture which are ADC’s wherein all the cytotoxic agent groups are conjugated to the lysine residues of the same peptide segment of the light chain, that would distinguish from the references. In this regard, the references teach that the claimed product is made. This meets the claim. Specifically, the claims only recite preparation of ADC’s conjugated at lysine residues of the light chain and Behrens teaches that this product is made; and moreover, there is nothing in the claims that distinguishes the claimed product mixture since the required ADC is prepared.
Notwithstanding the fact that Bhat may teach that precise conjugation is not possible, Applicant’s claimed embodiment is taught. i.e.:
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See also Panowski:
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Again, it does not matter that the methods of the prior art prepare heterogenous mixtures, since the claim does not recite an amount or yield of ADC’s wherein all of the cytotoxic agent groups are conjugated to the lysine residues of the same peptide segment of the light chain that would distinguish from the references.
In this way, those of ordinary skill could have applied the recited HIC technique to the recited ADC’s in the manner required and in a predictable fashion for the purposes of obtaining a more purified and homogenous ADC product. As outlined above, the Baek teaches that antibody-drug conjugates are separated by HIC successfully with excellent efficiency and high recovery. The secondary references are added for the proposition that the recited ADC’s are applicable to this process. Specifically, the secondary references teach that the recited ADC’s were within the purview of those of ordinary skilled in the art. Baek teaches that separation of various ADC samples were obtained using the recited HIC columns and mobile phases. In this manner, those of ordinary skill would have recognized that applying the known technique to the recited ADC’s would have yielded predictable results. Accordingly, using the recited HIC methods to separate the recited ADC’s would have been prima facie obvious.
Applicant indicates that the claims have been amended to address that they do not require a percentage of the product mixture which are ADC’s wherein all the cytotoxic agent groups are conjugated to the lysine residues of the same peptide segment of the light chain that would distinguish from the references. However, the claims have not been amended in this manner.
Moreover, notwithstanding Applicant’s remarks, Bhat discloses site-specific labeling of native mAbs at lysine residues in the kappa light chain constant domain of human mAbs by employing pentafluorophenyl esters as the active ester species for the conjugation.
The claims do not clarify the methods provide an increased percentage of an ADC wherein all the cytotoxic agent groups are conjugated to the lysine residues of the same peptide segment of the light chain relative to the mixture of ADC’s. Therefore, the rejection is maintained.
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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