DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
The rejection under section 112(a) is withdrawn in view of the amendments and remarks in connection with this ground of rejection.
The rejection under section 103 is maintained, below:
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
Claims 14, 23-25, 29-36 remain rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Doronina et al. ("Doronina", US 7,994,135) or Doronina et al., Nature Biotechnology (2003), 21(7), 778-784 (Doronina II) in view of Balan et al. ("Balan", Bioconjugate Chem., 2007, 18, 61-76, or Khalili et al., Bioconjugate Chem. 2012, 23, 2262−2277 (Khalili).
Doronina teaches preparing antibody drug conjugates by reducing one or more disulfide bonds in a binding protein and reacting with a conjugating agent (column 192, lines 10-37 and Figure 36). Doronina teaches incubating Trastuzumab with dithiothreitol (reducing agent) and reacting with drug linker reagent (conjugating agent). Doronina teaches antibody drug conjugate of Trastuzumab-MC-vc-PAB-MMAE (columns 49-50) (Antibody-maleimidocaproyl-val-cit-para-aminobenzyloxycarbonylmonomethylauristatin F). The linker MC-vc-PAB has the structure:
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Doronina teaches amino acid spacer units that can be used as linkers which include alanine and valine in the table list (column 65, lines 15-50).
Doronina II demonstrates that the MC-Val-Cit-PAB-MMAE conjugate was well known in the art:
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However, the Doronina references do not explicitly teach the polyethylene glycol spacer or the three-carbon bridge attachment of the antibody. However, Balan teaches site specific pegylation of protein disulfide bonds using a three-carbon bridge. Balan teaches that conjugation is conducted to a protein by using a bis-alkylation unsaturated monosulfone functionalized PEG reagents (Abstract, Scheme 1, page 65, Figure 1):
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Balan teaches that the antibodies can be conjugated across a disulfide bond without destroying their tertiary structure of abolishing biological activity (Abstract).
Importantly, the addition of sulfone reagent conjugating system would provide the polyethylene glycol spacer or the three-carbon bridge attachment of the antibody, namely, the structure:
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Balan teaches that the means for attaching the PEGylated 3- carbon bridge to proteins was known:
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, and moreover, provides reason to use this linkage:
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Based on the above, Doronina demonstrates what was accepted in the art: Val-Cit-PAB-MMAE is a protease liable linker drug conjugate that is widely known and used. In this context those of ordinary skill would have had a reasonable expectation that combining MC-Val-Cit-PAB-MMAE with this linkage, which Balan teaches exploits antibody disulfides without disrupting tertiary structure, could successfully provide a therapeutic ADC. Indeed, the require reasonable expectation of success is provided here see MPEP 2144.08 (“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).”).
Khalili also teaches the conjugation of an antibody to PEG utilizing a bis-sulfone reagent that attaches to two cysteines of the antibody. Khalili teaches that bis-sulfone conjugates are superior because they do not suffer the problems of maleimide conjugates that are labile to hydrolysis and exchange reactions (p. 2263). Khalili teaches the mechanism of attachment in scheme 1 and 2 (p. 2263):
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In this way, those of ordinary skill could have applied the sulfone reagent method of Balan, instead of the MC coupling, in a predictable fashion for the purposes of obtaining the recited disulfide conjugates. Specifically, the Doronina references teach the typical Trastuzumab-MC-vc-PAB-MMAE conjugates via the MC coupling. The secondary references are added for the proposition that pegylated disulfide is applicable to this method of antibody coupling. Specifically, the secondary references teach that this coupling technique 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 conjugate moieties, such as the vc-PAB-MMAE moiety, would have yielded predictable results. Accordingly, using the sulfone reagent method of the secondary references to obtain the recited pegylated disulfide conjugates would have been prima facie obvious. Therefore, the difference between the claimed process and the process taught by the references is that the references may 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).). However, based on the above, the references teach the elements of the claimed process 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).
Applicant argues that Doronina does only teaches monovalent maleimide conjugation. However, the rejection is a combination of Doronina can the secondary references that demonstrate that the claimed manner of conjugation to proteins was known.
In this regard, Applicant argues that there is no reason to combine Doronina with Balan. However, the Balan is relevant since it specifically teaches that the claimed method of conjugation to proteins was known. For example, Balan teaches that the means for attaching the PEGylated 3- carbon bridge to proteins was known:
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, and moreover, provides reason to use this linkage:
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Balan provides explicit motivation: “Our studies therefore suggest that peptides, proteins, enzymes, and antibody fragments can be site-specifically PEGylated across a native disulfide bond using three-carbon bridges without destroying their tertiary structure or abolishing their biological activity.” Another observed characteristics, such as the alleged unexpected results set forth in Applicant’s remarks, would have been a necessary aspect of the conjugation.
Similarly, Khalili teaches the conjugation of an antibody to PEG utilizing a bis-sulfone reagent that attaches to two cysteines of the antibody.
Doronina merely demonstrates what was accepted in the art: Val-Cit-PAB-MMAE is a protease liable linker drug conjugate that is widely known and used. In this context those of ordinary skill would have had a reasonable expectation that combining Val-Cit-PAB-MMAE with this linkage, which Balan teaches exploits antibody disulfides without disrupting tertiary structure, could successfully provide a therapeutic ADC. Indeed, the require reasonable expectation of success is provided here see MPEP 2144.08 (“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).”).
As outlined in the rejection, those of ordinary skill would have recognized that applying the known technique of conjugation to other conjugate moieties, such as the vc-PAB-MMAE moiety, would have yielded predictable results. Applicant remarks do not address that the conjugation set forth by the secondary references could have resulted in a reasonable expectation of preparing the recited conjugates. Moreover, Balan clearly sets forth motivation to use this method:
During this process, irreversible denaturation of the protein did not occur. Mechanistically, the conjugation is conducted by a sequential, interactive bis-alkylation using α,β-unsaturated β‘-monosulfone functionalized PEG reagents. The combination of (a) maintaining the protein's tertiary structure after disulfide reduction, (b) the mechanism for bis-thiol selectivity of the PEG reagent, and (c) the steric shielding of PEG ensure that only one PEG molecule is conjugated at each disulfide bond. PEG was site-specifically conjugated via a three-carbon bridge to 2 equiv of the tripeptide glutathione, the cyclic peptide hormone somatostatin, the tetrameric protein l-asparaginase, and to the disulfides in interferon α-2b (IFN)… Our studies therefore suggest that peptides, proteins, enzymes, and antibody fragments can be site-specifically PEGylated across a native disulfide bond using three-carbon bridges without destroying their tertiary structure or abolishing their biological activity. The stoichiometric efficiency of this approach also enables recycling of any unreacted protein. It therefore offers the potential to make PEGylated biopharmaceuticals as cost-effective medicines for global use.
As stated above, the secondary references teach that the recited coupling technique was recognized as part of the ordinary capabilities of one skilled in the art. Moreover, the secondary references provide specific motivation of using this technique, as shown above. In this manner, those of ordinary skill would have recognized that applying the known technique to other conjugate moieties, such as the vc-PAB-MMAE moiety, would have yielded predictable results. Therefore, the rejection is maintained.
THIS ACTION IS MADE FINAL. 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 acting supervisor, Janet Epps-Smith, can be reached at telephone number (571)272-0757. 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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