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 .
Claim Rejections - 35 USC § 103
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 (i.e., changing from AIA to pre-AIA ) 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.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 21-44 are rejected under 35 U.S.C. §103 as being unpatentable over Kozlowski et al. (US 7,659,361 B2) in view of Tumey et al., “Mild Method for Succinimide Hydrolysis on ADCs: Impact on ADC Potency, Stability, Exposure, and Efficacy,” Bioconjugate Chemistry, 2014, 25, 1871–1880.
Claim 21
Kozlowski teaches maleimide-functional polymer conjugates and reaction of maleimide groups with nucleophiles, including thiols, to form succinimide-containing conjugates (Kozlowski, col. 3, lines. 15-45; col. 10, lines. 5–40). Kozlowski further teaches intentional hydrolysis/ring opening of the succinimide ring to form the corresponding ring-opened succinamic-acid conjugate (col. 4, lines. 10-45; col. 5, lines. 1-25).
Kozlowski additionally teaches chromatographic purification of the product mixture following hydrolysis/ring opening, including gel-permeation and ion-exchange chromatography, and expressly teaches further purification of compositions containing polymer succinamic-acid conjugates to obtain or isolate different PEGylated succinamic-acid species (Kozlowski, col. 14, lines. 20-65). Kozlowski also teaches reverse-phase chromatography, including RP-HPLC using a C18 column, for separation of isomeric conjugates (col. 16, line 52 through col. 17, line. 23).
Kozlowski does not expressly disclose the particular mixture comprising the four ring-opened thiosuccinimide compounds of Formulae (I)–(IV) recited in claim 21.
Tumey teaches maleimide-thiol conjugation resulting in a succinimide-thioether linkage and intentional hydrolysis of the succinimide-thioether ring to form a ring-opened linker (Tumey, p. 1871, Abstract; p. 1872, Fig. 1). Tumey further teaches preparation and characterization of hydrolyzed succinimide-linked antibody-drug conjugates and explains that hydrolysis of the succinimide-thioether linkage provides increased conjugate stability (Tumey, pp. 1872–1873, section “Preparation and Characterization of Hydrolyzed Succinimide Linked ADCs”; pp. 1874-1875).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the maleimide-thiol conjugate process of Kozlowski by employing the succinimide-thioether hydrolysis taught by Tumey to intentionally convert the corresponding thiosuccinimide linkage to stable ring-opened hydrolysis products, because Tumey teaches that hydrolysis of the succinimide-thioether ring stabilizes the maleimide-thiol conjugate by converting the ring to its ring-opened form (Tumey, p. 1871, Abstract; p. 1872, Fig. 1; pp. 1872-1873).
Upon producing the ring-opened products, one having ordinary skill in the art would have subjected the resulting product mixture to the chromatographic purification taught by Kozlowski because Kozlowski expressly teaches chromatographic purification following succinimide-ring hydrolysis and further purification to obtain or isolate different PEGylated succinamic-acid species (Kozlowski, col. 14, lines. 20-65), as well as chromatographic separation of isomeric conjugates (col. 16, line 52 through col. 17, line 23).
Claim 22
Kozlowski teaches collecting chromatographic fractions and analyzing the collected fractions following chromatographic separation (col. 16, line 52 through col. 17, line 23). Accordingly, recovery of an eluate containing one or more of the separated target compounds would have been an ordinary consequence of performing the chromatographic separation taught by Kozlowski.
Claims 23–24
Kozlowski teaches further purification of conjugate-containing compositions, including chromatographic purification to obtain or isolate different conjugate species (col. 14, lines 20-65), and teaches chromatographic separation and collection of fractions (col. 16, l. 52 through col. 17, line 23).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to subject a recovered fraction containing more than one desired species to an additional chromatographic separation in order to further resolve and purify the individual species, consistent with Kozlowski's express teaching of further chromatographic purification.
Claims 25–33
Kozlowski expressly teaches reverse-phase chromatography using an RP-HPLC C18 column for separating conjugate isomers having the same molecular weight (col. 17, lines 10-23). Thus, Kozlowski teaches the use of reverse-phase chromatography and an alkyl-bonded silica stationary phase for resolving closely related conjugate species.
To the extent that claims 25-33 further specify particular aqueous/organic mobile phases, proportions, or acidic modifiers not expressly disclosed by Kozlowski, selection and adjustment of such conventional RP-HPLC operating parameters would have been within the ordinary skill in the art for implementing Kozlowski's expressly disclosed RP-HPLC C18 separation and obtaining chromatographic resolution of the conjugate species.
Claims 34–39
Kozlowski teaches polymer conjugates comprising PEG polymers, functionalized polymer linkers, biologically active agents, and succinamic-acid conjugates resulting from ring opening of succinimide-containing conjugates (Kozlowski, col. 2, lines. 40–65; col. 7, lines 1-35; col. 9, lines 5-30). Tumey further teaches use of maleimide-thiol succinimide chemistry and subsequent ring-opening hydrolysis in antibody-drug conjugates (Tumey, pp. 1871-1873, Fig. 1 and “Preparation and Characterization of Hydrolyzed Succinimide Linked ADCs”).
Accordingly, the additionally recited polymer, linker, and conjugated-moiety limitations would have been obvious in the combined conjugate system for the reasons set forth with respect to claim 21.
Claim 40
Kozlowski expressly teaches treating a polymer-succinimide conjugate under conditions effective to open the succinimide ring and form the corresponding polymer-succinamic-acid conjugate (col. 4, lines 10-45; col. 5, lines 1-25). Tumey likewise expressly teaches intentional hydrolysis of the succinimide-thioether ring formed by maleimide-thiol conjugation to produce a ring-opened linker (Tumey, p. 1871, Abstract; p. 1872, Fig. 1; p. 1873, “Preparation and Characterization of Hydrolyzed Succinimide Linked ADCs”). Thus, formation of Mixture 1 by ring opening of a thiosuccinimide group would have been obvious for the reasons discussed with respect to claim 21.
Claims 41–43
Tumey teaches hydrolysis of maleimide-thiol-derived succinimide-thioether linkages to ring-opened hydrolysis products (p. 1872, Fig. 1; pp. 1872–1875), while Kozlowski teaches chromatographic purification following ring opening and further purification to obtain or isolate different PEGylated succinamic-acid species (col. 14, ll. 20–65), as well as RP-HPLC separation of isomeric conjugates (col. 16, l. 52–col. 17, l. 23).
Accordingly, separation and recovery of individual ring-opened species from the resulting mixture would have been obvious for the reasons discussed with respect to claim 21.
Claim 44
Kozlowski teaches hydrolysis/ring opening of a succinimide-containing conjugate to form a ring-opened succinamic-acid conjugate (col. 4, lines. 10-45; col. 5, lines 1-25), and Tumey expressly teaches hydrolysis of the maleimide-thiol-derived succinimide-thioether ring to produce a ring-opened linker (Tumey, p. 1871, Abstract; p. 1872, Fig. 1). Therefore, the limitation that Mixture 1 results from ring opening of a thiosuccinimide group would have been obvious for the reasons discussed with respect to claim 21.
Response to Arguments
Applicant's arguments have been fully considered but are not persuasive.
Applicant argues that Kozlowski does not disclose the particular four ring-opened thiosuccinimide compounds of Formulae (I)–(IV). The rejection does not rely upon Kozlowski as expressly disclosing the claimed four-component mixture. Rather, Kozlowski is relied upon for maleimide/nucleophile conjugation chemistry, intentional succinimide-ring hydrolysis, formation of ring-opened succinamic-acid conjugates, and chromatographic purification of the resulting products. Tumey is relied upon for its teaching that the corresponding maleimide-thiol-derived succinimide-thioether linkage may intentionally be hydrolyzed to form stable ring-opened products (Tumey, p. 1871, Abstract; p. 1872, Fig. 1; pp. 1872–1873).
Applicant further argues that Kozlowski's chromatographic disclosure is limited to separation of PEG conjugates according to molecular weight and PEG-biomolecule positional isomers. This argument does not address Kozlowski's additional disclosure concerning purification after succinimide-ring hydrolysis. Kozlowski teaches chromatographic purification of the mixture resulting from hydrolysis/ring opening and expressly states that compositions containing polymer succinamic-acid conjugates may be further purified to obtain or isolate different PEGylated succinamic-acid species (Kozlowski, col. 14, lines 20–65). Kozlowski additionally teaches RP-HPLC using a C18 column to separate isomeric conjugates (col. 16, line 52 through col. 17, line 23).
The rejection therefore does not rest merely on a general assertion that chromatography could have been used. It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the maleimide-thiol conjugate process of Kozlowski by employing the succinimide-thioether hydrolysis taught by Tumey because Tumey teaches that such hydrolysis converts the succinimide-thioether linkage to a more stable ring-opened form. After performing that hydrolysis, Kozlowski itself provides reason to chromatographically purify the resulting mixture because Kozlowski expressly teaches chromatographic purification following ring opening and further purification to obtain or isolate different ring-opened succinamic-acid conjugate species.
Applicant also argues that neither reference establishes that the claimed compounds could be chromatographically separated with a reasonable expectation of success. However, Kozlowski expressly teaches chromatographic purification of ring-opened succinamic-acid conjugate-containing compositions and isolation of different PEGylated succinamic-acid species, as well as RP-HPLC separation of closely related isomeric conjugates. These teachings would have provided one having ordinary skill in the art with a reasonable expectation that chromatographic separation could be employed to resolve the resulting ring-opened conjugate species.
Finally, Applicant relies upon Examples 1-3 as evidence of unexpected results because the examples demonstrate chromatographic separation of the four ring-opened compounds. The examples have been considered. However, demonstrating that the claimed compounds can be separated does not, by itself, establish that the result was unexpected. Applicant has not identified comparative evidence demonstrating that the claimed chromatographic separation produces a result unexpectedly different in kind or degree from the chromatographic purification and separation of ring-opened/isomeric conjugate species taught by the prior art. Accordingly, the evidence presented is insufficient to outweigh the evidence of obviousness.
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TAM M NGUYEN whose telephone number is (571)272-1452. The examiner can normally be reached Mon - Frid.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Prem C Singh can be reached at 571-273-6381. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/TAM M NGUYEN/ Primary Examiner, Art Unit 1771
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