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 .
DETAILED ACTION
1. The Amendment filed January 09, 2026 in response to the Office Action of October 09, 2025 is acknowledged and has been entered. Claims 3, 4, and 6 have been cancelled. Claims 1and 7 have been amended. Claims 9-14 were previously withdrawn. been added.
2. Claims 1, 2, 5, 7, 8 and 15-19 are currently being examined.
New Grounds of Rejection
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.
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.
3. Claim(s) 1, 5, 8 and 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2020/101498 (WO 2020/101498 A1 Scheeren et al. May 22, 2020, filed Nov. 18, 2019), “Scheeren”.
Scheeren teaches conjugates that comprise a ubiquitin dimer or multimer, comprising a distal moiety conjugated to a proximal moiety. The distal moiety comprises a polypeptide comprising a distal ubiquitin at its C-terminus, said ubiquitin comprising at least one of the following mutations: K6X, K11X, K27X, K29X, K33X, K48X, K48X, or K63X, where X is selected from R, A or C. The proximal moiety comprises a polypeptide comprising either a proximal ubiquitin at its C-terminus or a proximal ubiquitin at its N-terminus; said ubiquitin comprising a blocked C-terminus. See abstract and ¶¶ 0006-0010.
Scheeren teaches the conjugates comprise monoclonal antibodies (Mab) or Fabs. See ¶¶ 0001, 0019, 0020, 0038-0043, 0113 and 0114 and Figures 1-5.
Scheeren teaches the conjugates can comprise Fc domains which is a carrier as claimed. See ¶¶ 0037-0038 and 0198 and Figs. 1 and 20. Although Scheeren does not teach that the Fc domains prolong the in vivo stability and duration of the conjugate, it has the same structure as claimed and thus would have the same function.
Scheeren teaches conjugating ubiquitin Fab (UbiFab) to a UbiFab dimer to form trimers. See Fig. 5A-5D and ¶¶ 0094-0098.
Scheeren teaches in order to ensure that the UbiFab dimer cannot act as a ‘proximal ubiquitin’ with the selected E2/E3 enzyme system, both the distal ubiquitin and the proximal ubiquitin comprise a mutation K6R to form the correct structure. The distal ubiquitin also comprises a second mutation, K48R, which was provided to ensure it could only be a distal ubiquitin in the reaction that formed the dimer. See ¶¶ 0095, 0097 and 0098 and Fig. 5A-5D.
Although Scheeren does not teach a working example where the conjugates comprise a distal ubiquitin and a proximal ubiquitin comprising a mutation K6R and an Fc domain, it would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of Scheeren and make such ubiquitin conjugates because Scheeren teaches the conjugates can comprise an Fc domain and Scheeren teaches making conjugates with both the distal ubiquitin and the proximal ubiquitin that comprise a mutation K6R. One would have been motivated to make conjugates with both the distal ubiquitin and the proximal ubiquitin that comprise a mutation K6R to ensure the proper structure of the conjugate as taught by Scheeren.
4. Claim(s) 1, 2, 5, 8 and 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2020/101498 (WO 2020/101498 Scheeren et al. May 22, 2020, filed Nov. 18, 2019)), “Scheeren” as applied to claims 1, 5, 8 and 15-16 above, and further in view of US 2013/0011334 A1 (Steuernagel et al. Jan. 10, 2013, of record).
Scheeren teaches as set forth above, but does not teach using a linker of claim 2.
Steuernagel teaches hetero-multimeric modified ubiquitin capable of binding the extracellular domain B of fibronectin (ED-B) with high affinity for the treatment of cancer. See abstract, ¶¶ 0019-0021, 0111-0112, Example 7 and claims 1-8.
Steuernagel teaches that the hetero-multimeric modified ubiquitin can be fused to other proteins like cytokines or an Fc domain. See ¶¶ 0076-0089.
Steuernagel teaches using linkers comprising GGGGS. See ¶¶ 0038, 0104-0105 and 0213 and claim 4.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of Scheeren and Steuernagel use the linkers of Steuernagel for joining the protein domains of the multimeric biomolecule together because Steuernagel teaches using linkers to link protein domains and to provide the domains with flexibility to interact with their binding targets.
5. Claim(s) 1, 5, 7, 8 and 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2020/101498 (WO 2020/101498 Scheeren et al. May 22, 2020, filed Nov. 18, 2019)), “Scheeren” as applied to claims 1, 5, 8 and 15-17 above, and further in view of WO 2020/007899 A1 (Lang et al. Jan. 09, 2020, filed July 03, 1019, of record), “Lang” .
Scheeren teaches as set forth above, but does not teach wherein leucine at the 73rd position from the N-terminus of one of the ubiquitins is substituted with proline.
Lang teaches the mutation leucine 73 to proline substitution (L73P) in the ubiquitin C-terminus confers resistance to various deubiquitinases (DUB) families.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of Scheeren and Lang and substitute the leucine at the 73rd position from the N-terminus of one of the in the ubiquitin conjugates of Scheeren with proline in the ubiquitin conjugates because Lang teaches the L73P substitution in the ubiquitin C-terminus confers resistance to various DUB families. One would have been motivated to make the L73P substitution in the ubiquitin conjugates of Scheeren to reduce deubiquitination of the conjugates and increase their stability of the conjugates.
6. Claim(s) 1, 5, 8 and 15-17 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2020/101498 (WO 2020/101498 Scheeren et al. May 22, 2020, filed Nov. 18, 2019)), “Scheeren” as applied to claims 1, 5, 8 and 15-16 above, and further in view of US 2008/0194481 A1 (Rosen et al. Aug. 14, 2008), “Rosen”.
Scheeren teaches as set forth above.
Scheeren additionally teaches treating disease with the ubiquitin conjugates. See ¶¶ 0049-0051 and 0166-0168.
Rosen teaches albumin fusion proteins comprising a therapeutic protein (e.g., a polypeptide, antibody, or peptide, or fragment or variant thereof) fused to albumin. See Abstract and ¶¶ 0009-0011.
Rosen teaches the albumin fusion proteins prolong the shelf life of the therapeutic protein, to increase the plasma stability of the therapeutic protein compared to its unfused state, and/or stabilize the therapeutic protein and/or its activity in solution (or in a pharmaceutical composition) in vitro and/or in vivo. ¶¶ 0009, 0069, 0147, 0168, 0169, and 1510-1523.
Rosen teaches that following a single intravenous or subcutaneous injection, BNP-HSA had terminal elimination half-lives of 11.2 (intravenous delivery) or 19.3 h (subcutaneous delivery), while the half-life of recombinant BNP in mice was 3.1 min. See ¶ 1522.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of Scheeren and Rosen and fuse albumin to the ubiquitin conjugates of Scheeren because Rosen teaches albumin fusion proteins can stabilize the therapeutic protein and/or its activity in solution in vitro and/or in vivo and increase its half-life in vivo. One would have been motivated to fuse albumin to the ubiquitin conjugates of Scheeren because teaches using the ubiquitin conjugates for therapy and fusing the conjugates to albumin would stabilize the activity and duration of the ubiquitin conjugates in vivo and increase the duration of the therapeutic response.
7. Claim(s) 1, 5, 8, 15, 16, 18 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2020/101498 (WO 2020/101498 Scheeren et al. May 22, 2020, filed Nov. 18, 2019)), “Scheeren” as applied to claims 1, 5, 8 and 15-16 above, and further in view of US 2009/0143276 A1 (Holtet et al. June 4, 2009, of record), “Holtet”.
Scheeren teaches as set forth above.
Scheeren additionally teaches the ubiquitin conjugate can comprise a pharmaceutically active polypeptide. See ¶¶ 0061-0062 and claim 4.
Scheeren teaches as set forth above, but does not teach wherein the biomolecule is a receptor antagonist, in particular an IL-1R antagonist ((IL-1-RA) . .
Holtet teaches the invention is directed to a fusion protein of an IL-1Ra polypeptide sequence fused to a trimerizing or multimerizing domain. Holtet teaches three or more of fusion proteins may trimerize or multimerize to provide compositions providing for greater stability and improved pharmacokinetic properties than IL-1Ra alone, and provide a favorable safety profile. See abstract, ¶¶ 0030-0031 and claims 1-12.
Holtet teaches one of the fusion protein domains can be ubiquitin. See ¶ 0060.
Holtet teaches using linkers to link the fusion proteins together. See ¶¶ 0042, 0052, and 0145 and claim 11.
Holtet teaches linking the fusion protein to stabilizing Fc domain. See ¶¶ 0055.
Holtet teaches the fusion proteins are part of trimeric complexes that are used in pharmaceutical compositions for treating diseases mediated by IL-1. Effective treatment of inflammatory diseases, such as rheumatoid arthritis and diabetes, are described. See abstract and ¶¶ 0077-0111 and claims 18-22.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of Scheeren and Holtet and fuse the ubiquitin conjugates of Scheeren with an IL-1Ra polypeptide sequence fused to a trimerizing domain of Holtet because Scheeren teaches the ubiquitin conjugate can comprise a pharmaceutically active polypeptide and Holtet teaches one of the IL-1Ra polypeptide trimeric fusion proteins can be ubiquitin. One would have been motivated to fuse the ubiquitin conjugates of Scheeren with an IL-1Ra polypeptide sequence fused to a trimerizing domain of Holtet so that the fusion proteins can be used for treating diseases mediated by IL-1 as taught by Holtet.
Conclusion
8. All other objections and rejections recited in the Office Action of October 09, 2025 are withdrawn in view of Applicant’s amendments and arguments.
9. No claims allowed.
10. 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 extension fee 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 date of this final action.
11. Any inquiry concerning this communication or earlier communications from the examiner should be directed to PETER J REDDIG whose telephone number is (571)272-9031. The examiner can normally be reached on M-F 8:30-5:30 Eastern Time
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gregory Emch, can be reached at 571-272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Peter J Reddig/
Primary Examiner, Art Unit 1642