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 .
Application Status
Claims 1, 9, 26, 34-38, 40-42, 45, and 58-59 are pending and examined on the merits herein.
Grounds of Rejection Withdrawn
All previous objections and rejections of claims 2-3, 22-25, and 27-29 are moot in view of claim cancellations.
Previous objection of claim 26 is withdrawn in view of the updated sequence listing and claim amendment.
Previous rejection of claims 1, 9, 34-36, 38, and 40 under 35 U.S.C. 102 regarding Morrison US 2016/0115252 A1 are withdrawn in view of claim amendments.
Previous rejection of claims 1, 26, 34, 38, 41-42, and 45 under 35 U.S.C. 102 regarding Morrison’948 US 2018/0162948 A1 are withdrawn in view of claim amendments.
Previous rejection of claims 26, 37, 41-42, and 45 under 35 U.S.C. 103 regarding Morrison US 2016/0115252 A1 are withdrawn in view of claim amendments.
Claim Objections
Claim 1 is objected to because of the following informalities:
In line 9, claim 1, reads: “and said second proteolysis linker” should read and second proteolysis resistant linker
Appropriate correction is required.
Claim Rejections - 35 USC § 103
New Rejection Necessitated By Amendment
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.
Claims 1, 9, 26, 34-36, 38, 40-42, 45, and 58-59 are rejected under 35 U.S.C. 103 as being unpatentable over UCLA (US 2016/0115239 A1; cited in previous office action) and Timmerman (WO 2014/194100 A1; PTO-892).
Regarding claim 1, UCLA teaches a chimeric construct comprising an interferon attached to an antibody that binds CD138 (claim 1), wherein said interferon is a type II interferon (IFNγ) (claim 6), wherein said antibody is directly joined to said interferon with a peptide linker (claim 34), wherein said peptide linker is proteolysis resistant (claim 35). Morrison further teaches that certain linkers were not suitable for the production of an antibody IFN fusion molecule due to the interferon being removed from the fusion protein by proteolysis (para 0192).
Regarding claim 26 and 58, UCLA teaches CD138 VH and VL antibody sequences comprising SEQ ID NOs: 52 and 53 respectively (paragraph 0237), with 100% sequence identity to the instant claimed SEQ ID NOs: 15 and 16 respectively.
Regarding claim 34-35, UCLA teaches of human anti-CD138 IgG1 (para 0258).
Regarding claim 36, UCLA teaches that for use in a human it is desirable for the antibody to human, humanized, or chimeric human antibody (para 0157).
Regarding claim 38, UCLA teaches a pharmaceutical formulation comprising a construct according to any of claims 1-43 in a pharmaceutically acceptable excipient (claim 44).
Regarding claim 40, UCLA teaches wherein said formulation is a formulated for administration via a route selected from the group consisting of oral administration, intravenous administration, intramuscular administration, direct tumor administration, inhalation, rectal administration, vaginal administration, transdermal administration, and subcutaneous depot administration (claim 47).
Regarding claim 41, UCLA teaches a method of inhibiting growth and/or proliferation of a cell that expresses or overexpresses CD138, said method comprising contacting said cell with a chimeric construct according to any of claims 1-43, or a formulation according to any one of claims 44-47 in an amount sufficient to inhibit growth or proliferation of said cell (claim 48).
Regarding claim 42, UCLA teaches wherein said cell is a cancer cell (claim 49), wherein said cancer cell is a metastatic cell (claim 50), wherein said cancer cell is in a solid tumor (claim 51).
Regarding claim 45, UCLA teaches wherein said cancer cell is cell produced by a cancer selected from the group consisting of multiple myeloma, ovarian carcinoma, cervical cancer, endometrial cancer, kidney carcinoma, gall bladder carcinoma, transitional cell bladder carcinoma, gastric cancer, prostate adenocarcinoma, breast cancer, prostate cancer, lung cancer, colon carcinoma, Hodgkin's and non-Hodgkin's lymphoma, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), acute myeloblastic leukemia (AML), a solid tissue sarcoma, colon carcinoma, non-small cell lung carcinoma, squamous cell lung carcinoma, colorectal carcinoma, hepato-carcinoma, pancreatic cancer, and head and neck carcinoma (claim 52).
Regarding claim 59, UCLA teaches anti-proliferative effects of an anti-CD20-IFN alpha construct (figure 7 and 14).
UCLA does not teach wherein the first and second proteolysis resistant linker comprise an IgG1 hinge delta cys linker, the specific sequence of that linker, or that the IFN gamma is a full length or murine IFN gamma.
Regarding claims 1 and 58, Timmerman teaches a chimeric construct comprising an interferon attached to an antibody (claim 1), wherein said interferon is a type II interferon (IFNy) (claim 12), wherein said antibody is joined to said interferon with a peptide linker (claim 94), wherein said peptide linker joins said interferon to the carboxyl terminus of the CH3 domain of said antibody (claim 95), wherein said peptide linker joins the amino terminus of said interferon to the carboxyl terminus of the CH3 domain of said antibody (claim 96), wherein said peptide linker joins the carboxyl terminus of said interferon to the carboxyl terminus of the CH3 domain of said antibody (claim 97), wherein said peptide linker is proteolysis resistant (claim 98), wherein the amino acid sequence of said peptide linker is SEQ ID NO: 75, with 100% sequence identity to the instant claimed SEQ ID NO: 6. Timmerman further teaches that the IgG1 hinge delta cys linker had superior activity in the chimeric molecule relative to other linkers, but similar to the IgG3 hinge (Figures 8-14).
Regarding claim 9, Timmerman teaches wherein said interferon gamma is a full- length interferon gamma (claim 13) and wherein said interferon is a murine interferon (claim 19).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to use as IgG1 delta cys linker as the specific proteolysis resistant linker as taught by Timmerman in the CD138 antibody- interferon gamma fusion molecule as to target a tumor antigen as taught by UCLA. The ordinary artisan would have been motivated to do so because Timmerman and UCLA both teach an interferon antibody fusion construct with a proteolysis resistant linker and Timmerman further demonstrated that the IgG1 delta cys linker had superior activity relative to other proteolysis resistant linkers. Therefore it would be obvious to the ordinary artisan to use the proteolysis linker with demonstrated superior activity in the anti-CD138-IFN gamma construct of UCLA. It would further be obvious to the ordinary artisan to combine treatment of the anti-CD138-IFN gamma fusion protein with the anti-CD20-IFN alpha fusion construct that has demonstrated anti-proliferative effects as taught by UCLA.
Claim 37 is rejected under 35 U.S.C. 103 as being unpatentable over UCLA (US 2016/0115242 A1, IDS entered June 2, 2022) and Timmerman (WO 2014/194100 A1; PTO-892) as applied to claims 1, 9, 26, 34-36, 38, 40-42, 45, and 58 above, and further in view of Arbabi-Ghahroudi (Front Immunol, 2017, 8:1589; cited in previous office action).
The teachings of UCLA and Timmerman regarding claim 1 are detailed above.
UCLA and Timmerman does not teach wherein the antibody is a camelid antibody.
However, Arbabi-Ghahroudi teaches that camelid single-domain antibodies known as sdAbs, VHHs, or nanobodies (abstract) with key characteristics that include their high affinity and specificity (equivalent to conventional antibodies), high thermo-stability, good solubility and strictly monomeric behavior, small size, relatively low production cost, ease of genetic engineering, format flexibility or modularity, low immunogenicity, and a higher penetration rate into tissues while the short half-life and immunogenicity can be mitigated by protein fusion and humanization respectively (page 4, column 1, paragraph 3). Arbabi-Ghahroudi further teaches that overwhelming evidence in the literature suggests that camelid VHHs, as the so-called “third generation” of antibodies, have many added features that supersede those of conventional mAbs and antibody fragments (Fab and scFv) (page 5, column 2, paragraph 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to use a camelid antibody to target a tumor antigen as taught by Arbabi-Ghahroudi in the interferon gamma-CD138 antibody fusion molecule of UCLA and Timmerman. The ordinary artisan would have been motivated to do so because as Arbabi-Ghahroudi teaches that camelid antibodies have high affinity and specificity (equivalent to conventional antibodies), high thermo-stability, good solubility and strictly monomeric behavior, small size, relatively low production cost, ease of genetic engineering, format flexibility or modularity, low immunogenicity, and a higher penetration rate into tissues which offer an advantage over conventional antibodies. The advantages offered by the structure of the camelid antibody in the fusion molecule with interferon gamma would result in better tumor penetrance and therefore increased efficacy, which translates into a clinical benefit for cancer patients.
Response to Arguments
Applicant's arguments filed August 6, 2025 have been fully considered but they are not persuasive.
Applicant submits: The UCLA application describes CD138 antibody fused to IFN, particularly IFNa2, IFNa2YNS and IFNγ. The UCLA application fails to describe a chimeric polypeptide comprising an anti-CD138 antibody linked to IFN-y using a IgG1 hinge L1cys linker.
According to the MPEP: "The mere fact that references can be combined or modified does not render the resultant combination obvious unless the results would have been predictable to one of ordinary skill in the art. KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 417, 82 USPQ2d 1385, 1396 (2007)." MPEP 2143.01 111. In the instant case, the Examples of the application provide evidence that the linker in the context of the antibody is important for the stability and efficacy of the construct, and that linkers that connect IFN-y to one antibody may not be sufficient, in terms of stability and activity, to link a different antibody to IFN-y.
Example I of the instant application further shows that just being functionally effective against a cell line was not sufficient for selection of suitable linkers. While this helped reduce the spectrum of available linkers to 2-3 linkers, the linkers varied in terms of proteolytic stability.
These results clearly show that the specific combination of the CD138 antibody with IFNy linked with IgG I hinge L1cys, as recited in the amended claim, provide an unexpectedly superior combination for therapeutic and production purposes. Therefore, the construct of the current claims provides unexpected properties not found in the cited art and should be considered as evidence of non-obviousness. In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963).
In response: The UCLA application teaches a CD138-IFNgamma fusion construct with a proteolysis resistant linker, but does not teach the specific IgG1 delta cys linker. However the newly cited Timmerman reference teaches the specific IgG1 delta cys linker and demonstrates results showing superior activity in an antibody interferon fusion. Although citing the IgG3 hinge as yielding the best results (similar to the results of Timmerman) that linker is not proteolysis resistant and therefore would not meet the instant claims or the teachings of the UCLA or Timmerman references.
Therefore these results are not surprising but the ordinary artisan had a reasonable expectation of success to construct an anti-CD138- interferon gamma fusion molecule with a proteolysis resistant IgG1 delta cys linker with superior activity as taught by the prior art.
Conclusion
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.
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/AMBER K FAUST/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643