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 .
Priority
The instant application is a 35 U.S.C. 371 national phase application and claims priority to International Application No. PCT/IB2020/055705 (filing date 06/18/2020), which claims the benefit of the prior-filed European Provisional Patent Application No. EP19180939.1, filing date 06/18/2019.
Status of Application/Claims
The claims, filed 12/22/2025, are acknowledged. Claims 19 is canceled. Claims 1-18 and 20-21 are currently pending and are examined on the merits herein.
Information Disclosure Statement
No new information disclosure statements (IDSs) are submitted.
Withdrawn Objections & Rejections
Regarding the requirement to perfect priority: Applicant submitted a corrected Application Data Sheet on 07/29/2025 providing the Access Code (B5D9) for the priority European Patent Application No. 19180939.1. Thus, priority is perfected.
Response to Arguments
Regarding the rejections for claims 1-18 and 20-21 under 35 U.S.C. 103 for obviousness: No claims are amended. All claims are dependent upon claim 1. Applicant traverses all obviousness rejections made in the non-final office action mailed 09/30/2025. Applicant arguments for the rejections of all claims are based on traversal of the obviousness rejection for claim 1 over Lieschke in view of Nagamune (and evidenced by Tugues; see obviousness rejection for claims 1, 9, 12, and 17 on p.3-6 of non-final mailed 09/30/2025).
Applicant Argument 1: Applicant argues that the prior art does not disclose that the KE-linker can be used to produce functional IL-12 fusion proteins, nor suggests the surprising increase in immunological activity (see applicant arguments submitted 12/22/2025, p.6, para.2). Applicant further states that Lieschke does not teach that flexible linkers can be used to produce functional IL-12, but that Lieschke discloses IL-12 fusion proteins that incorporate both a GS-linker and a mutant (truncated) Δp35 subunit. Applicant calls into question whether the functionality of the p40-GS-Δp35 construct exhibiting increased immunological activity is due to the GS-linker or the mutant Δp35 subunit.
Examiner Response 1: Regarding the Lieschke “Δp35 mutant” of the p40-GS-Δp35 construct, Lieschke teaches that this is a construct wherein “…the first 22 amino acids were deleted” and further states that the “analogous human IL-12 fusion protein also retained high in vitro bioactivity” (p.35, col.1, para.2). Firstly, the construct comprising an IL12 p40 subunit and an IL-12 p35 subunit reads on claim 1 as the claim only requires “an IL12 p40 subunit” (line 2) and “an IL12 p35 subunit” (line 4). Further, the first 22 amino acids deleted by Lieschke encode the signal sequence for the human p35 subunit. Thus, the “mutant” p35 subunit used by Lieschke is the same as instant p35 construct of claim 3 SEQ ID NO: 2 (see comparison of SEQ ID NO: 2 and human IL-12 p35 from UniProt—P29459. IL12A_HUMAN, p.7 with signal sequence amino [AltContent: textbox (Instant SEQ ID NO: 2 (human IL-12 subunit alpha):
RNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEFYPCTSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMMALCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDELMQALNFNSETVPQKSSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNAS
UniProt—P29459 IL12A_HUMAN:[img-media_image1.png])]acids 1-22 highlighted below).
Regarding applicant argument that Nagamune does not teach that the KE-linker can replace the GS-linker in the IL-12 fusion protein of Lieschke, Nagamune expressly categorizes poly-glycine and GS linkers with the KE linker as similar-in-kind “flexible peptide linkers” (p.38-39, section 3.5.2.3. Flexible peptide linkers). Further, Chen et al., Fusion protein linkers: Property, design, and functionality. Adv. Drug Delivery Rev (2013), 65, p.1357-1369 (herein referred to as Chen), in addition to Nagamune, also teaches flexible linkers, categorizing the KE-linker as a flexible linker within the same “flexible linker” category as poly-glycine linkers and GS-linkers (p.1360, col.2, para.2; Table 2), and teaches that the flexible linkers are commonly used to join domains together to produce functional fusion proteins. Given that wild type IL-12 is normally expressed as a heterodimer produced by two separate genes and requires the subunits to assemble for functionality, one of ordinary skill in the art would expect that linking the p40 and p35 subunits in a single construct with a flexible linker, such as the GS linker of Lieschke or the KE linker of Nagamune, would facilitate co-expression and assembly of the subunits for enhanced functionality.
Applicant Argument 2: Applicant also argues that the increased immunological activity exhibited by Lieschke’s construct may be the result of increased expression and that one of ordinary skill in the art cannot reasonably conclude from Lieschke that the flexible linker enables the functional IL-12 fusion protein and produces improved immunological activity (applicant arguments, 12/22/2025, p.3). Further, applicant states that Nagamune does not disclose any example of the substitution of the GS-linker and KE-linker fusion protein and does not suggest that flexible linkers are generally interchangeable (applicant arguments, 12/22/2025, p.3).
Examiner Response 2: The examiner agrees that the increased immunological activity is likely due to increased expression of the p40 and p35 subunits and that the co-expression of the two subunits better facilitates heterodimerization, and thus increased immunological function. However, the prior art teaches that flexible linkers are routinely used for producing single chain constructs and Chen also teaches that linkers “…offer many other advantages for the production of fusion proteins, such as improving biological activity, increasing expression yield, and achieving desirable pharmacokinetic profiles…” (abstract). The prior art also specifically further teaches that the GS and KE linkers are even more “similar-in-kind” as they are categorized together as “flexible linkers” used for producing single chain constructs (as described above). Thus, one of ordinary skill in the art would expect higher expression and activity for constructs where the required subunits are co-expressed with a poly-glycine linker, GS-linker, or the KE-linker. The choice of which flexible linker to use is a matter of simple substitution and routine optimization. Absent any evidence that the KE linker, specifically, provides for an unexpected result of enhanced immunological activity compared to another flexible linker that is similar-in-kind, applicant has failed to illustrate that the specific KE linker is responsible for any unexpected functional result of expression or immunological activity. As applicant compares the use of KE linker to other linkers that are not similar in kind (i.e., applicant’s “IR,” “TC,” and “FA” linkers produce separate subunits rather than tethered subunits), there is no evidence in the disclosure for a result that would be unexpected compared to what is provided by the combination of teachings in the prior art. Further, similar to Lieschke, applicant’s p40-flexible linker-p35 construct produces increased expression (Fig.3). Thus, by applicant’s reasoning (on p.3, para.3 of applicant arguments), the enhanced immunological activity of the single chain construct p40-KE linker-p35 is likely due to enhanced expression facilitated by the flexible linker rather than some other unknown special property of the KE linker specifically.
In summary, the obviousness rejection hinges on whether or not applicant has provided evidence of unexpected results that would overcome what is known about flexible linkers taught by the prior art. Applicant compared a construct comprising the flexible KE-linker to constructs containing linkers that do not comprise other flexible linkers and do not produce single chain IL-12 peptide constructs. Thus, the examiner maintains the rejection on the basis that one of ordinary skill in the art would expect that the KE-linker (as compared to the IR/TC/FA linkers) would be expected to produce the results in applicant disclosure Fig.3 (enhanced IL-12 levels) and Fig.7 (enhanced immune activity). Thus, applicant arguments are not persuasive and the following 35 U.S.C. 103 rejections in the non-final office action mailed 09/30/2025 for obviousness are maintained:
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.
/JAMI MICHELLE GURLEY/Examiner, Art Unit 1647
/ANNE M. GUSSOW/Supervisory Patent Examiner, Art Unit 1683