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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 06/09/2025 has been entered.
Response to Amendment
Applicant’s remarks and amendments to the claims filed 09/08/2025 have been acknowledged. Claim 14 has been amended. Claims 15 and 19 have been canceled.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 14 and 16-18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The claims are broadly drawn to a method of treating cancer in a subject comprising administering a fusion protein comprising a human IFNα2 antagonist having a R120E mutation and a VHH or VNAR targeting domain directed to CD19.
The specification teaches that the therapeutic efficacy of oncolytic viruses is believed to be due to a defective IFN response exhibited by many tumor cells. However, the genetic heterogeneity of tumors that impact the IFN response is highly variable and impairs the efficacy of virus-mediated tumor lysis. Therefore, by inhibiting the IFN response specifically in tumor cells, a tumor-targeted IFN antagonist would permit the specific destruction of tumor cells by an oncolytic virus (see Background of Invention). Applicant developed a targeted IFNa antagonist comprising the R120E mutation which abrogates IFN-IFNAR1 binding and confers the antagonistic activity of human IFNa2 (Example 1). The 4-11-IFNa2-R120E fusion protein exhibited targeted inhibition of IFNa activity on mouse leptin receptor (mLR)-expressing cells. Even at the higher concentration tested, the 4-11-IFNa2-R120E fusion protein was unable to inhibit IFNa2 action on untargeted HL116 cells (Figure 2A). In contrast, it exhibited a dose-dependent inhibition on HL116-mLR10 cells which express the target of the 4-11 nanobody (Figure 2B) (Example 2). The type I IFN antagonist IFNa2-R120E was fused to the anti-human CD20 nanobody 2HCD25 inhibits the IFN action specifically in the majority of the B cell population in peripheral blood mononuclear cells (PBMCs) that were treated with human IFNa2, leaving intact the IFN response in the CD19 negative cell population (Example 4). The CD20-targeted type I IFN antagonist also inhibits the antiproliferative activity of type I IFN in human lymphoblastoid B-cell line expressing CD20. However, it is stated that the IFNa2 mutations L153A and R149A which decrease the affinity of IFNa2 for IFNAR2 by a factor of 10 and 100, respectively in combination with the inhibiting mutation R120E decreases the antagonistic activity of the R120E mutation, proving that the inhibitory effect is due to the binding of the targeted antagonist (Example 5).
The specification does not teach that the claimed anti-CD19-IFNa2-R120E targeted antagonists recited by the independent claim can be used as a monotherapy to effectively treat cancer in a subject.
The prior art teaches that type I interferons (IFNs), including IFN-α, IFN-β, and their subtypes, have been demonstrated to inhibit tumor growth directly and indirectly by acting upon tumor and immune cells, respectively. For example, recombinant IFN-α2 was the first human immunotherapeutic for cancer by the United States Food and Drug Administration, and since then, type I IFNs have been widely used alone or in combination with other immunotherapeutic agents to treat solid and hematologic malignancies. Furthermore, accumulating evidence indicates that endo- and exogenously enhancing type I IFNs have a synergistic effect on anti-tumor immunity (Yu et al, see entire document, in particular Abstract and Introduction) (Yu, Renren, Bo Zhu, and Degao Chen. "Type I interferon-mediated tumor immunity and its role in immunotherapy." Cellular and Molecular Life Sciences 79.3 (2022): 191, of record). As such, artisans would reasonably expect that immunotherapeutic that enhance type I IFN signaling will have an anti-tumor effect and can thus effectively treat cancer in a subject. However, the charge-reversal mutation R120E is known to cause drastic loss of the antiviral and antiproliferative activity for both IFN-α2 and IFN-α2/α1 (Pan et al, see entire document, in particular, Abstract). (Pan, Manjing, et al. "Mutation of the IFNAR-1 receptor binding site of human IFN-α2 generates type I IFN competitive antagonists." Biochemistry 47.46 (2008): 12018-12027, of record). And, as further demonstrated by Applicant, a CD20-targeted type I IFN antagonist also inhibits the antiproliferative activity of IFN-α2 in human lymphoblastoid B-cell line expressing CD20 (Example 5 of Specification). Given that the IFN-α2-R120E antagonist blocks the anti-tumor activity of IFN-α2, artisans would not reasonably expect that the fusion protein recited by independent claim 14 to be able to effectively treat cancer in a subject. The dependent claims do not appear to cure the deficiencies of the independent claim.
Further, conventional antibodies targeting CD19 demonstrate limited activity in preclinical models, despite high CD19 expression and antibody internalization. As a result, CD19-targeting antibodies are used in other immunotherapy formats such as bispecific antibodies such as bispecific CD19xCD3 T cell engagers (BiTE) for T cell recruitment, antibody drug conjugate for delivery of toxic payloads, Fc- engineered antibodies with enhanced ADCC activity, and chimeric-antigen receptor (CAR)-transduced T cells, which have yielded promising results in clinical trials for the treatment of hematological malignancies (Hammer, see entire document, in particular, Abstract and Introduction)(Hammer, Ohad. “CD19 as an attractive target for antibody-based therapy.” mAbs vol. 4,5 (2012): 571-7. doi:10.4161/mabs.21338, of record). As such, the CD19-targeting VHH or VNAR domain present in the fusion protein may not be sufficient to confer anti-tumor activity and thus treat cancer in a subject commensurate in scope of the claims given that the modified human IFNa2 antagonist of claim 14 IFNa2-R120E lacks antitumor activity.
Therefore, the specification is not enabled over the full scope of the claims.
Response to Arguments
Applicant's arguments filed 09/08/2025 have been fully considered but they are not persuasive.
With respect to the 35 USC 112a enablement rejection, Applicant argues that the specification explains that the claimed fusion protein can be used in the treatment of cancer by targeting the action of a type I IFN antagonist to specific tumor cells expressing a given cell surface marker in order to inhibit the action of endogenous IFN specifically on the cell subset involved in the onset of cancer, leaving the other cells and organs fully responsive. Additionally, the working examples provide evidence that Applicant developed a targeted IFN-alpha antagonist comprising a R120E mutation that abrogates IFN-IFNAR1 binding and confers antagonistic activity of human IFNα2 and also was shown to inhibit the anti-proliferative activity of type I IFN. Thus, Applicant asserts that given the disclosure of the therapeutic relevance of the fusion protein, artisans would understand that the claimed invention could treat cancer and thus satisfy the enablement requirement.
In response to applicant’s arguments, the Examiner reiterates given that the IFN-α2-R120E antagonist blocks the anti-tumor activity of IFN-α2, artisans would not reasonably expect that the claimed fusion protein alone (as a monotherapy) to be able to effectively treat cancer in a subject as discussed above. The dependent claims particularly 16-17 further reciting a second mutation that decreases binding activity of the IFNa antagonists do not appear to cure the deficiencies of the independent claim.
With respect to the double patenting rejection over co-pending application 17/042,512, Applicant argues that there is no teaching or suggestion in the present application for the surprising choice of a heterodimeric configuration in the Fc-based chimeric protein complex of the co-pending claims, especially since the instant claims have been amended to recite a fusion protein consisting of IFN antagonist and a VHH or VNAR domain.
In view of the amendments to claim 14, Applicant’s arguments with respect to the double patenting rejection over the ‘512 application are persuasive. The rejection of the ‘512 application under double patenting has been withdrawn.
Conclusion
No claims are allowable.
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/LIA E TAYLOR/Examiner, Art Unit 1641
/MICHAEL SZPERKA/Primary Examiner, Art Unit 1641