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 § 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.
Claim 62 is 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 claim recites “a nucleic acid or plurality of nucleic acids encoding the IFN receptor agonist of claim 1.” However, the term “a nucleic acid” is interpreted to encompass a single nucleotide as well as longer polynucleotide sequences, as neither the claims nor the specification impose any length or structural limitations of a nucleic acid. The specification does not teach how to make or use such embodiments, nor would a person having ordinary skill in the art be able to do so. Accordingly, the claim encompasses non-enabled embodiments.
Therefore, claim 62 is rejected under 35 U.S.C. 112(a) for lack of enablement.
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.
Claims 1, 2, 4, 5, 7, 8, 10, 25, 27, 30, 31, 62-69, 72, and 73 are rejected under 35 U.S.C. 103 as being unpatentable over Fu et al., WO2018236701A1.
Independent claim 1 is drawn to an interferon receptor agonist comprising an Fc domain, a type 1 IFN moiety attenuated by masking by an IFNaR1 moiety and an IFNaR2 moiety. Claims 2-11, 13, 15, 17, and 25-31 include specific structural configurations and sequence variants. Claims 62-65 are drawn to nucleic acids encoding said agonist, host cells, methods of producing, and a pharmaceutical composition. Claims 66-69, 72, and 73 are drawn to methods of administering said agonist.
Fu et al. discloses a human interferon prodrug comprising an IFNaR domain, which may be either IFNaR1 or IFNaR2 [see claims 8 and 9], one or more Type 1 interferon (IFN) domains [see claims 1 and 4], which may be IFN-a, IFN-β, IFN-K, IFN-δ, IFN- ε, IFN-τ, IFN-ω or IFN-ζ [see claim 10], that retains interferon activity when not engaged by the IFNAR domain [see claim 1], and an Ig Fc domain [see claim 1] (instant claim 1). The Fc domain may be an IgG [see claim 2], which inherently discloses a dimeric Fc structure comprising a first polypeptide chain comprising an Fc domain and a second polypeptide chain comprising a second Fc domain associated with the first (instant claim 1). Fu et al. discloses that the INFaR domain is fused to the N-terminal of the IFN domain via a protease-cleavable linker, functionally unmasking the IFN when cleaved, and that the IFN domain is fused to the N-terminal of the Fc domain via a second linker [see claims 1 and 6] (instant claims 2, 4, 5, 7, 8, 10 and 25). Fu et al. demonstrate the activity of the prodrug using purified human IFNaR1 or IFNaR2 extracellular domains in combination with a human IFNa2-Fc [see specification, p.45, paragraph 2], the latter of which is known in the art as a variant of IFNa2b that differs by a single amino acid (instant claim 27). The human IFNaR1 extracellular domain necessarily comprises SD1-SD4 and the IFNR2 extracellular domain necessarily comprises D1 and D2, implicitly requiring the natural human sequences encoding their structures (instant claims 30 and 31). Nucleic acid constructs encoding the prodrug [see claim 11] (instant claim 62), recombinant cells engineered to express the prodrug [see claim 21] (instant claim 63), and methods of recovering the prodrug from procaryotic or eucaryotic expression system are disclosed [see p.24, paragraph 2] (instant claim 64). The prodrug may be formulated and administered with a pharmaceutically acceptable excipient [see specification, p.25, paragraph 3] (instant claim 65) as a treatment for cancer [see claim 25] (instant claim 66) and can be delivered via any conventional route [see specification, p.26, paragraph 4] (instant claim 73), including local administration, wherein the linker is selectively cleavable by a protease overexpressed in the tumor microenvironment (instant claims 67 and 68) to reduce systemic toxicity [see p.7 paragraph 2] (instant claim 69). Finally, Fu et al. note the potential use of the prodrug in combination with additional advanced interferon therapy formats, such as antibody-cytokine bispecific fusion proteins [see p.8 paragraph 1] (instant claim 72).
Fu et al. do not disclose the limitation of claim 1 of an IFN agonist wherein both IFNaR1 and IFNaR2 simultaneously mask the IFN domain, or even an embodiment wherein IFNaR1 and IFNaR2 are both present.
However, it would have been obvious to one of ordinary skill in the art to include both IFNaR1 and IFNaR2 in the same construct to enhance masking given that IFN naturally interacts with both receptor subunits. One would be motivated to do so because using both components would predictably further attenuate IFN activity, and combining known receptor components to predictably improve binding strength would have been routine for one of ordinary skill in the art (instant claim 1). Given this, it would have been obvious to utilize the teachings of Fu et al. as discussed above and further generate a prodrug comprising both IFNaR1 and IFNaR2, thereby fully disclosing instant claims 1, 2, 4, 5, 7, 8, 10, 25, 27, 30, 31, 62, 63, 65-69, 72, and 73.
Therefore, claims 1, 2, 4, 5, 7, 8, 10, 25, 27, 30, 31, 62-69, 72, and 73 are rejected under 35 U.S.C. 103.
Claims 3, 6, 9, 11, and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Fu et al. as applied to claims 1, 2, 4, 5, 7, 8, 10, 25, 27, 30, 31, 62-69, 72, and 73 above, and further in view of Liu et al. (2017).
The disclosure of Fu et al. is discussed above.
Fu et al. do not disclose the IFN moiety being C-terminal to the Fc domain or N-terminal to the first IFNaR domain.
Liu discloses attachment of VH and VL domains to the C-termini of the Fc domain in a “knob and hole” style of Fc heterodimer. This combined with the disclosure of Fu et al., teaches that Fc domains are a modular platform that can tolerate N or C terminal placement, and, in general, and as such, rearrangement of the domains would have been an obvious design choice dictated by routine optimization. One of ordinary skill in the art would have been motivated to combine these teachings and vary the position of the moieties to reflect the native receptor geometry and to optimize masking as necessary (instant claims 3, 6, 9, 11, and 13).
Therefore, claims 1-11, 13, 25, 27, 30, 31, 62-69, 72, and 73 are rejected under 35 U.S.C. 103.
Claims 15, 17, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Fu et al. as applied to claims 1, 2, 4, 5, 7, 8, 10, 25, 27, 30, 31, 62-69, 72, and 73, and further in view of Faust et al. (2020).
The disclosure of Fu et al. is discussed above.
Fu et al. does not disclose heterodimeric Fc arrangements in which distinct polypeptide chains carry different receptor moieties.
At the time of the invention, homodimerization of Fc domains was well known in the art. Faust et al. discloses the generation of a heterodimeric two-chain insulin-Fc fusion protein using the “knobs in holes” approach described in the instant application [see abstract]. Faust teaches that the complementary steric mutations in the opposing Fc chains provide a reliable strategy to promote preferential heterodimerization of two distinct Fc-containing polypeptides, thereby increasing the proportion of the desired heterodimeric species compared to homodimeric byproducts. It would have been obvious to combine the teachings of Fu et al. with the teachings of Faust et al. to generate heterodimeric polypeptides, and one would have been motivated to do so given that the native IFN receptor is itself a heterodimer of IFNaR1 and IFNaR2 domains, and to decrease homodimeric binding of the FC domains, which could alter IFN masking properties (instant claims 15 and 17).
Additionally, to include a second IFN moiety masked by an additional IFNaR1 and IFNaR2 (instant claim 26) would similarly be obvious given that Fu et al. disclose the use of additional IFN moieties and this is a predictable extension of the existing prodrug design requiring no more knowledge than routine protein engineering and fusion strategies (instant claim 26).
Therefore, claims 1, 2, 4, 5, 7, 8, 10, 15, 17, 25-27, 30, 31, 62-69, 72, and 73 are rejected under 35 U.S.C. 103.
Claims 28 and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Fu et al. as applied to claims 1, 2, 4, 5, 7, 8, 10, 25, 27, 30, 31, 62-69, 72, and 73 above, and further in view of Thomas et al. (2011).
The disclosure of Fu et al. is discussed above.
Fu et al. do not disclose the particular attenuating mutations or sequence variants recited in the claims.
Thomas et al. disclose how different TFN subtypes bind differently to IFNaR1 and IFNaR2, specifically disclosing key point mutations including L26A, L30A, and R149A, that contribute to receptor interaction and signaling [see p627, Probing Differential IFN Signaling with Structure-Based Mutational Analysis]. It would have been obvious to one of ordinary skill in the art to combine the disclosure of Fu et al. with the teachings of Thomas et al., and one would have been motivated to do so to further modulate IFN activity, with a reasonable expectation of success (instant claims 28 and 29).
Therefore, claims 1, 2, 4, 5, 7, 8, 10, 25, 27-30, 31, 62-69, 72, and 73 are rejected under 35 U.S.C. 103.
Conclusion
No claims are allowed.
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/T.D.J./ Examiner, Art Unit 1675
/JEFFREY STUCKER/ Supervisory Patent Examiner, Art Unit 1675
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