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
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application is a 371 of PCT/CA2021/050383 filed on 03/23/2021, which claims the benefit of US Provisional Application Nos. 63/146,567 filed on 02/05/2021 and 62/993,334 filed on 03/23/2020. Claims 1-2, 5, 8-9, 16, 37, 42, 48, and 67-74 do not have support in US Provisional Application No. 62/993,334, because it does not teach wherein the p40 polypeptide comprises one or more mutations that reduce IL12 activity as required by instant Claim 1. However, US Provisional Application No. 63/146,567 does provide support for the p40 polypeptide comprising mutations that reduce IL12 activity. Therefore, Claims 1-2, 5, 8-9, 16, 37, 42, 48, and 67-74 receive an effective filing date of February 5, 2021.
Election/Restriction
Applicant's election without traverse of Group I (Claims 1-2, 5, 8-9, 16, 37, 42, 48, and 67-74) and species election of:
First linker cleavage sequence as set forth in SEQ ID NO: 10
A scFv antibody fragment
Comprising a single chain IL-12 polypeptide having the orientation p40-linker-p35
in the reply filed on September 19, 2025 is acknowledged.
Claim Status
Claim listing filed on September 19, 2025 is pending. Claims 3-4, 6-7, 10-15, 17-36, 38-41, 43-47, and 49-66 are canceled. Claims 1, 8, and 16 are amended. Claims 67-74 are new. Claims 1-2, 5, 8-9, 16, 37, 42, 48, and 67-74 are examined upon their merits.
Information Disclosure Statement
The information disclosure statements filed on 08/30/2023, 08/02/2024, and 09/19/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Specification
The disclosure is objected to because of the following informalities:
There is no Table B. Table A begins on page 16 and Table C begins on page 50. For clarity, Tables should be labeled either alphabetically or numerically by order of appearance.
Page 116, line 7 recites "Error! Reference source not found."
Appropriate correction is required. Applicant is urged to carefully review the specification for additional informalities.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Specifically, there is a hyperlink on page 146, line 14. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The disclosure is objected to because the sequence listing is not incorporated by reference at the beginning of the specification. MPEP § 2413.04 states that since the "Sequence Listing XML" is not the text of the specification, but rather is sequence data in an XML file format, an incorporation by reference statement is needed to ensure that the content of the "Sequence Listing XML," submitted to the USPTO as an XML file, is considered part of the disclosure capable of providing 35 U.S.C. 112(a) support for the disclosure and any claims relating to nucleotide and/or amino acid sequences. The required incorporation by reference statement identifies: (i) the name of the file; (ii) the date of creation of the file; and (iii) the size of the file in bytes.
Claim Objections
Claim 9 is objected to because of the following informalities: “having the amino acid sequence” in the 3rd line should recite “having the amino acid sequences.” Appropriate correction is required.
Applicant is advised that should Claim 1 be found allowable, Claim 2 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. Claim 1 recites “wherein at least one of the first, second or third linkers is protease cleavable” and Claim 2 recites “wherein one or more of the first linker, the second linker, and the third linker is protease cleavable” which is redundant. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 1-2, 5, 8-9, 16, 37, 42, 48, and 67-74 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “a masking moiety” and “mutations relative to the sequence set forth in SEQ ID NO: 22 that reduce IL12 activity when compared to a wildtype IL12 polypeptide.” Note, the specification defines that the “masking moiety” blocks or reduces the binding of IL12 to its native receptor(s) and/or blocks its functional activity (page 31, lines 21-23). Claims 2, 5, 8-9, 16, 37, 42, 48, and 67-74 are dependent on Claim 1 and do not further define the claimed masking moiety and the claimed mutations. These phrases are considered functional language because the feature (the masking moiety) is defined by what it does (blocks or reduces the binding or activity of IL12) rather than by what it is (MPEP § 2173.05(g)). Further, the mutations are defined by what they do (reduce IL12 activity) rather than by what they are. To determine if functional language is ambiguous, the following factors are considered: (1) whether there is a clear cut indication of the scope of the subject matter covered by the claim; (2) whether the language sets forth well-defined boundaries of the invention or only states a problem solved or a result obtained; and (3) whether one of ordinary skill in the art would know from the claim terms what structure or steps are encompassed by the claim. These factors are examples of points to be considered when determining whether language is ambiguous and are not intended to be all inclusive or limiting (MPEP § 2173.05(g)). The claims are directed to functional results obtained without any required structure. The metes and bounds of the masking moieties and the mutations cannot be determined, and Claims 1-2, 5, 8-9, 16, 37, 42, 48, and 67-74 are rejected for indefiniteness.
Claim 1 recites “mutations relative to the sequence set forth in SEQ ID NO: 22 that reduce IL12 activity when compared to a wildtype IL12 polypeptide.” While this phrase is considered functional language (see above rejection), it also includes relative terminology, specifically the term “reduce” (MPEP § 2173.05(b)). The specification teaches that “by reduced or inhibited binding or activity it is meant that binding or functional IL12 activity is lower than the binding or functional IL12 activity of an appropriate control, such as wild type IL12” (page 23, lines 20-22). This definition does not overcome the relative terminology because it is still unclear how the IL12 functional activity is measured and what the threshold of “reduce” is. For example, is a 1% reduction as compared to wildtype IL12 encompassed by the claims? A 0.05% reduction? It is important to understand the metes and bounds of “reduce” because the terminology is used to define the p40 mutations. The specification does not provide a definition of “reduce” in such a way that one of ordinary skill in the art would understand what is claimed. Claims 1-2, 5, 8-9, 16, 37, 42, 48, and 67-74 are rejected for the indefinite relative terminology in Claim 1.
Note, Claim 1 recites “wherein the IL12 activity of the masked IL12 fusion protein is attenuated as compared to the IL12 activity of the IL12 containing polypeptide released after cleavage of the at least one protease cleavable linker.” This language is not indefinite because the function of masked cytokines was understood in the art prior to filing. Here, “attenuated” is interpreted with the broadest reasonable interpretation as any decrease (even a non-significant change) in cytokine function as measured by methods known in the art prior to the time of filing.
Claim 73 recites wherein the masked IL12 fusion protein further comprises a targeting domain, and Claim 74 recites wherein the targeting domain specifically binds to a tumor-associated antigen. The specification recites that the targeting domain “targets the fusion protein to a site of action (e.g. sites of inflammation, a particular anatomical site such as an organ, or to a tumor)” (page 55, lines 13-15). “Targeting domain” is considered functional language because the feature (the targeting domain) is defined by what it does (targets the fusion protein to a site of action/binds to a tumor-associated antigen) rather than by what it is (MPEP § 2173.05(g)). The metes and bounds of the targeting domain cannot be determined, and Claims 73-74 are rejected for indefiniteness.
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 1-2, 5, 8-9, 16, 37, 42, 48, and 67-74 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 written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 is directed to a masked IL12 fusion protein comprising an Fc domain, a masking moiety, and an IL12 polypeptide comprising a p40 and a p35 polypeptide wherein the p40 polypeptide comprises one or more mutations that reduce IL12 activity. Therefore, Claim 1 encompasses a genus of masked IL12 fusion proteins that can comprise any type of masking moiety and any combination of p40 mutations. Claim 8 defines wherein the masking moiety is a scFv antibody fragment that can comprise any structure. Claim 9 defines wherein the scFv comprises the CDRs set forth in SEQ ID NOs: 13-18. Note, “the amino acid sequence set forth in” encompasses any fragment of two or more amino acid residues within the recited sequence. Therefore, Claim 9 is still directed to a genus of possible CDR amino acid sequences. Alternative claim language to encompass the recited CDRs in their entirety could recite “having the amino acid sequences comprising SEQ ID NOs…” Claim 67 recites wherein the mutations can comprise up to 15 substitutions in any combination.
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant has possession of and what Applicant is claiming. In order to provide adequate written description and evidence of possession of this claimed genus of fusion proteins, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof.
In the instant case, the specification teaches two species of masking moieties and their functional properties: (1) briakinumab scFv (Tables 5-7) and (2) IL12Rβ2 (Tables 11 and AA). Further, the specification teaches four species of p40 mutation combinations and their functional properties: (1) S175V, A179T, S183T, S294N; (2) D41S, E45R, K58S, E59S, K195D; (3) K99S, E100S, R159S; and (4) E187S, T202S, S204R (Tables 19-20). However, two species of masking moieties and four species of p40 mutations do not sufficiently convey to one of ordinary skill that the inventor was in possession of the claimed genus of fusion proteins comprising any type of masking moiety and any combination of p40 mutations at the time of filing.
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (MPEP § 2163.05.Ib). In the absence of sufficient recitation of distinguishing identifying characteristics or structure-to-function attributes for the entire genus of fusion proteins comprising any type of masking moiety and any combination of p40 mutations, the specification does not provide adequate written description of the claimed genus. Therefore, in view of the case law directed to an appropriate number of representative species, claims 1-2, 5, 8-9, 16, 37, 42, 48, and 67-74 are rejected for insufficient written description.
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
Claims 1-2, 5, 8-9, 16, 37, 42, 48, and 67-74 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for fusion proteins comprising the masking moieties briakinumab scFv or IL12Rβ2 and the p40 mutations listed in Table 19 as well as those known in the art prior to filing, does not reasonably provide enablement for the genus of fusion proteins comprising any type of masking moiety and any combination of p40 mutations. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
MPEP § 2164.01(a) states that there are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure
does not satisfy the enablement requirement and whether any necessary experimentation is “undue”. These factors include, but are not limited to:
A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01.
The breadth of the claims and nature of the invention:
The nature of the invention is complex. As understood with the broadest reasonable interpretation, Claim 1 is directed to a genus of masked IL12 fusion proteins that can comprise any type of masking moiety and any combination of p40 mutations. Claim 8 defines wherein the masking moiety is a scFv antibody fragment that can comprise any structure. Claim 9 defines wherein the scFv comprises the CDRs set forth in SEQ ID NOs: 13-18 which is still directed to a genus of possible CDR amino acid sequences due to the “set forth in” language (see above written description rejection). Claim 67 recites wherein the mutations can comprise up to 15 substitutions in any combination.
When analyzing the scope of enablement, the claims are analyzed with respect to the teachings of the specification and are to be "given their broadest reasonable interpretation consistent with the specification." See MPEP 2111 [R-5]; Phillips v. AWH Corp., 415 F.3d 1303, 75 USPQ2d 1321 (Fed. Cir. 2005); and In re Hyatt, 211 F.3d 1367, 1372, 54 USPQ2d 1664, 1667 (Fed. Cir. 2000). Applicant always has the opportunity to amend the claims during prosecution, and broad interpretation by the examiner reduces the possibility that the claim, once issued, will be interpreted more broadly than is justified. In re Prater, 415 F.2d 1393, 1404-05, 162 USPQ 541, 550- 51 (CCPA 1969).
The state of the prior art and level of predictability in the art:
The level of predictability in the art depends, most importantly, on whether the claimed invention can be practiced by one of ordinary skill in the art. In AMGEN INC. ET AL. v. SANOFI ET AL. (No. 21-757, decided May 18, 2023), the Supreme Court held that Amgen was not enabled for “the entire genus” of antibodies that (1) “bind to specific amino acid residues on PCSK9,” and (2) “block PCSK9 from binding to [LDL receptors]” (872 F. 3d 1367, 1372) even though Amgen identified the amino acid sequences of 26 antibodies that perform these two functions. The case law applies to the instant claims which encompass a genus of fusion proteins comprising any masking moiety that binds and blocks IL12, yet the inventors have only disclosed two species of masking moieties: briakinumab scFv and IL12Rβ2. Further, the claims encompass a genus of IL12 fusion proteins wherein the p40 polypeptide can have any combination of mutations that reduce IL12 activity, yet the inventors have only disclosed four p40 mutation combinations with the required function (specification Table 19).
In Amgen, the Supreme Court has stated that despite recent advances, aspects of antibody science remain unpredictable. For example, scientists understand that changing even one amino acid in the sequence can alter an antibody's structure and function. See id., at 14. But scientists cannot always accurately predict exactly how trading one amino acid for another will affect an antibody's structure and function. Ibid. The unpredictability of antibody structure and function applies to the instant masking moieties that can comprise antibodies or antibody fragments. The unpredictability of mutations in polypeptide structure and function further applies to the IL12 p40 domain of the instant application.
The case law shows a continued lack of predictability even after the effective filing date of the instant invention, and there is no support in the Applicant’s disclosure leading one of ordinary skill to overcome the lack of predictability in the genus of fusion proteins claimed. The specification provides no guidance or direction for structure that must be maintained such that the functional properties of the invention are preserved (IL12 binding and reduced IL12 activity).
Level of skill in the art:
The level of skill would be high encompassing protein science, antibodies, binding assays, immunology, etc.
Amount of direction provided by inventor and the existence of working examples:
The specification teaches two species of masking moieties and their functional properties: (1) briakinumab scFv (Tables 5-7) and (2) IL12Rβ2 (Tables 11 and AA). Further, the specification teaches four species of p40 mutation combinations and their functional properties: (1) S175V, A179T, S183T, S294N; (2) D41S, E45R, K58S, E59S, K195D; (3) K99S, E100S, R159S; and (4) E187S, T202S, S204R (Tables 19-20).
However, two species of masking moieties and four species of p40 mutations do not adequately represent the scope of fusion proteins that encompasses any type of masking moiety and any combination of p40 mutations which could include thousands of possible variations. Further, the maximum number of p40 mutations evaluated in combination was five (as listed in combination (2) above), and the instant claims recite “one or more mutations” with no maximum number of mutations. Claim 67 encompasses up to 15 p40 mutations in combination. A person having ordinary skill in the art would have to make a substantial inventive contribution in order to make and characterize a representative number of fusion proteins to encompass the claimed genus.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure:
In light of the unpredictability surrounding the claimed subject matter, the undue breadth of the claimed invention’s intended use, and the lack of adequate guidance, one wishing to make and practice the presently claimed invention would be unable to do so without engaging in undue experimentation. Given that structure is essential to function, a person having ordinary skill in the art would have to perform further experimentation to make the fusion proteins encompassed by the claims and screen their characteristics in order to practice the invention commensurate with the scope of the claims.
The instant specification does not enable the invention to make and use the entire genus of fusion proteins that comprise any masking moiety and any combination of p40 mutations; therefore, Claims 1-2, 5, 8-9, 16, 37, 42, 48, and 67-74 are rejected.
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.
Claims 1-2, 8-9, 16, 37, 42, 48, 67, and 71-74 are rejected under 35 U.S.C. 103 as being unpatentable over Lu WO 2021/062406 (filed Sept. 2020; of record in IDS) as evidenced by Kegg Drug: Briakinumab (accessed online 11/26/2025) in view of Chevrier WO 2017/172771.
In regard to Claims 1-2, 8, 16, and 71-72, Lu teaches an IL12 prodrug comprising an IL12 cytokine, a masking moiety, and a dimeric carrier moiety wherein the masking moiety binds to the IL12 cytokine and inhibits a biological activity of the IL12 cytokine (paragraph [0010]). The IL12 comprises subunits p40 and p35 wherein p40 comprises SEQ ID NO: 5 (paragraph [0056]) which is 100% identical to instant SEQ ID NO: 22. The carrier moiety can be an Fc domain (paragraph [0017]). The masking moiety can be an scFv that binds to p40 (paragraph [0013]). The masking moiety can be linked to the carrier moiety by a protease cleavable peptide linker (paragraph [0057]). The IL12 cytokine can be a single chain having the orientation, from N- to C- terminus, p40-linker-p35 wherein the masking moiety is fused to the C-terminus of a first Fc polypeptide by a linker and the IL12 is fused to the C-terminus of a second Fc polypeptide by a linker (as shown below in Fig. 5B).
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In regard to Claim 9, Lu teaches wherein the masking moiety is an scFv that comprises the same light chain CDRs and heavy chain CDRs as the IL12 antibody briakinumab (paragraphs [0060]-[0061]). Note, the specification defines that SEQ ID NOs: 13-18 are the heavy and light chain CDRs of briakinumab (Table 5) which is further evidenced by KEGG DRUG: Briakinumab (accessed online 2025) which teaches the heavy chain and light chain amino acid sequences of briakinumab.
In regard to Claims 37 and 42, Lu teaches wherein the Fc domain comprises “knobs-into-holes” mutations in the CH3 domains to form heterodimers. For example, a first Fc CH3 domain can comprise R409D/K370E mutations to form the "knob chain" and a second Fc CH3 domain can comprise D399K/E357K mutations to form the "hole chain" wherein the knob and hole mutations bind one another to form a stable heterodimer (paragraph [0076]).
In regard to Claim 48, Lu teaches pharmaceutical compositions comprising the IL12 prodrug and a pharmaceutically acceptable carrier (paragraph [00112]).
In regard to Claims 73-74, Lu teaches that the carrier moiety can further comprise an antigen-binding domain that specifically binds a tumor-associated antigen to target the fusion protein to a tumor site (paragraphs [0058] and [0016]).
While Lu teaches that the cytokine may be a mutant cytokine comprising at least one mutation and altered activity level relative to the wildtype cytokine (paragraph [0046]), Lu fails to teach wherein the IL12 polypeptide comprises one or more p40 mutations that reduce IL12 activity (Claim 1), specifically the mutation E45R (Claim 67).
Chevrier teaches a fully human monoclonal antibody (p40 mAb) directed against human IL12 p40 that binds to the p40 subunit and blocks the binding of IL12 to its receptor (page 74, paragraph 2). The interaction between IL12 and the p40 mAb defines an important neutralizing epitope that sheds light upon the cytokine-receptor interactions (page 74, paragraph 2). Three IL12 p40 residues, E45, E59, and D62, were found to contribute significantly to the binding interactions of IL12 with the p40 mAb (page 78, paragraph 1). The E45R mutation significantly reduced IL12 binding affinity to the p40 mAb as compared to wild type IL12 (page 79, paragraph 1).
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was made, to modify the IL12 prodrug taught by Lu to include an E45R mutation in the p40 IL12 domain to reduce IL12 activity as taught by Chevrier. Chevrier teaches that the E45R mutation reduces IL12 binding affinity to a p40 mAb, and the p40 mAb binds the same epitope involved in IL12 receptor binding. Therefore, it would be obvious to one of ordinary skill that the E45R mutation would also reduce binding affinity to the IL12 receptors which in turn reduces overall IL12 activity. The motivation to reduce IL12 activity even in the unmasked cytokine is because IL12 is known to have limited therapeutic efficacy due to its narrow therapeutic index (Lu paragraph [0003]). A narrow therapeutic window means that the safe and effective dose is very close to the toxic dose. Therefore, there is motivation to decrease the potency of IL12 for therapeutic purposes which can be accomplished by introducing known mutations that decrease IL12 binding affinity.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Lu WO 2021/062406 (filed Sept. 2020; of record in IDS) as evidenced by Kegg Drug: Briakinumab (accessed online 11/26/2025) in view of Chevrier WO 2017/172771 as applied to Claims 1-2, 8-9, 16, 37, 42, 48, 67, and 71-74 above, and further in view of Dixit US 2023/0331809 (effectively filed July 2020 and not a prior art exception due to a different inventive entity; MPEP § 2154.01(c)).
The teachings of Lu and Chevrier as they apply to Claims 1-2, 8-9, 16, 37, 42, 48, 67, and 71-74 are outlined in the rejection above and encompass an IL12 prodrug comprising a protease cleavable linker between the masking moiety and a first Fc polypeptide. Lu and Chevrier fail to teach wherein the protease cleavable linker specifically comprises SEQ ID NO: 10 (Claim 5).
Dixit teaches masked fusion proteins (abstract) wherein the fusion protein can comprise a protease cleavable linker comprising the amino acids sequence MSGRSANA (SEQ ID NO: 28) (paragraph [0011]) which is 100% identical to instant SEQ ID NO: 10.
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was made, to substitute equivalents, each of which is taught by the prior art to be useful for the same purpose (See MPEP 2144.06-II). It would have been obvious to substitute the protease cleavable linker taught by Lu and Chevrier for the known protease cleavable linker taught by Dixit. Both protease cleavable linkers are taught to be effective in masked fusion proteins which supports that the linkers could be substituted with predictable results.
Claim 70 is rejected under 35 U.S.C. 103 as being unpatentable over Lu WO 2021/062406 (filed Sept. 2020; of record in IDS) as evidenced by Kegg Drug: Briakinumab (accessed online 11/26/2025) in view of Chevrier WO 2017/172771 as applied to Claims 1-2, 8-9, 16, 37, 42, 48, 67, and 71-74 above, and further in view of Jooss WO 2020/160189.
The teachings of Lu and Chevrier as they apply to Claims 1-2, 8-9, 16, 37, 42, 48, 67, and 71-74 are outlined in the rejection above and encompass an IL12 prodrug comprising an Fc domain with knob-in-hole mutations in the CH3 domains. Lu and Chevrier fail to teach wherein the knob-in-hole mutations specifically comprise mutations L351Y, F405A, and Y407V in a first IgG1 Fc polypeptide and mutations T366L, K392M, and T394W in a second IgG1 Fc polypeptide (Claim 70(i)).
Jooss teaches fusion proteins comprising an Fc domain (abstract and Fig. 116). The Fc domain can comprise an IgG1 Fc domain with knob-in-hole mutations (paragraphs [00128]-[00131]), specifically “a first Fc-bearing chain of the variant Fc region comprises a L351Y mutation, а F405A mutation, and a Y407V mutation and the second Fc-bearing chain of the variant Fc region comprises a T366L mutation, a K392M mutation, and a T394W mutation” (paragraph [00130], combination (e)).
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was made, to substitute equivalents, each of which is taught by the prior art to be useful for the same purpose (See MPEP 2144.06-II). It would have been obvious to substitute the knob-in-hole mutations taught by Lu and Chevrier for the known knob-in-hole mutations taught by Jooss, because knob-in-hole mutations are known to stabilize Fc domains and are commonly used in recombinant proteins (Lu paragraph [0076]). Thus, the knob-in-hole mutations could be substituted with predictable results.
Conclusion
No claim is allowed.
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/SARAH COOPER PATTERSON/Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675