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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 06/12/2026 has been entered.
Claims Status
The amendments and remarks filed 05/12/2026 are acknowledged and entered.
Claims 1, 3, 11-15, 17, 19, and 21-27 are pending.
Claims 1, 3, 11-15, 17, 19, and 21-25 are amended.
Claims 2, 4-10, 16, 18, 20, and 28 are canceled.
Claims 3, 21-23, and 25-27 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claims. Election was made without traverse on 12/19/2023.
Therefore, claims 1, 11-15, 17, 19, and 24 are under examination.
Withdrawn
The previous rejections of claims 13 and 15 under 35 U.S.C. are withdrawn. Applicant has amended the claims to overcome the rejections. However, new grounds of rejection under 35 U.S.C. 103 are applied to claims 13 and 15 below.
Maintained Rejections
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, 11-12, 14, 17, and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Bai (WO 2016073704; 05/02/2024 PTO-892) in view of Lo et al., 1998 (04/25/2025 PTO-892), Timans et al., 2004 (US 20040198955; 10/18/2024 PTO-892), and Kim (WO 2018030806; 04/25/2025 PTO-892).
Regarding claims 1 and 17, Bai teaches an IL27Fc fusion protein comprising a signal peptide, EB13, a PV or GS linker (flexible linker), P28, and Fc domain (first polypeptide chain) in N- to C- terminal orientation [0185; Figure 10A]. See below:
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Since this structure comprises only one EBI3 and one p28, this meets the limitation of “monovalent” as defined by Applicant as an IL27 receptor agonist that has only a single IL27 heterodimer (i.e., one EBI3xp28 heterodimer) [see 0061 of the instant specification]. Further, the p28 moiety necessarily comprises an IL27Rα binding domain and a gp130 binding domain of p28, and the EBI3 moiety necessarily comprises a p28 binding domain of EBI3 because these are inherent properties of p28 and EBI3. Applicant is reminded that chemical compounds and their properties are inseparable (In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA1963)), as are their processes and yields (In re Von Schickh, 362 F.2d 821, 150 USPQ 300 (CCPA 1966)).
Further, Bai teaches that the fusion protein comprises a wild type human p28 peptide (residues 28-243 of SEQ ID NO: 142) [0048]. Thus, since the p28 moiety necessarily comprises an IL27Rα binding domain and a gp130 binding domain of p28 because this is an inherent property of p28, then this wild type human p28 peptide of Bai also necessarily comprises 95% sequence identity to an IL27Rα binding domain and/or a gp130 binding domain of a human p28 protein.
SEQ ID NO: 142 of Bai has 100% sequence identity to residues 28-243 of SEQ ID NO: 2 of the instant claim, which correspond to the amino acid sequence of interleukin-27 subunit alpha (p28) as evidenced by UniProt, 2020 (instant PTO-892) [see pages 4-5]. Thus, as the examiner stated above, and since SEQ ID NO: 2 of the instant claim comprises a wild type human p28 moiety, the p28 peptide of Bai necessarily comprises an amino acid sequence having at least 95% sequence identity to an IL27Ra binding domain and/or a gp130 binding domain of SEQ ID NO: 2.
However, Bai does not specifically teach that the first polypeptide chain comprises in N- to C-terminal orientation: (a) a first Fc domain; (b) the EBI3 moiety; and (c) the p28 moiety, that the EBI3 moiety comprises an amino acid sequence having at least 95% sequence identity to a p28 binding portion of SEQ ID NO: 1, or that the IL27Fc fusion protein comprises a second polypeptide chain comprising a second Fc domain associated with the first Fc domain to form an Fc heterodimer, wherein the first Fc domain and/or second Fc domain comprise one or more mutations that permit heterodimerization.
Lo teaches that the use of a signal-peptide-Fc as an N-terminal fusion partner can ‘fool’ the cellular processes to express and secrete many different types of proteins at a high level and that this fusion approach is superior to an X-Fc construct (i.e. C-terminal Fc) because the use of Fc at the N-terminus ensures that the Fc-X is directed efficiently through the secretory pathway [page 499, left column, second paragraph]. Lo further teaches that overall, the Fc-X construct (i.e. N-terminal Fc) achieves high level expression of proteins [page 499, right column, fourth paragraph].
Timans teaches SEQ ID NO: 10, which is the polypeptide sequence of EBI3 [0058].
SEQ ID NO: 10 of Timans has 100% sequence identity to SEQ ID NO: 1 of the instant claim.
Kim teaches heterodimeric Fc-fused proteins comprising a first Fc region and a second Fc region of a Fc region pair of an immunoglobulin while a subunit of a biologically active protein is bound to at least one of N-terminal or C-terminal of the first Fc region and/or the second Fc region, and the protein can be fused to the Fc [see Abstract]. Further, Kim teaches that the use of the heterodimeric Fc-fused proteins remarkably increases the in vivo half-life of a biologically active protein contained in the heterodimeric Fc-fused protein, and thus, various types of biological activities can be maintained for a long time in the body [see Abstract]. Kim also teaches that heterodimer Fc-based heterodimeric proteins (e.g. IL27) can be prepared by the structures below:
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[see page 32, Figure 2 of Kim]. Kim further teaches that the first Fc region and the second region are mutated so as to promote the formation of heterodimers [see paragraph 3].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the IL27Fc fusion protein as taught by Bai to have the first Fc domain be an N-terminal Fc, as taught by Lo, thereby arriving at an IL27 fusion protein comprising a first polypeptide chain comprising in an N- to C- terminal orientation: the first Fc domain, the EBI3 moiety, and the p28 moiety. One would have been motivated to make this modification because Lo teaches that an N-terminal Fc (i.e. Fc-X construct) is superior to a C-terminal Fc (X-Fc construct) because it ensures that the Fc-X is directed efficiently through the secretory pathway and achieves high level expression of proteins. There would be a reasonable expectation of success in making this modification because this is a known structure in the art for Fc fusion proteins, as taught by Lo.
It further would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the EBI3 moiety of the IL27Fc fusion protein of Bai to specifically be the EBI3 as taught by Timans. One would have been motivated to use this sequence for the EBI3 moiety because it is a known sequence in the art, and it is obvious to use known variations in the prior art for predictable outcomes. See MPEP 2143 (F).
Additionally, it would have been obvious to modify the IL27Fc fusion protein of Bai to further comprise a second polypeptide chain comprising a second Fc domain associated with the first Fc domain to form an Fc heterodimer wherein the first Fc domain and/or second Fc domain comprise one or more mutations that permit heterodimerization, as taught by Kim. One would have been motivated to make this modification because Kim teaches that the use of the heterodimeric Fc-fused proteins remarkably increases the in vivo half-life of a biologically active protein contained in the heterodimeric Fc-fused protein. There would be a reasonable expectation of success in making this modification because this is a known structure in the art for heterodimeric Fc fusion proteins, as taught by Kim.
Regarding the claim limitation of “wherein the stoichiometry of the Fc domains: EBI3 moiety in the IL27 receptor agonist is 2:1”, since it would have been obvious to arrive at the claimed structure, as taught by the art above, and the structure comprises only one EBI3 moiety and two Fc domains, then the stoichiometry of the Fc domains: EBI3 moiety in the IL27 receptor agonist is necessarily 2:1.
Claim 11 is included in this rejection because Bai teaches that the Fc portion may comprise the hinge region and CH2 and CH3 domains of the human IgG1, IgG2, IgG3, IgG4, or IgA [0066]. Further, Kim teaches that both Fc regions comprise a hinge region [depicted in Figure 2] and the term Fc region comprises a CH2 region, CH3 region, and hinge domain [92]. Thus, both the first and second Fc domains comprise a hinge domain.
Claims 12 and 14 are included in this rejection because Bai teaches that the use of IgG1 in the fusion protein is an exemplary IgG isotype source for an IgG Fc, and that other Fc subclasses may also be used based on the same design depicted in Figure 10 [0187]. Bai further teaches that the Fc domain can be human IgG1, IgG2, IgG3, and IgG4 [0066]. Kim teaches that the Fc domain can be IgG1, IgG2, IgG3, or IgG4 [Table 2] and uses IgG4 in specific proteins of the invention [244]. Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have picked among the various embodiments of Bai and Kim and arrived at both the first and second Fc domains being IgG4 Fc domains because both Bai and Kim teach that this is a suitable domain to use for the Fc domains.
Claim 24 is included in this rejection because Bai teaches a pharmaceutical composition comprising the fusion protein of the present disclosure formulated in any pharmaceutically acceptable carrier(s) or excipient(s) [0146].
Claims 1, 11-12, 14, 17, 19, and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Bai (WO 2016073704; 05/02/2024 PTO-892) in view of Lo et al., 1998 (04/25/2025 PTO-892), Timans et al., 2004 (US 20040198955; 10/18/2024 PTO-892), and Kim (WO 2018030806; 04/25/2025 PTO-892), as applied to claims 1, 11-12, 14, 17, and 24 above, and further in view of UniProt, 2020 (instant PTO-892).
The teachings of Bai, Lo, Timans, and Kim are above.
However, Bai, Lo, Timans, and Kim do not specifically teach that the p28 moiety has an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 2.
Regarding claim 19, UniProt teaches the sequence of IL27A (p28) [see page 8].
The sequence of UniProt has 100% sequence identity to SEQ ID NO: 2 of the instant claim.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the p28 moiety in the IL27Fc fusion protein as taught by Bai, Lo, Timans, and Kim, to specifically be the p28 moiety as taught by UniProt. One would have been motivated to use this sequence for the p28 moiety because it is a known sequence in the art, and it is obvious to use known variations in the prior art for predictable outcomes. See MPEP 2143 (F).
New Grounds of Rejection Necessitated by Amendment
Claims 1, 11-14, 17, and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Bai (WO 2016073704; 05/02/2024 PTO-892) in view of Lo et al., 1998 (04/25/2025 PTO-892), Timans et al., 2004 (US 20040198955; 10/18/2024 PTO-892), and Kim (WO 2018030806; 04/25/2025 PTO-892), as applied to claims 1, 11-12, 14, 17, and 24 above, and further in view of Escobar-Cabrera et al., 2017 (instant PTO-892).
The teachings of Bai, Lo, Timans, and Kim are above. Further, Bai teaches that the Fc region can be modified by replacing one or more amino acid residues with different amino acid residues to alter the effector functions of the Fc, such that the Fc portion is deficient (reduced) binding an Fcy receptor [0067].
However, Bai, Lo, Timans, and Kim do not specifically teach that each of the first Fc domain and the second Fc domain has reduced effector function.
Regarding claim 13, Escobar-Cabrera teaches novel asymmetric Fc mutations for heterodimeric Fc regions with reduced or silenced effector function [see Abstract] such as antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC) [page 2, first paragraph].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the first and second Fc domains in the IL27Fc fusion protein as taught by Bai, Lo, Timans, and Kim, to each comprise mutations that results in reduced or silenced effector functions, as taught by Escobar-Cabrera. One would have been motivated to have made this modification because Escobar-Cabrera teaches novel asymmetric Fc mutations for heterodimeric Fc regions with reduced or silenced effector function and one would want to have reduced or silenced effector function to minimize or eliminate antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC).
Claims 1, 11-12, 14-15, 17, and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Bai (WO 2016073704; 05/02/2024 PTO-892) in view of Lo et al., 1998 (04/25/2025 PTO-892), Timans et al., 2004 (US 20040198955; 10/18/2024 PTO-892), and Kim (WO 2018030806; 04/25/2025 PTO-892), as applied to claims 1, 11-12, 14, 17, and 24 above, and further in view of Wu (US 20210188934; instant PTO-892).
The teachings of Bai, Lo, Timans, and Kim are above.
However, Bai, Lo, Timans, and Kim do not specifically teach that the first Fc domain comprises amino acids 1-228 of SEQ ID NO:51 and the second Fc domain comprises the amino acid sequence of SEQ ID NO:68.
Regarding claim 15, Wu teaches SEQ ID NO: 105 which comprises an IgG4 Fc (hole) with reduced effector function [page 36; Table 5A] and SEQ ID NO: 113 which comprises a Fc (knob) region [page 38; Table 5A].
Residues 139-366 of SEQ ID NO: 105 are the residues of the whole sequence that correspond to the Fc region and have 100% sequence identity to SEQ ID NO: 68 of the instant claim. Residues 440-667 of SEQ ID NO: 113 are the residues of the whole sequence that correspond to the Fc region and have 100% sequence identity to residues 1-228 of SEQ ID NO: 51.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the first and second Fc domains in the IL27Fc fusion protein as taught by Bai, Lo, Timans, and Kim, to specifically be the Fc domains as taught Wu. One would have been motivated to use these known sequences for the Fc domains because they are known sequences in the art for hole and knob Fc domains, and it is obvious to use known variations in the prior art for predictable outcomes. See MPEP 2143 (F).
Response to Arguments
The rejections of claims 1, 11-12, 14, 17, 19, and 24 under 35 U.S.C. 103 over Bai, Lo, Timans, Kim, and UniProt are maintained. On page 7 of the remarks, Applicant argues that Bai’s disclosure confirms that the Figure 10A fusion protein forms dimers [see paragraph 0185 of Bai] and that the complete expressed protein thus contains two EBl3 moieties, two p28 moieties and two Fcs, which is bivalent for IL27, and thus, Bai’s homodimer is bivalent, not monovalent. This is not found persuasive because as stated in the office action mailed 04/25/2025, this is an inaccurate representation of the teachings as a whole of Bai. While the fusion protein of Bai may form dimers, Bai nonetheless still teaches a monomeric fusion protein comprised of, from N to C termini, a signal peptide, EBI3, a linker, p28 and Fc, which is monovalent for IL27 [see paragraph 0185; Figure 10A of Bai]. Further, Applicant argues that Bai neither discloses nor suggests a monovalent IL27 receptor agonist with an Fc domain: EBl3 moiety stoichiometry of 2:1 as now claimed. This is not found persuasive because in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
On page 8 of the remarks, Applicant argues that Kim’s Figure 2 depicts only general structural categories and that Kim never generates, expresses, characterizes, or provides data for any IL27-containing construct or for any construct in which both
cytokine subunits reside on the same chain C-terminal to the Fc, and does not teach what an appropriate order of IL27 subunits is in a construct, let alone one in which both subunits are on a single polypeptide chain C-terminal to an Fc domain. This is not found persuasive because in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The Examiner did not rely upon Kim to teach the protein that is monovalent for IL27, but rather, relied upon the teachings of Kim for the motivation as to why one skilled in the art would want to modify the protein of Bai to comprise a second Fc domain associated with the first Fc domain (of Bai) to form a heterodimeric Fc-fused protein and do so with a reasonable expectation of success.
Further on page 8 of the remarks, Applicant argues that only biological activity data in Kim's examples for its mono-IL12-Fc construct shows that the monovalent construct has reduced IL12 signaling activity relative to the bivalent bi-IL12-Fc homodimer (Kim, Fig. 26), and that the Office articulates no rationale as to why the skilled artisan would, in view of Kim's mono-IL12-Fc construct, choose to make a monovalent IL27 construct, but rather, the skilled artisan reading Kim would therefore be discouraged, not motivated, from adopting a monovalent single-chain architecture for a cytokine therapeutic, because Kim's only characterized example of such an architecture demonstrates reduced cytokine signaling. This is not found persuasive because again, in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The Examiner did not rely upon Kim to teach that the protein is monovalent for IL27, but rather, relied upon the teachings of Kim for the motivation as to why one skilled in the art would want to modify the monovalent protein of Bai to comprise a second Fc domain associated with the first Fc domain (of Bai) to form a heterodimeric Fc-fused protein and do so with a reasonable expectation of success. The structure of Figure 26 of Kim that Applicant is arguing is a completely different structure than the one the Examiner relied upon in the rejection and Kim still explicitly teaches that the structures depicted in Figure 2, inclusive of the structure the Examiner did rely upon in the rejection, increases the in vivo half-life of a biologically active protein contained in the heterodimeric Fc-fused protein. Therefore, one would be motivated to adopt a monovalent single-chain architecture for a cytokine therapeutic.
On page 9 of the remarks, Applicant argues that Lo does not teach, describe, suggest, or characterize any Fc-X construct with a heterodimeric Fc, and that the properties of Lo and Kim cannot be combined because Lo and Kim describe structurally incompatible Fc architectures without any guidance on how to reconcile them. This is not found persuasive because Applicant does not provide any objective evidence why the why the Fc-X structure taught by Lo for homodimers would not work for heterodimers. Thus, one of ordinary skill in the art would still be motivated to use the Fc-X structure for its superior orientation and there is no evidence to undermine that this orientation would not work for heterodimers. Applicant appears to be arguing that Lo and Kim are in different fields of endeavor and cannot be combined, but nevertheless, both Lo and Kim discuss fusion proteins, and someone interested in constructing fusion proteins would look at the art relevant to the arrangement of proteins and therefore, the teachings of Lo and Kim are still pertinent. Additionally, Applicant has not pointed to any technical hurdle for arranging a heterodimer given the guidance of the homodimer in Lo and so, this does not support Applicant’s argument that that the structures of Lo and Kim are incompatible. Applicant further argues that Lo contains no discussion of, and provides no guidance on, how to place two cytokine subunits on an Fc dimer, let alone sequentially on a single chain C-terminal to an Fc, how to ensure that those two subunits fold and associate with each other intramolecularly in the context of an Fc fusion, or how to engineer a second chain bearing a heterologous Fc that can associate intermolecularly with the first. This is not found persuasive because in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The Examiner did not rely upon the teachings of Lo for anything other than the motivation to put a N-terminal Fc on the monovalent protein of Bai.
On page 10 of the remarks, Applicant argues the teachings of Lo that Fc-X is generally “superior” to X-Fc is only specific to proteins that are not normally secreted or that are poorly expressed, arguing that EB13, by contrast, is itself a secreted protein, and the expression problem of Lo does not apply to EB13 or to p28, both of which are naturally secreted. This is not found persuasive because Applicant does not present any objective evidence as to why the Fc-X orientation would not work for other proteins, and just because the rejection of record didn’t use the reference for purposes of secretion doesn’t mean that the Fc-X orientation wouldn’t be applicable to other proteins. Applicant is reminded that “arguments of counsel cannot take place of factually supported objective evidence” (see MPEP §2145).
On page 10 of the remarks, Applicant argues that Lo addresses expression yield and Kim addresses in vivo half-life and that these are distinct objectives and thus, the references do not cross-reference each other or suggest that their respective approaches can or should be combined. This is not found persuasive because simply because the two references are solving different problems does not mean that they cannot be combined. Applicant does not point to any reason as to why a heterodimer cannot be arranged in the same way (i.e. Fc-X) as the homodimer of Lo. Applicant is reminded that “arguments of counsel cannot take place of factually supported objective evidence” (see MPEP §2145). Further, Applicant argues that to arrive at claim 1's architecture, an N-terminal Fc heterodimer bearing the EBl3 subunit of IL27 on the same polypeptide chain as, and N-terminal to, the p28 subunit, the skilled artisan would need to: (1) identify Lo's N-terminal Fc orientation as desirable for an IL27 construct (despite Lo's rationale not applying to IL27); (2) recognize that Lo's homodimeric Fc must be converted to a heterodimeric Fc (despite Lo providing no such teaching); (3) select a prophetic heterodimerization configuration from Kim's Fig. 2 among multiple possible heterodimeric Fc configurations; (4) apply that approach to an IL27 construct (despite Kim providing no IL27 data); (5) place both subunits on a single chain C-terminal to the Fc (despite neither Lo nor Kim testing such a configuration); and (6) place the EBl3 moiety N-terminal to the p28 moiety within the single chain. This is not found persuasive because one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The Examiner has addressed the arguments as they pertain to each of the individual references above and the response to the arguments will not be reiterated and are incorporated herein. The rejection clearly sets forth why it would have been obvious to combine the teachings with a reasonable expectation of success to arrive at the claimed construct.
On page 11 of the remarks, Applicant argues that the Office dismissed Applicant's unexpected results in legal error and that the argument in part was on the grounds that "the features upon which Applicant relies (i.e., greater signaling activity) are not recited in the rejected claim(s)” referring to Table 7 of the instant specification for support of the unexpected results, alleging that the results demonstrate that IL27M16 (a monovalent IL27 Fc fusion configured as claimed herein) results in a lower EC50 than bivalent IL27 Fc constructs, and that incorporating the EBl3 and p28 subunits of IL27 on the C-terminus of a single Fc domain resulted in increased potency (an approximately 3-fold EC50 reduction) as compared to appending them to the C-termini of separate Fe domains constructs. This is not found persuasive because Applicant has only cited a part of the Office’s argument in response to the alleged unexpected results, and to reiterate the remainder of what was stated in the office action mailed 02/13/2026 [see Page 17], “even if the claims did recite the alleged feature of greater signaling activity, the table does not depict results of a protein with the p28 and EBI3 on a single polypeptide chain with a homodimeric Fc domain. Therefore, the Examiner cannot make a determination of a trend that would lead to a conclusion of unexpected results. The burden is on Applicant to provide to the Examiner a trend proving the unexpected results. See MPEP 716.02(b).” Thus, Applicant’s arguments of unexpected results are not persuasive to rebut the 103 rejection.
On page 11 of the remarks, Applicant argues that Timans, Rudge, and UniProt do not teach, describe, suggest, or characterize any IL27 fusion protein of any kind, let alone a protein having the monovalent IL27, N-terminal Fc heterodimer with an Fc domain: EBl3 moiety stoichiometry of 2:1, as recited in claim 1, and that none of Timans, Rudge, or UniProt supplies any motivation to combine the elements of claim 1 in the manner required, any guidance toward the IL27 receptor agonist architecture of claim 1 or any reasonable references do not remedy the deficiencies of Bai, Kim,
and Lo. The previous rejection applied over Rudge is withdrawn, therefore, the arguments pertaining to this reference are moot. However, regarding the arguments against Timans and UniProt, this is not found persuasive because in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The Examiner relied upon the teachings of Timans and UniProt only for the teachings of known sequences in the art. Applicant further argues that Timans characterizes IL27 as a naturally occurring two-chain heterodimer of EBl3 and p28 held together by non-covalent interactions on separate polypeptide chains - which is precisely the opposite of the single-chain Fc-EBl3-p28 fusion architecture of claim 1, and which would direct a skilled artisan to maintain the two-subunit, separate-chain configuration rather than fuse them, and thus, since Timans teaches that IL27 naturally exists as two noncovalently
associated chains, this lends no support to and arguably discourages the claimed single chain design. First, Applicant’s argument that Timans arguably discourages the claimed single-chain design is not persuasive because this is an argument without merit. Second, this is not found persuasive because Applicant is arguing the single reference of Timans out of context. Simply because Timans teaches that IL27 naturally exists as two noncovalently associated chains, this in no way criticizes the reference of Bai which teaches a monomeric fusion protein comprised of, from N to C termini, a signal peptide, EBI3, a linker, p28 and Fc, which is monovalent for IL27. Applicant does not point to any technical reason that given the single chain of Bai one of ordinary skill in the art looking to Timans could not use the sequence of Timans for the EBI3 of Bai.
On pages 12-13, Applicant summarizes the entirety of arguments presented above. The Examiner has addressed each of the arguments and the response will not be reiterated and is incorporated herein.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Brittney E Donoghue whose telephone number is (571)272-9883. The examiner can normally be reached Mon - Fri 7:30 - 3:30.
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/B.E.D./Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
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