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 .
Applicant’s remarks, filed 1/7/2026, are acknowledged and entered into the record. Applicants amended claims 1 and 7, and canceled claim 6, in the remarks of 1/7/2026.
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. The present application is drawn from PCT/US2020/029876, filed 4/24/2020; and claims benefit under 35 U.S.C. 119(e) to U.S. Provisional applications 62/837853 and 62/837833, each filed on 4/24/2019.
Status of Claims
Claims 1-2, 7 and 86-103 are pending and are being examined on the merits.
Claim Rejections – Withdrawn
Double Patenting
The rejection of claims 1-2, 86-87, 90-92 and 96-103 on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 and 16-18 of U.S. Patent No. 12,098,190, is withdrawn. Specifically, applicants amended instant claim 1 to include the limitations of now canceled claim 6. Thus, the claims of US ‘190 no longer anticipate instant claim 1.
The rejection of claims 1-2, 6-7, 86-93 and 95-103 on the ground of nonstatutory double patenting as being unpatentable over claims 40-44, 46-54 and 57-59 of copending Application No. 18/153,720 in view of Michelfelder et al., (from IDS filed 1/11/2022, cite: 36; J. Am Soc Nephrol.; published 1/15/2018) and Bao et al., (from IDS filed 1/11/2022, cite: 14; US 2019/0071477; with priority to 12/28/2016), is withdrawn. Specifically, application 18/153,720 was abandoned on 12/16/2025, thus obviating the rejection for double patenting over the invention of application 18/153,720.
Claim Rejections – Maintained, Amended
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim Rejections
The following rejections are amended to include additional claims which are now anticipated based on applicant’s amendments to instant claim 1.
Claims 1-2, 7, 86-87, 90-92 and 96-103 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 and 16-18 of U.S. Patent No. 12,098,190 in view of Michelfelder et al., (from IDS filed 1/11/2022, cite: 36; J. Am Soc Nephrol.; published 1/15/2018).
US patent ‘190 claims an anti-human C5 antibody with the VH-CDRs 1-3 of SEQ ID NOs: 3-5, respectively, and VL-CDRs 1-3 of SEQ ID NOs: 8, 9 and 11, respectively (claim 1b); and with the VH comprising amino acid residues 20-144 of SEQ ID NO: 2 and a VL comprising amino acid residues 21-127 of SEQ ID NO: 13 (claims 2b and 3b). The CDRs, VH and VL of the anti-C5 antibody of ‘190 are 100% identical in amino acid sequence to the anti-C5 antibody moiety of instant claims 1(i) and 86(i).
US ‘190 also claims antigen binding fragments of the anti-C5 antibody (claim 4) or whereby the anti-C5 antibody is a full length antibody (claim 5); wherein the antibody comprises an Fc fragment derived from IgG4 (claim 6), wherein the IgG4 heavy chain constant domain comprises the sequence of SEQ ID NO: 32 (claim 7). Patent ‘190 claims a fusion protein comprising the anti-C5 antibody and an effector molecule (claim 8); an isolated nucleic acid encoding the antibody (claim 9), a vector comprising the nucleic acid (claim 10), wherein the vector is a viral vector (claim 11), wherein the vector is an adenovirus vector (claim 12); a host cell comprising the nucleic acid (claim 13). Patent ‘190 also claims a method of treating a complement pathway-mediated disorder comprising administering the anti-C5 antibody (claim 16) or administering the vector (claim 17), and a method of reducing the activity of a complement system of an individual comprising administering the anti-C5 antibody (claim 18).
However, patent ‘190 does not teach a fusion protein comprising the anti-C5 antibody and an FH1-4 domain; of claims 1 and 7.
Michelfelder et al. teaches the fusion protein MFHR1 as a novel basis for complement therapeutics, including for the treatment of aHUS (abstract). Michelfelder teaches that by combining proximal (C3) and terminal (C5) cascade inhibition activities, the MFHR1 fusion protein substantially inhibits alternative and classic pathway activation and offers a novel basis for therapeutics aimed at treating uncontrolled complement system activation pathologies (pg. 1141, abstract, significance statement). Michelfelder teaches that MFHR1 comprises a C5 convertase/C5b-9 inhibitory fragment of the FHR-1 (Factor H related protein-1) with the C3 regulatory and surface binding properties of FH protein (abstract); thus Michelfelder teaches a fusion protein comprising a C5 inhibitory moiety and a FH protein fragment moiety. The MFHR1 fusion protein comprises directly linking the FRH-11-2 domain, the FH1-4 domain, and the FH19-20 domain (pg. 1142, col. 2, last paragraph; pg. 1143, Fig. 1A). Michelfelder teaches the FH1-4 domain has the properties of binding C3b, decay acceleration and cofactor activity (pg. 1143, Fig. 1, legend), consistent with Fig. 44, and as described in the specifications (specs., pg. 72, lines 10-16). Michelfelder teaches the FH1-4 domain is N-terminally linked to FHR-11-2 domain, and C-terminally linked to FH19-20 domain; thus demonstrating that a FH1-4 domain may be N- or C-terminally linked in a fusion format.
It would have been obvious to one of skill in the art to combine the anti-C5 antibody and an effector molecule in the fusion protein of ‘190 (claim 8), wherein the effector molecule is a FH1-4 domain of the fusion protein MFHR1, as taught by Michelfelder et al. One would have been motived to do so given the suggestion by Michelfelder et al. that co-targeting inhibition of proximal (C3) and terminal (C5) cascades results in substantial inhibition of the complement system, and provides a basis for therapeutic strategies directed towards complement-associated diseases, such as aHUS. Also, that the anti-C5 antibody inhibits terminal (C5) cascade and that FH1-4 inhibits the proximal (C3) cascade. There would have been a reasonable expectation for success given the knowledge that MFHR1 is a fusion protein comprising an C5 inhibitory moiety and a FH1-4 domain, and that MFHR1 effectively inhibited complement pathway activity, as taught by Michelfelder et al. Thus, the invention was prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Regarding claims 1 and 7; as the instant anti-C5 antibody comprises the identical antigen binding domain of US ‘190, the modified fusion protein of ‘190 and Michelfelder claims 1-3 and 8 makes obvious the fusion protein of claim 1, wherein the fusion protein comprises an anti-C5 antibody moiety and a Factor H moiety. Further, wherein the FH moiety comprises the SCR domains of FH1-4, the modified fusion protein of ‘190 and Michelfelder makes obvious the fusion protein of claim 7.
As the instant anti-C5 antibody comprises the identical antigen binding domain of US ‘190, the modified fusion protein of ‘190 and Michelfelder, claims 1-3 and 8, anticipates the fusion protein of instant claims 1 and 86, and possesses the inherent pH dependent properties of the anti-C5 antibody of instant claim 2. US ‘190 claim 4 anticipates instant claim 87; ‘190 claim 5 anticipates instant claim 90; ‘190 claims 6-7 anticipate instant claims 91-92; ‘190 claims 9-13 anticipate instant claims 96-99; ‘190 claims 16-18 anticipate instant claims 100-103.
Claims 1-2, 7, 86-103 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 and 16-18 of U.S. Patent No. 12,098,190; published 9/24/2024 in view of Michelfelder et al., (from IDS filed 1/11/2022, cite: 36; J. Am Soc Nephrol.; published 1/15/2018) and Bao et al., (from IDS filed 1/11/2022, cite : 14; US 2019/0071477; with priority to 12/28/2016).
The reasons why claims 1-2, 7, 86-87, 90-92 and 96-103 are anticipated by US Patent ‘190 over Michelfelder are described above. Specifically, US patent ‘190 claims an anti-human C5 antibody with the VH-CDRs 1-3 of SEQ ID NOs: 3-5, respectively, and VL-CDRs 1-3 of SEQ ID NOs: 8, 9 and 11, respectively (claim 1b); and with the VH comprising amino acid residues 20-144 of SEQ ID NO: 2 and a VL comprising amino acid residues 21-127 of SEQ ID NO: 13 (claims 2b and 3b). The CDRs, VH and VL of the anti-C5 antibody of ‘190 are 100% identical in amino acid sequence to the anti-C5 antibody moiety of instant claims 1(i) and 86(i). Thus, US ‘190 claims the identical anti-C5 antibody moiety of the instant claims, and further claims the anti-C5 antibody moiety as a fusion protein (claim 8). Michelfelder teaches a fusion protein may comprise an FH1-4 domain.
However, the combination of US ‘190 and Michelfelder do not teach wherein the FH1-4 domain is fused to the C-terminus of one, or both, of the anti-C5 antibody heavy chain, with or without a linker (claims 88-89, 93 and 95).
Bao et al. teaches recombinant complement factor H-immunoglobulin fusion protein with complement regulatory activity (title). Bao teaches the FH domain is linked to an IgG Fc domain (see Fig. 1). Bao teaches the FH-Ig fusion protein may comprise the SCR (1-4) domain of FH (pg. 3, para. 0031). Bao teaches the order of arrangement of the FH portion and the Fc portion of the FH-Ig fusion protein may be that the Fc portion is at the N-terminus and the FH portion is at the C-terminus, i.e., Fc-FH (pg. 4, para. 0041). Bao teaches that in some embodiments the FH portion and the Fc portion are covalently linked; the covalent linker may be a peptide linker, such as (G4S)n. The covalent linker can also be a peptide bond connecting the FH part and the Fc part (pg. 4, para. 0041); whereby when n is 0, it means that the two parts of the fusion protein are linked by peptide bonds and not by the linker peptide (pg. 5, para. 0043). Regarding valency, Bao teaches that the fusion protein is at least bivalent, meaning at least two FH fragments in a single fusion protein, and a disulfide bond paring between two Fc fragments, resulting in a symmetric, antibody-like fusion protein (pg. 5, para. 0045; Fig. 1). Thus, Bao teaches FH-Ig-Fc fusion proteins whereby the FH regions are linked to each of the heavy chain Fc C-terminal domains, resulting in symmetric heavy chain Fc-FH domains; and whereby the coupling is direct (via peptide bonds) or via a peptide linker.
It would have been obvious to one of skill in the art to modify the format of the fusion protein of US ‘190 and Michelfelder to comprise a FH1-4 domain linked to each heavy chain C-terminal of the anti-C5 antibody, either directly or via a peptide linker. One would have been motivated to do so to optimize the format to produce the desired properties of the fusion protein. There would have been a reasonable expectation for success given that multiple FH fragment domains may be linked to the N- or C-terminal of each IgG Fc domain, directly or via a peptide linker, as taught by Bao et al.
Thus, Bao et al. teaches IgG-FH fusion proteins, wherein the FH moiety is the FH1-4 domain, whereby a FH domain may be attached to the C-terminus of each of the Fc heavy chain constant regions, with or without a linker. Therefore, the modified fusion protein of US ‘190 and Michelfelder, in the format of Bao, makes obvious instant claims 88-89, 93 and 95.
Regarding claim 94; the amino acid residues 20-471 of SEQ ID NO: 72 correspond to the VH of SEQ ID NO: 59 (residues 20-144; of claim 86(xi)) and the Fc domain of SEQ ID NO: 61 (residues 145-471; of claim 92). Likewise, the amino acid residues 21-234 of SEQ ID NO: 74 correspond to the VL of SEQ ID NO: 25 (residues 21-127; of claim 86(xi)) and the human kappa constant domain (residues 128-234). US ‘190 SEQ ID NOs: 59 and 25, of claim 2(a) are 100% identical to instant SEQ ID NOs: 59 and 25; and US ‘190 SEQ ID NO: 61, of claim 7(d), is 100% identical to instant SEQ ID NO: 61. Thus, the combination of US ‘190 claims 2(a) and 7(d), Michelfelder and Bao, makes obvious instant claim 94.
Response to Arguments
Applicant's arguments filed 1/7/2026 have been fully considered but they are not persuasive. Applicants amended instant claim 1 to include the various fusion protein partners of now canceled claim 6, including a Factor H (FH) or fragment thereof. Applicants contend that Michelfelder is not a fusion protein comprising an anti-C5 antibody and thus there is no teaching or suggestion in Michelfeder of a fusion protein comprising an anti-C5 antibody (remarks, pg. 12, paras. 3-5). Further, applicants contend that Michelfelder teaches a different fusion protein, not comprising an anti-C5 antibody, and that different proteins have different biochemical properties. Thus, as Michelfelder requires functionality, including wherein the fusion protein does not display steric hinderance, and whereby the fusion protein of Michelfelder does not functionally and specifically bind to human C5, there is no reasonable expectation for success for the skilled artisan combining the teachings of US ‘190, Michelfelder and Bao to obtain a fusion protein with an anti-C5 antibody and a fusion protein partner (remarks, pg. 13, paras. 1-3).
In response, the examiner re-iterates that US ‘190 recites anti-C5 antibodies which comprise the CDRs of SEQ ID NOs: 3-5 and 8, 9 and 11 with 100% amino acid sequence identity, in claim 1b. Further, US ‘190 claims a fusion protein comprising the anti-human C5 antibody of claim 1b. Michelfelder teaches alternative fusion proteins comprising an FH domain, as a fusion protein partner. Bao teaches antibodies comprising the FH domain (of Michelfelder), whereby the FH domain is linked to one (or both) of the C-terminus of an antibody Fc domain. Thus, the combination of references teach every component of the instantly claimed fusion protein.
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). Engineering fusion proteins, or immunoconjugates, comprising an antibody, or the antigen-binding fragment thereof, are well known techniques in the art; thus, the point of novelty of the fusion proteins of US ‘190 are the specific structural domains of the anti-C5 antibody moiety of the fusion protein. Michelfelder teaches FH1-4 as fusion protein partners; and Bao teaches FH1-4 fragments may be attached to an antibody Fc C-terminus as an immunoconjugate. As the fusion proteins of the instant invention comprise an identical anti-C5 antibody moiety, regarding the CDRs of the binding domain, of US ‘190, and further comprise a FH1-4 fragment, as was described in the art by Michelfelder and Bao, there is not a novel inventive concept or structural component that patentably differentiates the fusion protein of the instant claims from the corresponding invention of US ‘190. That is, there is no additional property to the instant fusion proteins that would offer an alternative point of novelty over any other fusion protein or immunoconjugate which comprises the anti-C5 antibody moiety of US ‘190. As Bao teaches linking the FH fragments to the C-terminus of any antibody, there is more than a reasonable expectation for success in linking the FH fragments to the anti-C5 antibodies of US ‘190, either as an immunoconjugate or as a fusion protein. Thus, the antibody of US ‘190, over Michelfelder and Boa, clearly make obvious the fusion protein of the instant claims, because the instant claims rely on the same point of novelty, over the art, of the anti-C5 antibodies of US ‘190, with art-recognized fusion protein partners included in the immunoconjugates of US ‘190. Applicant’s arguments are not found persuasive; therefore the rejections are maintained.
Claims 1-2, 7, 87, 90-92 and 101-103 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3 and 11-14 of U.S. Patent No. 11,578,137; issued 2/14/2023, in view of Sampei et al., (from IDS filed 1/11/2022, cite: 23; WO 2017/104779; published 6/22/2017) and Michelfelder et al., (from IDS filed 1/11/2022, cite: 36; J. Am Soc Nephrol.; published 1/15/2018).
US patent ‘137 claims an anti-human C5 antibody with the VH-CDRs 1-3 of SEQ ID NOs: 3-5, respectively, and VL-CDRs 1-3 of SEQ ID NOs: 8, 9 and 10, respectively (claims 1(a) and 3). The CDRs of the anti-C5 antibody of US ‘137 are 100% identical in amino acid sequence to the anti-C5 antibody moiety of instant claims 1(xv), wherein the antibody moiety comprises the CDRs of instant SEQ ID NOs: 3-5 and 8-10, respectively.
US patent ‘137 also claims a method of treating a complement pathway-mediated disorder comprising administering the anti-C5 antibody (claim 11), wherein the disorder is atypical hemolytic uremic syndrome (aHUS; claim 12), and a method of reducing the activity of a complement system of an individual comprising administering the anti-C5 antibody (claim 13), wherein the antibody of the method is an antibody fragment (claim 14).
However, US ‘137 does not claim a fusion protein comprising the anti-C5 antibody or a fragment thereof, and a fusion protein partner.
Sampei et al. teaches anti-C5 antibodies and methods of use (title). Sampei teaches that antibodies targeting C5 are approved for the treatment of atypical hemolytic uremic syndrome (aHUS; pg. 3, para. 0014); however antibodies with altered pH-dependent binding eliminate antigens from plasma more rapidly than typical antibodies because they dissociate from the antigen within the endosome during recycling process (pg. 4, para. 0017). Specifically, Sampei teaches an anti-C5 antibody which binds to an epitope within the beta chain of C5 with higher affinity at neutral pH than at acidic pH. Sampei teaches the anti-C5 antibody may be a bi- or multi-specific antibody including recombinant co-expression of two immunoglobulins having different specificities (pg. 15, para. 0046; pg. 47, para. 0162). Sampei teaches the anti-C5 antibody may be an antibody fragment, (e.g., a Fv, Fab or scFv), or may be a full length antibody, or may comprise an Fc derived from human IgG4 (pg. 41, para. 0141). Sampei also teaches the anti-C5 antibodies as immunoconjugates, wherein the antibody is conjugated to one or more heterologous molecules, including but not limited to a cytotoxic agent (pg. 18, para. 0064; pg. 64, para. 0230), or an enzymatically active toxin, which includes proteins and polypeptides encoding said proteins (pg. 65, para. 0232).
It would have been obvious to one of skill in the art to substitute the anti-C5 antibody moiety of US ‘137 into the anti-C5 antibody domain of the immunoconjugates of Sampei et al. There would have been a reasonable expectation for success given that the anti-CD5 antibody of Sampei and the anti-CD5 antibody of US ‘137 are alternative species of the genus of anti-CD5 antibodies which may be substitutable for the same purpose.
The combination of US ‘137 and Sampei et al. teaches an anti-C5 antibody, or fragment thereof, as an immunoconjugate, comprising a fusion protein partner, as described above. However, Sampei does not teach wherein the fusion protein partner is a Factor H (FH) or a fragment thereof.
Michelfelder et al. teaches the fusion protein MFHR1 as a novel basis for complement therapeutics, including for the treatment of aHUS (abstract). Michelfelder teaches that by combining proximal and terminal cascade inhibition activities, the MFHR1 fusion protein substantially inhibits alternative and classic pathway activation and offers a novel basis for therapeutics aimed at treating uncontrolled complement system activation pathologies (pg. 1141, abstract, significance statement). Michelfelder teaches that MFHR1 comprises a C5 convertase/C5b-9 inhibitory fragment of the FHR-1 (Factor H related protein-1) with the C3 regulatory and surface binding properties of FH protein (abstract); thus Michelfelder teaches a fusion protein comprising a C5 inhibitory moiety and a FH protein fragment moiety. The MFHR1 fusion protein comprises directly linking the FRH-11-2 domain, the FH1-4 domain, and the FH19-20 domain (pg. 1142, col. 2, last paragraph; pg. 1143, Fig. 1A). Michelfelder teaches the FH1-4 domain has the properties of binding C3b, decay acceleration and cofactor activity (pg. 1143, Fig. 1, legend), consistent with Fig. 44, and as described in the specifications (specs, pg. 72, lines 10-16). Michelfelder teaches the FH1-4 domain is N-terminally linked to FHR-11-2 domain, and C-terminally linked to FH19-20 domain; thus demonstrating that a FH1-4 domain may be N- or C-terminally linked in a fusion format.
It would have been obvious to one of skill in the art to modify the anti-C5 antibody immunoconjugate of the combination of US ‘137 and Sampei et al. to comprise a FH1-4 domain, thus arriving at an anti-C5 antibody-FH1-4 domain fusion protein. One would have been motivated to do so given the suggestion by Michelfelder et al. that co-targeting inhibition of proximal (C3) and terminal (C5) cascades results in substantial inhibition of the complement system, and provides a basis for therapeutic strategies directed towards complement-associated diseases, such as aHUS. There would have been a reasonable expectation for success given the knowledge that MFHR1 is a fusion protein comprising an C5 inhibitory moiety and a FH1-4 domain, and that MFHR1 effectively inhibited complement pathway activity, as taught by Michelfelder et al. Thus, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made.
The anti-C5 antibody-FH fusion protein of the combination of US ‘137 claims 1 and 3, Sampei and Michelfelder makes obvious the fusion protein of instant claim 1 (embodiment xv), and whereby the anti-C5 antibody binds to C5 with a higher affinity at neutral pH than at acidic pH, of instant claim 2. US ‘137 claims 1 and 3, Sampei and Michelfelder make obvious wherein the fusion protein partner comprises FH or a fragment thereof, and wherein the fragment is a FH1-4 domain, of claim 7. US ‘137 claims 1, 3 and 14, in view of Sampei and Michelfelder, make obvious the use of antibody fragments of instant claim 87 or the full length antibody of instant claim 90; and wherein the antibody comprises a Fc derived from human IgG4 of instant claim 91. The specifications describe SEQ ID NO: 32 as an example amino acid sequence of a human IgG4 constant heavy chain (pg. 69, line 25); thus the human IgG4 Fc of the anti-C5 antibody of US ‘137 claims 1, 3 and 14, in view of Sampei and Michelfelder, makes obvious instant claim 92. The methods of US ‘137 claims 11-14, in view of Sampei and Michelfelder, make obvious the methods of instant claims 101-103.
Claims 1-2, 7, 87-93, 95 and 101-103 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3 and 11-14 of U.S. Patent No. 11,578,137; issued 2/14/2023, in view of Sampei et al., (from IDS filed 1/11/2022, cite: 23; WO 2017/104779; published 6/22/2017) and Michelfelder et al., (from IDS filed 1/11/2022, cite: 36; J. Am Soc Nephrol.; published 1/15/2018) and Bao et al., (from IDS filed 1/11/2022, cite: 14; US 2019/0071477; with priority to 12/28/2016).
The reasons why the combination of US ‘137 claims 1, 3 and 14, in view of Sampei and Michelfelder, make obvious instant claims 1-2, 7, 87, 90-92 and 101-103 are described above. However, the combination of US ‘137, Sampei and Michelfelder do not teach wherein the FH1-4 domain is fused to the C-terminus of one, or both, of the anti-C5 antibody heavy chain, with or without a linker (claims 88-89, 93 and 95).
Bao et al. teaches recombinant complement factor H-immunoglobulin fusion protein with complement regulatory activity (title). Bao teaches the FH domain is linked to an IgG Fc domain (see Fig. 1). Bao teaches the FH-Ig fusion protein may comprise the SCR (1-4) domain of FH (pg. 3, para. 0031). Bao teaches the order of arrangement of the FH portion and the Fc portion of the FH-Ig fusion protein may be that the Fc portion is at the N-terminus and the FH portion is at the C-terminus, i.e., Fc-FH (pg. 4, para. 0041). Bao teaches that in some embodiments the FH portion and the Fc portion are covalently linked; the covalent linker may be a peptide linker, such as (G4S)n. The covalent linker can also be a peptide bond connecting the FH part and the Fc part (pg. 4, para. 0041); whereby when n is 0, it means that the two parts of the fusion protein are linked by peptide bonds and not by the linker peptide (pg. 5, para. 0043). Regarding valency, Bao teaches that the fusion protein is at least bivalent, meaning at least two FH fragments in a single fusion protein, and a disulfide bond paring between two Fc fragments, resulting in a symmetric, antibody-like fusion protein (pg. 5, para. 0045; Fig. 1). Thus, Bao teaches FH-Ig-Fc fusion proteins whereby the FH regions are linked to each of the heavy chain Fc C-terminal domains, resulting in symmetric heavy chain Fc-FH domains; and whereby the coupling is direct (via peptide bonds) or via a peptide linker.
It would have been obvious to one of skill in the art to modify the format of the fusion protein of US ‘137, Sampei and Michelfelder to comprise a FH1-4 domain linked to each heavy chain C-terminal of the anti-C5 antibody, either directly or via a peptide linker. One would have been motivated to do so to optimize the format to produce the desired properties of the fusion protein. There would have been a reasonable expectation for success given that multiple FH fragment domains may be linked to the N- or C-terminal of each IgG Fc domain, directly or via a peptide linker, as taught by Bao et al.
Thus, Bao et al. teaches IgG-FH fusion proteins, wherein the FH moiety is the FH1-4 domain, whereby a FH domain may be attached to the C-terminus of each of the Fc heavy chain constant regions, with or without a linker. Therefore, the modified fusion protein of US ‘137, Sampei, and Michelfelder, in the format of Bao, makes obvious instant claims 88-89, 93 and 95.
Response to Arguments
Applicant's arguments filed 1/7/2026 have been fully considered but they are not persuasive. Applicants contend that Sampei teaches the anti-C5 antibodies may be conjugated to one or more “heterologous molecules”, and that does not teach or suggest a fusion protein comprising a complement system protein fusion partner (e.g. FH), because Sampei never discloses that the fusion partner may be a complement system protein (remarks, pg. 14 last paragraph – pg. 15 top paragraph). Further, applicants contend that Michelfelder is not a fusion protein comprising an anti-C5 antibody and thus there is no teaching or suggestion in Michelfeder of a fusion protein comprising an anti-C5 antibody (remarks, pg. 15, paras. 2-3). Applicants contend that Michelfelder teaches a different fusion protein, not comprising an anti-C5 antibody, and that different proteins have different biochemical properties. Thus, as Michelfelder requires functionality, including wherein the fusion protein does not display steric hinderance, and whereby the fusion protein of Michelfelder does not functionally and specifically bind to human C5, there is no reasonable expectation for success for the skilled artisan combining the teachings of US ‘137, Sampei and Michelfelder to obtain a fusion protein with an anti-C5 antibody and a fusion protein partner; and that Sampei does not remedy the deficiencies of Michelfelder (remarks, pg. 16, paras. 2-3). Further, applicants contend that Bao does not cure the deficiencies of Sampei and Michelfelder (remarks, pg. 17, para. 4).
In response, the examiner reiterates that US ‘137 recites anti-C5 antibodies which comprise the CDRs of SEQ ID NOs: 3-5 and 8-10 with 100% amino acid sequence identity, in claim 1(XV). Sampei teaches pH-dependent anti-C5 antibodies for use in treatments of complement system disorder, whereby the antibodies may be immunoconjugates, wherein the antibody is conjugated to one or more heterologous molecules, including but not limited to a cytotoxic agent, or an enzymatically active toxin, which includes proteins and polypeptides encoding said proteins. Sampei does not require the immnoconjugate to be a cytotoxic agent; rather, Sampei teaches the art of modifying anti-C5 antibodies as immunoconjugates comprising a heterologous molecule, which encompasses anti-C5 fusion proteins.
Michelfelder teaches alternative fusion proteins comprising an FH domain, as a fusion protein partner. Bao teaches antibodies comprising the FH domain (i.e., of Michelfelder), whereby the FH domain is linked to one (or both) of the C-terminus of an antibody Fc domain (i.e., of the anti-C5 antibodies of Sampei). Thus, the combination of references teaches every component of the instantly claimed fusion protein. 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). Engineering fusion proteins, or immunoconjugates, comprising an antibody, or the antigen-binding fragment thereof, are well known techniques in the art; thus, the point of novelty of the invention of US ‘137 are the specific structural domains of the anti-C5 antibody moiety of the fusion protein. Sampei teaches pH-dependent anti-C5 antibodies which may be fusion proteins comprising a fusion protein partner. Michelfelder teaches FH1-4 as fusion protein partners; and Bao teaches FH1-4 fragments may be attached to an antibody Fc C-terminus as an immunoconjugate. As the fusion proteins of the instant invention comprise an identical anti-C5 antibody moiety, regarding the CDRs of the binding domain, of US ‘137, and further comprise a FH1-4 fragment, as was described in the art by Michelfelder and Bao, there is not a novel inventive concept or structural component that patentably differentiates the fusion protein of the instant claims from the corresponding invention of US ‘137 in view of Sampei, Michelfelder and Bao. That is, there is no additional property to the instant fusion proteins that would offer an alternative point of novelty over any other fusion protein or immunoconjugate which comprises the anti-C5 antibody moiety of US ‘137. As Bao teaches linking the FH fragments to the C-terminus of any antibody, there is more than a reasonable expectation for success in linking the FH fragments to the anti-C5 antibodies of US ‘137, either as an immunoconjugate or as a fusion protein. Thus, the antibody of US ‘137, over the anti-C5 immunoconjugates of Sampei, comprising the fusion protein partner of Michelfelder, and formatted according to Bao, clearly make obvious the fusion protein of the instant claims, because the instant claims rely on the same point of novelty, over the art, of the anti-C5 antibodies of US ‘137. Applicant’s arguments are not found persuasive; therefore the rejections are maintained.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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/JAMES RYLAND MELCHIOR/Examiner, Art Unit 1644
/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642