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 .
Status of Claims
Claims 1-2, 4-13, and 15-22 are currently pending.
Drawings
The drawings are objected to because Fig. 3 fails to show the labels A, C, E, and G as are described in the specification in lines 7-12 on pg. 34. The data represented in Fig. 3F also does not appear to correspond to the data presented in the graph directly to the left of Fig. 3F. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
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, 4-13, 15-17, and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Bao and Lou in WO 2017/114401A1 published on July 6, 2017 and Liu et al. in US 7,994,117 B2 published on August 9, 2011; alone or as evidenced by Aslam et al. J Mol Biol. 2001. 309: 1117-1138, Vidarsson et al. Front. Immunol. 2014. 5:520, and Davis et al. J Rheumatol. 2007. 34:11.
Applicant’s arguments filed Nov. 13, 2025 have been fully considered but they are not persuasive.
On pg. 8 in the last ¶ spanning pg. 9 Applicant states “Bao teaches… linking the two Fc elements together through at least one disulfide bond.” In the same ¶ Applicant alleges “Bao does not teach a single disulfide bond on the Fc portion and certainly does not teach no disulfide bonds in the Fc portion… Bao fails to teach… at most one cysteine residue forming a disulfide bridge[.]” Examiner respectfully points out that a teaching of “at least one disulfide bond” teaches the limitation of “a single disulfide bond,” and Applicant agrees that Bao and Lou teach “at least one disulfide bond”. In response to Applicant’s argument that “Bao… encourages several disulfide bonds when reviewing the document as a whole,” consider MPEP 2123 I: “A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989).” Nevertheless, the rejection of record additionally relies on the combination of Bao with Liu’s teachings that one or more cysteines of Fc can be mutated to Ala or Ser, reducing or eliminating the number of disulfide bonds without preventing Fc monomers from dimerizing through non-covalent interactions (cols. 13-14 in lines). 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).
Applicant alleges that “the Office Action has not established that a person of ordinary skill in the art at the time of filing the present application would go searching for teachings related to altering the Fc portion of Bao’s fusion protein.” (Remarks on pg. 9 in the last ¶). The presumption that a skilled artisan would had to have been motivated by a primary reference to “go searching for” teachings is not within the scope of considerations for obviousness analysis and is completely reliant on piecemeal analysis, contradicting the well-established precedent cited supra that one cannot show nonobvious by attacking references individually where the rejections are based on combinations of references. The question of law is whether the skilled artisan in view of the scope and content of the prior art and given the level of ordinary of skill in art would have found the invention as a whole obvious and it requires evidence of motivation to change a base device (see, e.g., Applicant’s citation of the Graham v. Deere inquiries on pg. 7 of the remarks); it is not whether the skilled artisan, given one reference, would have been motivated to go searching for additional teachings on relevant subject matter for the purpose of combining said teachings. The rejection over Bao in view of Liu is on the basis that, when the scope and content of teachings found in the prior art regarding Fc fusion proteins is taken into consideration, one having ordinary skill would have found the instant invention as a whole obvious in view of the explicit teachings of record prompting the skilled artisan to modify an Fc construct to have single or no disulfide bonds in Fc fusion proteins. The teachings of Liu are within the same field of endeavor as Bao, generally Fc fusion proteins, and further support the fact that a skilled artisan would have been motivated by explicit teachings found in multiple references within the same field of endeavor to construct the instantly claimed invention. The Examiner has found these facts sufficient to support a prima facie case of obviousness at least on the grounds that a person having ordinary skill would have found it obvious to try mutating IgG hinge cysteines in the construction of Bao’s Fc-SCR(1-7)-SCR(18-20).
Applicant explicitly disregards the teachings of Davis as it may pertain to findings of obviousness since Davis was not previously included in the rejection header (Remarks pg. 9 in the last ¶). While Examiner holds that the instant invention is obvious over the previously cited prior art references, Davis is cited herein in the rejection header. Davis teaches that removing hinge cysteines in IgG fusion proteins dampens complement activation, a desirable outcome for a construct intended to inhibit complement activity. MPEP 2144 I. states: “The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992); see also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); Ex parte Clapp, 227 USPQ 972 (Bd. Pat. App. & Inter. 1985) (examiner must present convincing line of reasoning supporting rejection); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning).” While the Examiner asserts that the references cited previously in the rejection header are sufficient to establish such a case, if nothing other than through reliance on an “obvious to try rationale,” it is noteworthy and appropriate to consider that these references are not necessarily representative of the full scope of relevant scientific knowledge that would have been apparent to the skilled artisan upon reading the disclosures of Bao and Liu, thus Davis has been cited in the rejection header. Note well, Davis was published in 2007, over a decade prior to the instant filing date, and the scientific principles contained therein would have been well-established by the time of the instant filing date. Whether or not Davis was cited, relied upon, or necessary in the rejection header, the evidence of record tends to indicate that the skilled artisan would have known the scientific principle that an effect of removing hinge cysteines is reducing complement activity, which would have been implied or, at least been apparent to the skilled artisan, from reading Liu’s explicit suggestions to modify the number of Fc cysteine residues.
Where Applicant alleges that “Liu does not provide a reason for removing cysteines to prevent disulfide bonds accept in an effort to form a monomer fusion protein.” Examiner respectfully disagrees and submits that this is not what the ordinarily skilled artisan would have understood from reading Liu’s discussion on removing cysteine residues. Col. 13 in lines 62-66 of Liu state: “Even if the Cys residues that normally form disulfide bonds in the Fc dimer are removed or replaced by other residues, the monomeric chains will generally dimerize through non-covalent interactions.” Thus, it is not clear how one would conclude that the skilled artisan would only apply Liu’s teachings on removing cysteine “accept in an effort to form monomer fusion protein.” Indeed, Liu suggests removing cysteines and teaches that doing so still results in dimerization. Moreover, and relevant to the foregoing discussion of Davis’s teachings on the effect of mutating hinge residues on reducing complement activity, in the same paragraph that Liu discusses removing cysteines Liu also discusses that modification can be made to “ablate the complement (C1q) binding site.” (see col. 14 in lines 47-61). According to MPEP 2141.03, the skilled artisan “is a hypothetical person who is presumed to have known the relevant art at the relevant time” and “it is also take into account ‘the inferences and creative steps that a person of ordinary skill in the art would employ.’ [KSR Int’l Co. v. Teleflex Inc.] at 418, 82 USPQ2d at 1396.” Thus, considering the level of ordinary skill in the art, the skilled artisan, knowing the relevant art at the relevant time, i.e. Davis, would have known that modifying hinge residues as taught by Liu reduces complement activity. Indeed, it is appropriate to conclude that a skilled artisan reading Liu would have been able to infer this advantage based on their knowledge of the art and the level of ordinary skill (generally, the skilled artisan, a scientist or physician, has at least one post-graduate degree in Molecular Biology, Biochemistry, Medicine, or a related field). In conclusion, a skilled artisan reading Liu would not have understood teaching on removing cysteine to apply to producing Fc monomers, rather it was evident that Liu pointed the skilled artisan toward a modification that was reasonably within the skilled artisan’s understanding as advantageous for applying to the Fc-SCR(1-7)-SCR(18-20) of Bao.
On pg. 9 of the Remarks in last ¶, Applicant cites Liu in col. 15, lines 3-11 discussing covalently linking an addition moiety to Fc to further improve half-life. It is not clear without further explanation how the cited portion of Liu rebuts the prima facie case. For example, this portion of Liu contemplates additional modification to improve half-life and does not discuss linking such moieties covalently through a disulfide bridge between a cysteine in the Fc protein. Indeed, Liu states these are modifications “other than insertions, deletions, or substitutions” and encompass the breadth of possible covalent bonds formed between amino acids other than cysteine on the structure of Fc proteins. Thus, the cited portion of Liu does not teach away from the instantly claimed invention nor does the cited portion overcome the preponderance of evidence supporting the prima facie case of obviousness.
In response to Applicant’s discussion on Liu’s preferred embodiments and working examples that contain more than one disulfide bridge, (pg. 9 in the last ¶) Examiner, again, notes “A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989).” Neither Bao nor Lui teach away from reducing hinge mutations as they do not discredit or other disparage doing so. Rather, Bao and Liu demonstrate that such modifications were within the level of skill at the time of instant filing and are, if not explicitly suggested as advantageous, then reasonably implied as useful in constructing Fc fusion proteins. In view of the foregoing discussions, a person having an ordinary level of skill in the art would have inferred an advantage to reducing the number of cysteines in the Fc region of Bao’s Fc-SCR(1-7)-SCR(18-20).
Examiner thanks Applicant for interview held on December 15, 2025 and the discussion regarding arguments of unexpectedly high activity when the FcRn binding module is fused to the N-terminus of relevant CCP containing constructs compared fusion at the C-terminus. The following remain an impediment to persuasively supporting patentability with said arguments:
#1 The evidence of record does not consistently point toward unexpectedly high properties resulting from fusion of a FcRn binding module N-terminal of the second CCP module.
#1A. It appears that the graph of Fig. 3F may inadvertently replicated Fig. 3D. Figure 3 is represented below with added annotation emphasizing incongruency between the scale of the y-axis and concentration.
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As an initial matter, it is noted that the difference between Fc-miniFH and Fc-miniFH-short is the removal of N-terminal amino acids in the IgG Fc sequence. (Fc-miniFH-short having SEQ ID NO: 8 has N-terminal “GGPSVFLFPPKPKDTL….”; whereas Fc-miniFH having SEQ ID NO: 10 has N-terminal “CPAPELLGGPSVFLFPPKPKDTL..”). The N-terminal cysteine residue of Fc-miniFH forms a single disulfide bond with another Fc comprising the hinge sequence. However, since Fc-miniFH-short does not have any hinge cysteine residues, Fc-mini-FH-short lacks interchain disulfide bonds.
The instant specification at lines 7-12 on pg. 34 describes Figs. 3B, D, F, and H as the “respective” concentration response plots. However, to what each graph is respective is unclear because while the specification states that Figs. 3A, C, E, and G are SPR sensorgrams for C3b, but Fig. 3 does not show any graphs labeled with A, C, E, or G.
If Fig. 3F is, as shown, accurately representative of C3b binding by Fc-miniFH, the evidence indicates that there is no improved C3b binding by fusing IgG Fc to the N-terminus rather than the C-terminus (i.e. miniFH-Fc in Fig. 3D and Fc-miniFH in 3F shown the same results), unless residues at the N-terminus of the IgG Fc sequence, including the remaining cysteine forming a single disulfide bond, have been deleted as shown in Fig. 3H’s depiction of C3b binding to Fc-miniFH-short. Additionally, there would be no clear correlation between the improved erythrocyte lysis inhibition of Fc-miniFH shown in Fig. 4 and the ability to bind C3b.
The KD values shown in each of Figs. 3B, D, F, and H as well as description of results in the instant specification on pg. 38 in lines 16-17 suggest that Fc-miniFH performs similarly to Fc-miniFH-short. If Fig. 3F is an inadvertent copy of Fig. 3D and the graph depicted to the left of 3F is a more accurate representation of C3b binding to Fc-miniFH, then the data would be interpreted in support of a conclusion that it is the fusion of IgG Fc to the N-terminus, rather than complete removal of disulfide bonds, that results in improved properties.
#1B. In Figs. 6-7, fusion of IgG Fc to the N-terminus of DAF CCP domains 1-4 results in improved C3b binding over fusion to the C-terminus. DAF CCP domains 1-4 are, as defined by the claims, a first CCP module. The construct in Figs. 6-7 lacks a second CCP module defined by the claims. Thus, the evidence does not support that the fusion of any FcRn binding module N-terminal of a second CCP module, as is claimed, results in unexpectedly high C3b and erythrocyte lysis inhibition.
#1C. Figs. 10 and 11 of Bao further demonstrate an inconsistency of the record regarding unexpected properties from fusing an FcRn binding module N-terminal of a second CCP module as defined in the claims. (see accompanying description in US 2019/0071477 A1 deemed an English Translation on pg. 2 in ¶ [0021] and pg. 3 in ¶ [0022]). Bao in Figs. 10 and 11 shows that IgG Fc fused C-terminal of FH CCPs 1-4 in the absence of a second CCP module results in improved C3b and erythrocyte lysis binding over CFH and CCPs(1-7)-CCPs(18-20)-Fc. Thus, one of ordinary skill would not be able to extrapolate that the effect of improved C3b binding and erythrocyte inhibition is due to fusing Fc N-terminal of a first CCP module alone, let alone fusion N-terminal of a second CCP. The data in instant Figs. 6-7 regarding ablation of activity with DAF(1-4)-Fc in view of Bao and Lou’s results showing that FH(1-4)-Fc improves C3b binding and erythrocyte lysis show that positive results from one decay accelerating CCP source (e.g. FH) cannot consistently be extrapolated to a different CCP source (e.g. DAF). In conclusion, Bao and Lou do not support generalizing consistently improved properties resulting from fusion of a FcRn binding module N-terminal of the second CCP module between different CCP module sources.
#2 The arguments and evidence supporting unexpectedly high C3b binding and inhibition of erythrocyte lysis are not commensurate in scope with the instant claims.
“The nonobviousness of a broader claimed range can be supported by evidence based on unexpected results from testing a narrower range if one of ordinary skill in the art would be able to determine a trend in the exemplified data which would allow the artisan to reasonably extend the probative value thereof. In re Kollman, 595 F.2d 48, 201 USPQ 193 (CCPA 1979).”
The scope of the instant claims encompasses a functionally claimed genus of “modules” which bind to FcRn. Naturally occurring members of this genus are IgG Fc and albumin. However, the evidence of record only shows that IgG Fc fused to the N-terminus of miniFH or miniFHshort or DAF(1-4) results in increased C3b binding and inhibition of erythrocyte lysis compared to fusion at the C-terminus. Additionally, the scope of instant claims does not require that the FcRn binding module is N-terminal of the first CCP module. However, the only results supporting the allegations of unexpectedly high properties are fusion of IgG Fc either N-terminal of both a first and second CCP module (Fc-miniFH) or fusion N-terminal of only a fist CCP (Fc-DAF1-4).
En arguendo, assume that Figs. 3 and 4 did actually support unexpectedly high properties for the scope of IgG Fc fused N-terminal of a first CCP module comprising Factor H CCPs 1-4 which is fused N-terminal of a second CCP module comprising Factor H CCPs 19-20. In view of the inconsistency in results between the instant specification’s DAF(1-4)-Fc and Bao and Lou’s Factor H(1-4)-Fc constructs, the skilled artisan would not have been able to reasonably extend the probative value of results of the instant specification for the full scope of the claimed multi-module polypeptides. Since fusion of Fc C-terminal of DAF(1-4) has dramatically different C3b and erythrocyte lysis inhibition compared to fusion of Fc C-terminal of FH(1-4), one would not be able to reasonably extrapolate that fusion of Fc N-terminal would reliably result in the same improved properties for the full range of multi-module polypeptides encompassed by the instant claims. Moreover, it is clear from the foregoing comparison between the instant Figs. 6-7 and Bao’s Figs. 10-11 that the results regarding Fc fusion to only a first CCP module cannot reasonably extend to the scope of the instant claims which require a second CCP module and do not require that the FcRn binding module is N-terminal of the first CCP module.
In conclusion, when Applicant’s arguments are taken as a whole and weighed against the evidence supporting the prima facie case of unpatentability, the instant claims, by a preponderance of evidence, remain unpatentable. See M.P.E.P. § 716.01(d).
Claims 1 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Bao and Lou in WO 2017/114401 A1 published on July 6, 2017 in view of Liu et al. in US 7,994,117 B2 published on August 9, 2011 as applied to instant claim 1 above, and further in view of Holers and Ristano in US 2013/0029912 A1 published on January 13, 2013; alone or as evidenced by Aslam et al. J Mol Biol. 2001. 309: 1117-1138, Vidarsson et al. Front. Immunol. 2014. 5:520, and Davis et al. J Rheumatol. 2007. 34:11.
Applicant’s arguments filed Nov. 13, 2025 have been fully considered but they are not persuasive.
On pg. 10 in the first full ¶ Applicant argues that Holers does not cure the deficiencies noted above. In view of the finding that Applicant’s arguments with respect to the combination of Bao and Liu is unpersuasive, the rejection of claims 1 and 18 further in view of Holers is maintained, there being no specific deficiency pointed out in the Remarks other than those pertaining to the combination of Bao and Liu.
Claims 1 and 21-22 are rejected under 35 U.S.C. 103 as being unpatentable over Schmidt in WO 2018/002131 A1 published January 4, 2018 in view of in view of Liu et al. in US 7,994,117 B2 published on August 9, 2011; alone or as evidenced by Vidarsson et al. Front. Immunol. 2014. 5:520 and Davis et al. J Rheumatol. 2007. 34:11.
The applied reference has a common inventor (Christoph Schmidt) and Applicant (Universitat Ulm) with the instant application. Based upon the earlier publication and effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2) and 102(a)(1).
Schmidt teaches a module polypeptide comprising DAF(1-4)-FH(19-20) (see claims 1, 2, and 7; Fig. 1A; and, e.g., Example 2).
While Schmidt teaches DAF(1-4)-FH(19-20), Schmidt does not teach fusing Fc to the N-terminus wherein the Fc comprises at most one cysteine residue forming a disulfide bridge with a second molecule of said Fc.
Liu et al. teaches that if the cysteine residues that normally form disulfide bonds in Fc dimers are removed or replaced by other residues, the monomeric chains will generally dimerize through non-covalent interactions (column 13, lines 50-67). Regarding the zero or at most one cysteine residue of instant claim 1 and 21. Liu et al. teaches preventing disulfide crosslinks of the Fc monomers by deleting or replacing the cysteine residues (column 14, lines 47-53). The resulting modification would not ablate the resulting peptides ability to bind an Fc receptor because, for example, IgG1 binds FcRn at the CH2-CH3 junction (pg. 10, left column, paragraph 3), whereas the disulfide bonds occur in the hinge region of Fc (pg. 3, right column). Moreover, Liu et al. teaches an Fc fusion protein, wherein the embodiment with Fc at the N-terminus, as in the instant invention, outperformed the embodiment with the Fc at the C-terminus (see Fig. 4 and column 6, lines 1-16).
A person having ordinary skill in the art would have found it obvious to fuse IgG Fc to the N-terminus of Schmidt’s DAF(1-4)-FH(19-20) in view of Liu’s teachings regarding Fc fusion proteins including deleting cysteine residues that form disulfide bonds between Fc molecules. The skilled artisan reading Liu would have understood that fusing Schmidt’s DAF(1-4)-FH(19-20) to IgG Fc would improve serum half-life (see Liu in col. 3 line 62 through col. line 19), and been motivated by the advantage of improving serum half-life to fuse Fc to DAF(1-4)-FH(19-20). Moreover, in view of Liu’s successful augmentation of activity by fusion at the N-terminus and given the limited number of solutions (N- or C-terminus) the person having ordinary skill would have been motivated to try fusion to the N-terminus. As previously noted on the record and in view of Liu’s teachings on improved half-life with IgG Fc, the skilled artisan would have had reasonable expectation of success in improving half-life by doing so and at least expected that fusion to the N-terminus would perform as well as fusion to the C-terminus. Moreover, in view of the scientific knowledge available in Davis evidencing the level of ordinary skill, regarding reduced complement activity resulting from removing hinge cysteine of IgG in Fc fusion proteins (Davis in, e.g., Fig. 1 on pg. 2205 and Fig. 2 on pg. 2207), the person having ordinary skill would have inferred an advantage from doing so upon reading Liu’s regarding reducing the number of disulfide bonds / cysteines in Fc. Indeed, given that Liu teaches this embodiment in the same paragraph as discussing modifications ablating complement activity, one would reason that Liu implicitly suggests such an advantage. Therefore, a person having ordinary skill in the art would have found it obvious to fuse IgG Fc to the N-terminus of Schmidt’s DAF(1-4)-FH(19-20) in view of Liu’s teachings regarding Fc fusion proteins including deleting cysteine residues that form disulfide bonds between Fc molecules.
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A) and 102(b)(1)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) and 102(b)(1)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement in combination with an exception under 102(b)(1)(A) or 102(b)(1)(B). See generally MPEP § 717.02.
Double Patenting
Claims 1-2, 4-13, and 15-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 25, 32, 35-37, 39, and 40 of U.S. Patent No. 12,312,387 (formerly Application No. 16/311,711) in view of Bao and Lou in WO 2017/114401A1 published on July 6, 2017 and Liu et al. in US 7,994,117 B2 published on August 9, 2011; alone or as evidenced by Vidarsson et al. Front. Immunol. 2014. 5:520 and Davis et al. J Rheumatol. 2007. 34:11.
Newly added claim 22 is further rejected on the same grounds that claim 21 is rejected provided that the scope of claim 21 is narrower. Insofar as Applicant has narrowed the scope of claim 21 to requiring that the first CCP module comprises CCP domains 1-4 of DAF, ‘387 (formerly ‘711) in claim 1 teaches a fist CCP module comprising CCPS 1 to 4 of DAF. All newly added limitations remain unpatentable relying on the teachings of ‘387 (formerly ‘711).
As discussed above, Davis evidences the advantage as it would apply to a complement control fusion protein taught by Bao that a skilled artisan would have inferred from reading Liu’s disclosure on reducing the number of disulfide bonds in Fc by mutating interchain-bond-forming cysteine residues.
Applicant's arguments filed Nov. 13, 2025 have been fully considered but they are not persuasive.
Applicant argues that the rejection does not provide a reasoned, fact-based explanation as to why the instant invention is obvious over ‘711 claims. To support this conclusion Applicant points out that the claims of ‘711 and the instantly filed application are not identical. (pg. 11, last ¶). However, in an obvious-type nonstatutory double patenting rejection, the reference claims and instantly filed claims need not be identical, but rather the instantly filed claims must be obvious over the reference claims in view of the art. Examiner maintains the position that the instantly filed claims are obvious of the ‘711 claims in view of Bao and Liu. While Applicant argues that Bao and Liu would not have rendered the instant claims obvious, referencing the above arguments regarding obviousness (Remarks pg. 11, last ¶). However, Applicants arguments regarding obviousness were not found persuasive, therefore, insofar as they apply to the double patenting rejection over ‘711, they are not persuasive for the same reasons detailed above.
Claims 1, 5-11, and 19-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of copending Application No. 19/201,093 in view of Liu et al. in US 7,994,117 B2 published on August 9, 2011; alone or as evidenced by Vidarsson et al. Front. Immunol. 2014. 5:520, Aslam et al. J Mol Biol. 2001. 309: 1117-1138 , and Davis et al. J Rheumatol. 2007. 34:11.
‘093 teaches a multimodule polypeptide comprising DAF(1-4)-FH(19-20) (see claims 1, 2, and 7; Fig. 1A; and, e.g., Example 2), relating to limitations recited in instant claims 1, 6, 21, and 22. Regarding instant claim 5, FH(19-20) binds C3b (Aslam on pg. 1118 in the first ¶ of the first col.). Regarding instant claim 7, ‘093 claim 9 teaches a sequence at least 70% identical to instant SEQ ID NO: 2.
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Regarding instant claims 19 and 20, SEQ ID NO: 2 of ‘093 as recited in claim 5 is the sequence of human DAF CCPs 1-4 and ‘093’s SEQ ID NO: 4 is CCPs 19-20 of human Factor H as demonstrated by the BLAST alignments shown below (first result shown).
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While ‘093 teaches a multimodule polypeptide comprising DAF(1-4)-FH(19-20), ‘093 does not teach fusing Fc to the N-terminus wherein the Fc comprises at most one cysteine residue forming a disulfide bridge with a second molecule of said Fc.
Liu et al. teaches that if the cysteine residues that normally form disulfide bonds in Fc dimers are removed or replaced by other residues, the monomeric chains will generally dimerize through non-covalent interactions (column 13, lines 50-67), relating to instant claim 10. Relating to instant claims 1, 9, and 21, Liu et al. teaches preventing disulfide crosslinks of the Fc monomers by deleting or replacing the cysteine residues (column 14, lines 47-53). The resulting modification would not ablate the resulting peptides ability to bind an Fc receptor because, for example, IgG1 binds FcRn at the CH2-CH3 junction (Vidarsson, pg. 10, left column, paragraph 3), whereas the disulfide bonds occur in the hinge region of Fc (Vidarsson, pg. 3, right column). Moreover, Liu et al. teaches an Fc fusion protein, wherein the embodiment with Fc at the N-terminus, as in the instant invention, outperformed the embodiment with the Fc at the C-terminus (see Fig. 4 and column 6, lines 1-16). Regarding instant claims 8 and 11, in col. 5 lines 58-63, Liu teaches using human IgG1 for Fc fusion compounds according to SEQ ID NO: 5, which is at least 70% identical to instant SEQ ID NO: 3 as shown below.
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A person having ordinary skill in the art would have found it obvious to fuse IgG Fc to the N-terminus of ‘093’s multimodule polypeptide comprising DAF(1-4)-FH(19-20) in view of Liu’s teachings regarding Fc fusion proteins including deleting cysteine residues that form disulfide bonds between Fc molecules. The skilled artisan reading Liu would have understood that fusing ‘093’s multimodule polypeptide comprising DAF(1-4)-FH(19-20) to IgG Fc would improve serum half-life (see Liu in col. 3 line 62 through col. line 19), and been motivated by the advantage of improving serum half-life to fuse Fc to the multimodule polypeptide DAF(1-4)-FH(19-20). Moreover, in view of Liu’s successful augmentation of activity by fusion at the N-terminus and given the limited number of solutions (N- or C-terminus) the person having ordinary skill would have been motivated to try fusion to the N-terminus. As previously noted on the record and in view of Liu’s teachings on improved half-life with IgG Fc, the skilled artisan would have had reasonable expectation of success in improving half-life by doing so and at least expected that fusion to the N-terminus would perform as well as fusion to the C-terminus. Moreover, in view of the scientific knowledge available in Davis evidencing the level of ordinary skill, regarding reduced complement activity resulting from removing hinge cysteine of IgG in Fc fusion proteins (Davis in, e.g., Fig. 1 on pg. 2205 and Fig. 2 on pg. 2207), the person having ordinary skill would have inferred an advantage from doing so upon reading Liu’s regarding reducing the number of disulfide bonds / cysteines in Fc. Indeed, given that Liu teaches this embodiment in the same paragraph as discussing modifications ablating complement activity, one would reason that Liu implicitly suggests such an advantage. Therefore, a person having ordinary skill in the art would have found it obvious to fuse IgG Fc to the N-terminus of 093’s multimodule polypeptide comprising DAF(1-4)-FH(19-20) in view of Liu’s teachings regarding Fc fusion proteins including deleting cysteine residues that form disulfide bonds between Fc molecules.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 5-11, 15-18 and 19-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of copending Application No. 19/201,093 in view of Liu et al. in US 7,994,117 B2 published on August 9, 2011; alone or as evidenced by Vidarsson et al. Front. Immunol. 2014. 5:520, Aslam et al. J Mol Biol. 2001. 309: 1117-1138 , and Davis et al. J Rheumatol. 2007. 34:11; as applied to instant claims 1, 5-11, and 19-22 above and further in view of Holers and Ristano in US 2013/0029912 A1 published on January 13, 2013.
See discussion above on ‘093 in view of Liu as applied to claims 1, 5-11, and 19-22.
While ‘093 in view of Liu teaches a multi-module polypeptide comprising DAF(1-4)-FH(19-20) and IgG1 Fc fused to the N-terminus having cysteines forming interchain disulfide bonds removed; ‘093 in view of Liu does not teach administering or applying said multi-module polypeptide or combining it with a complement protein C5 inhibiting polypeptide.
However, Holers teaches optimization of treating complement-mediated disorders such as PNH with an inhibitor of the complement alternative pathway, such as inhibiting activation of complement C3 (pg. 1, column 2, paragraph 0007). In some embodiments, the inhibitor of complement alternative pathway is a fusion of a monoclonal antibody to a complement inhibitory portion from Factor H (pg. 4, column 2, paragraph 0030). The inhibitor of complement alternative pathway is taught in combined usage with a terminal complement inhibitor that inhibits complement protein C5, such as eculizumab (pg. 4, column 1, paragraphs 0027 and 0028). Furthermore the inhibitor and complement alternative pathway and terminal complement inhibitor may be administered simultaneously or sequentially in either order (pg. 4, column 1, paragraph 0026).
A person having ordinary skill in the art would have found it obvious to combine the teachings of ‘093 in view of Liu and Holers. ‘093 in view of Liu teaches a complement regulatory fusion protein Fc-fist CCP-second CCP fusion protein having SCRs/CCP from DAF and complement factor H. The motivation for combination lies in the fact that Holers also teach a similar molecule comprising a fusion of an antibody with Factor H for treating PNH. Based on the suggestion from Holers that the C3 inhibiting fusion protein for treating PNH can optimize performance of known terminal complement inhibitors, such as eculizumab, a skilled artisan would have found a design improvement by doing as suggested. Therefore, it would have been obvious to a skilled artisan to combine the Fc-first CCP-second CCP of ‘093 in view of Liu and Holers with the simultaneous or sequential administration of a similar molecule with a complement protein C5 inhibitor (e.g. eculizumab). In doing so one would have arrived at the instant application with a reasonable expectation of success in view of the level of ordinary skill and explicit teachings contained in each reference.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant’s disclosure. Her et al. in WO 2013/082563 published June 6, 2013, cited herewith, also discloses constructs comprising Fc fused N-terminal of a complementary inhibitory domain (CID) which is a fragment of a complement regulatory protein including CR1, Factor H, DAF, and C4BP (see pg. 15 in ¶ [0049] and ¶ [0065] on pg. 26). Her constructed fusion proteins comprising CR1 CCPs with Fc fused either N- or C-terminal (see Fig. 1A an 1B; Example 1), and Her showed hemolysis inhibition for constructs with Fc fused N-terminal of the CR1 CCPs (see Fig. 3A and 3B; Example 3).
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/B.K.S./Examiner, Art Unit 1646
/ANNE M. GUSSOW/Supervisory Patent Examiner, Art Unit 1683