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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 03/09/2026 has been entered.
Response to Amendment
Applicant’s remarks and amendments to the claims received 03/09/2026 have been acknowledged. Claims 1, 23, and 35 have been amended. Claims 2-4, 13-14, 16, 18-22, 27-30, and 33 have been canceled. Claims 39-43 are newly added.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 10, 23, 35, 39, 40, and 43 are rejected under 35 U.S.C. 103 as being unpatentable over Van den Wijngaard (van den Wijngaard, R M J G J et al. The British journal of dermatology vol. 146,1 (2002): 80-7. doi:10.1046/j.1365-2133.2002.04604, of record), in view of Arata et al (WO2015191951A2), hereinafter Arata, Andrien et al (EP3594235A1, of record), hereinafter Andrien, Kulasekararaj et al (Kulasekararaj, Austin G et al. Blood vol. 133,6 (2019): 540-549. doi:10.1182/blood-2018-09-876805, Epub Date: 2018 Dec 3), hereinafter Kulasekararaj, Fenniche et al (Fenniche, Samy et al. Dermatology and therapy vol. 8,1 (2018): 127-135. doi:10.1007/s13555-017-0218-x), hereinafter Fenniche, and Batchelor et al (Batchelor, Jonathan et al. Trials vol. 16,Suppl 2 P68. 16 Nov. 2015, doi:10.1186/1745-6215-16-S2-P68), hereinafter Batchelor, as evidenced by Soliris® (eculizumab) prescribing information (Alexion Pharmaceuticals, Soliris® (eculizumab) Prescribing Information, revised 2017, OA.Appendix).
Van Den Wijngaard teaches that under homeostatic conditions, self-cells are protected from classical and alternative pathways of complement activation by membrane embedded complement regulatory proteins which inhibit the formation of C3/C5 convertases of the classical and alternative pathways. Decreased expression of these molecules on melanocytes, in the presence of circulating antibodies against these cells, can contribute to complement‐mediated melanocyte loss in vitiligo (et al, see Summary and Introduction). Thus, terminal complement activation plays a role in the destruction of melanocytes, leading to the characteristic white patches of depigmentation seen in vitiligo.
Van Den Wijngaard does not specifically teach administration of the anti-C5 antibody ravulizumab to treat vitiligo in a subject. Further, the dosage regimen of the anti-C5 antibody recited in the claims is not taught. Lastly, it is not taught that treatment efficacy is assessed by measuring repigmentation based on the comparison of pre-and post-treatment images or the Vitiligo Noticeability Scale (VNS).
However, Arata teaches that inhibition of C5 cleavage into C5a and C5b by C5 modulatory compounds is useful for treating diseases in which C5 cleavage contributes to disease progression, including vitiligo (Abstract, Para. 0009, Para. 0015, Para. 0018, Para. 0020, Para. 0173, Para. 00176, and Para. 00189).
Andrien further teaches an anti-C5 antibody which (a) binds to complement component human C5; (b) inhibits the cleavage of C5 into fragments C5a and C5b ; and (c) comprises the heavy and light chains of SEQ ID NOs: 14 and 11, corresponding to SEQ ID NO: 14 and 11 of the instant claims. The antibody or antigen-binding fragment can have one of the following characteristics (a) binds to complement component C5 at pH 7.4 and 25°C with a dissociation constant (KD) ≤ 1 nM;(b) binds to C5 at pH 6.0 and 25°C with a KD≥10 nM;(c) wherein the [(KD of the antibody or antigen-binding fragment thereof for C5 at pH 6.0 and 25°C)/(KD of the antibody or antigen-binding fragment thereof for C5 at pH 7.4 and 25°C)] is greater than or equal to 25. (see entire document, in particular, Abstract, Summary of Invention, and Claims). The anti-C5 antibody can be administered intravenously (Para. 0146) and, in some embodiments, in combination with an anti-inflammatory agent to treat inflammatory disorders (Para. 0194).
Kulasekararaj further teaches that ravulizumab administered to patients having a complemented-associated disorder and previously treated with eculizumab resulted in immediate and complete inhibition of C5 activity that was sustained throughout the 26-week treatment period (~6 months) (Key Points, Abstract, Methods: Trial Oversight and Study Design, and Additional Secondary Endpoints: Figure 3 discussion). In particular, ravulizumab is administered at (a) a loading dose of 2400 mg for patients >40 kg to <60 kg, 2700 mg for patients >60 kg to <100 kg, 3000 mg for patients 2100 kg; and (b) a maintenance dose of: 3000 mg for patients >40 kg to <60 kg, 3300 mg for patients >60 kg to <100 kg, or 3600 mg for patients100 kg, two weeks after the loading dose and then once a week for 8 weeks (Methods: Trial Oversight and Study Design and Supplemental Appendix, Section 2-Suppmental Figure 1). Eculizumab-experienced patients received eculizumab at the labeled dose for ≥ 6 months prior to study entry (Methods: Patients).
Fenniche further teaches that the efficacy of vitiligo treatment is based on the percentage of repigmentation of the treated area as determined by comparing pre-and post-treatment photos. In particular, repigmentation is graded into one of four categories: excellent re-pigmentation (ER) (> 75% re-pigmentation), good repigmentation (GR) (50–75% repigmentation), moderate repigmentation (MR) (25–50% repigmentation), and poor repigmentation (PR) (< 25% repigmentation) (“Assessment of Treatment Efficacy” section on Page 128).
Batchelor further teaches that the Vitiligo Noticeability Scale (VNS) is a patient‐reported outcome measure that can be used to assess how ‘noticeable’ vitiligo patches are after treatment from the patient's perspective. The VNS is a better and more consistent indicator of global treatment success than percentage re-pigmentation, with VNS scores of 4 or 5 interpreted as representing treatment success (see Summary, Short Abstract, and Table 1).
It would have been obvious to one of ordinary skill in the art to intravenously administer the anti-C5 antibody ravulizumab to a patient having vitiligo—either alone or in combination with an anti-inflammatory agent—for a 6-month treatment period after the loading dose, wherein (a) the patient has been previously treated with eculizumab; (b) ravulizumab and eculizumab are administered according to the instantly recited dosing regimens; and (c) treatment efficacy is determined by measuring repigmentation based on pre-and post-treatment images of the treated area or the vitiligo noticeability scale (VNS). One of ordinary skill in the art would have been motivated to do so because terminal complement activation is involved in the pathogenesis of vitiligo as taught by Van den Wijngaard; and inhibition of C5 cleavage into C5a and C5b by C5 modulatory compounds, in particular, is useful for treating complement-mediated disorders, including vitiligo as taught by Arata. Since ravulizumab specifically binds to human C5 and inhibits the cleavage of C5 into C5a and C5b as taught by Andrien, it can be used to treat vitiligo. Moreover, ravulizumab administered according to the instantly claimed dosing regimen results in complete and sustained inhibition of C5 activity throughout a 26-week treatment period (~6 months) in patients with a complement-associated disorder and previously treated with labeled-dose eculizumab as taught by Kulasekararaj. Lastly, artisans would have been motivated either measure repigmentation based on the comparison of pre-and post-treatment images as taught by Fenniche or apply the Vitiligo Noticeability Scale (VNS) as taught by Batchelor in order to assess the efficacy of vitiligo treatment. Therefore, one of ordinary skill in the art would reasonably expect the anti-C5 antibody ravulizumab—alone or in combination with an anti-inflammatory agent— to be able to treat vitiligo in a subject according to the regimen provided by Kulasekararaj, wherein the subject was previously administered labeled-dose eculizumab.
Claim 31 is rejected under 35 U.S.C. 103 as being unpatentable over Van Den Wijngaard in view of Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information, as applied to claims 1, 10, 23, 35, 39, 40, and 43 above, and further in view of Bodere et al (Borderé, Alicia Cecile et al. “Current and emerging therapy for the management of vitiligo.” Clinical, cosmetic and investigational dermatology vol. 2 15-25. 12 Mar. 2009, of record), hereinafter Bodere.
The teachings of Van Den Wijngaard in view of Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information have been discussed above and differ from the instantly claimed invention in that it is not taught that the anti-inflammatory agent include topical corticosteroids and/or phototherapy.
However, Bodere teaches that topical corticosteroids and photo(chemotherapy) can be used for the treatment of vitiligo (see Abstract).
It would have been obvious to one of ordinary skill in the art to modify the method of treating vitiligo as discussed previously such that the anti-inflammatory agent administered in combination with the anti-C5 antibody is a topical corticosteroid or photo(chemo)therapy. One of ordinary skill in the art would have been motivated to do so since topical corticosteroids and photo(chemo)therapy are both options for the treatment of vitiligo in a subject. Therefore, one of ordinary skill in the art would reasonably expect that the anti-C5 antibody ravulizumab administered in combination with a topical corticosteroid or phototherapy can effectively treat vitiligo in a subject.
Claim 41 is rejected under 35 U.S.C. 103 as being unpatentable over Van Den Wijngaard in view of Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information, as applied to claims 1, 10, 23, 35, 39, 40, and 43 above, and further in view of Kim et al (Kim, Hyun Jung et al. Acta dermato-venereologica vol. 98,2 (2018): 180-184. doi:10.2340/00015555-2836), hereinafter Kim.
The teachings of Van Den Wijngaard in view of Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that patient is refractory to topical treatment of vitiligo.
However, Kim teaches that the treatment of vitiligo is challenging and requires a multidisciplinary approach. Despite numerous available treatment options, including topical immune-suppressants, a high proportion of patients with vitiligo have resistant disease. Therefore, new therapeutic approaches are required to effectively treat refractory vitiligo in a patient (Abstract and first two paragraphs of Introduction).
It would have been obvious to one of ordinary skill in the art to modify the method of treating vitiligo as discussed previously such that the anti-C5 antibody ravulizumab is also administered to patients resistant (i.e. refractory) to existing treatment options, including topical therapy. One of ordinary skill in the art would have been motivated to do so because treatment of vitiligo requires multidisciplinary and novel therapeutic approaches given the high proportion of vitiligo patients refractory to available treatment options such as topical therapy as taught by Kim. Since terminal complement activation plays a role in vitiligo pathogenesis as taught by Van Den Wijngaard, blocking the cleavage of C5 into C5a and C5b using ravulizumab represents a therapeutic approach that would be beneficial in the treatment of vitiligo patients that are refractory to standard treatment options such as topical therapy. Therefore, one of ordinary skill in the art would reasonably expect that the anti-C5 antibody ravulizumab can be used to effectively treat patients having vitiligo that is refractory to topical treatment.
Claim 42 is rejected under 35 U.S.C. 103 as being unpatentable over Van Den Wijngaard in view of Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information, as applied to claims 1, 10, 23, 35, 39, 40, and 43 above, and further in view of Lee et al (Lee, Jong Wook et al. Blood vol. 133,6 (2019): 530-539. doi:10.1182/blood-2018-09-876136. Epub Date: 2018 Dec 3), hereinafter Lee.
The teachings of Van Den Wijngaard in view of Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that patient is naïve to anti-C5 therapy.
However, Lee teaches that ravulizumab results in immediate, complete, and sustained inhibition of C5 throughout the treatment period in C5 inhibitor–naive patients having a complement-mediated disorder (see Key Points, Abstract, and Figure 3).
It would have been obvious to one of ordinary skill in the art to modify the method of treating vitiligo as discussed previously such that the patient is naïve to anti-C5 therapy. One of ordinary skill in the art would have been motivated to do so since ravulizumab results in immediate, complete, and sustained inhibition of C5 throughout the treatment period in C5 inhibitor–naive patients having a complement-mediated disorder as taught by Lee. As such, subjects having a complement-related disease that is naïve to anti-C5 therapy is a recognized patient populations in which treatment with ravulizumab is therapeutically effective. Therefore, one of ordinary skill in the art would reasonably expect that the anti-C5 antibody ravulizumab can effectively treat vitiligo in a patient that is naïve to anti-C5 therapy.
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.
Claims 1, 10, 23, 35, 39, 40, and 43 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 9079949B1 in view of Van den Wijngaard (van den Wijngaard, R M J G J et al. The British journal of dermatology vol. 146,1 (2002): 80-7. doi:10.1046/j.1365-2133.2002.04604, of record), Arata et al (WO2015191951A2), hereinafter Arata, Andrien et al (EP3594235A1, of record), hereinafter Andrien, Kulasekararaj et al (Kulasekararaj, Austin G et al. Blood vol. 133,6 (2019): 540-549. doi:10.1182/blood-2018-09-876805, Epub Date: 2018 Dec 3), hereinafter Kulasekararaj, Fenniche et al (Fenniche, Samy et al. Dermatology and therapy vol. 8,1 (2018): 127-135. doi:10.1007/s13555-017-0218-x), hereinafter Fenniche, and Batchelor et al (Batchelor, Jonathan et al. Trials vol. 16,Suppl 2 P68. 16 Nov. 2015, doi:10.1186/1745-6215-16-S2-P68), hereinafter Batchelor, as evidenced by Soliris® (eculizumab) prescribing information (Alexion Pharmaceuticals, Soliris® (eculizumab) Prescribing Information, revised 2017, OA.Appendix).
The issued claims recite an antibody or antigen binding fragment that
(a) binds to complement component human C5;
(b) inhibits the cleavage of C5 into fragments C5a and C5b; and
(c) comprises the heavy and light chains of SEQ ID NOs: 14 and 11, corresponding to SEQ ID NO: 14 and 11 of the instant claims (issued claims 1 and 4). The antibody or antigen-binding fragment can have one of the characteristics recited in instant claim 10 (issued claims 6-8).
The issued claims do not teach administration of the anti-C5 antibody ravulizumab to treat vitiligo in a subject. Further, the dosage regimen of the anti-C5 antibody recited in the claims is not taught. Lastly, it is not taught that treatment efficacy is assessed by measuring repigmentation based on the comparison of pre-and post-treatment images or the Vitiligo Noticeability Scale (VNS).
However, Van Den Wijngaard teaches that under homeostatic conditions, self-cells are protected from classical and alternative pathways of complement activation by membrane embedded complement regulatory proteins which inhibit the formation of C3/C5 convertases of the classical and alternative pathways. Decreased expression of these molecules on melanocytes, in the presence of circulating antibodies against these cells, can contribute to complement‐mediated melanocyte loss in vitiligo (et al, see Summary and Introduction). Thus, terminal complement activation plays a role in the destruction of melanocytes, leading to the characteristic white patches of depigmentation seen in vitiligo.
Arata further teaches that inhibition of C5 cleavage into C5a and C5b by C5 modulatory compounds is useful for treating diseases in which C5 cleavage contributes to disease progression, including vitiligo (Abstract, Para. 0009, Para. 0015, Para. 0018, Para. 0020, Para. 0173, Para. 0176, and Para. 0189).
Andrien further teaches an anti-C5 antibody which (a) binds to complement component human C5; (b) inhibits the cleavage of C5 into fragments C5a and C5b ; and (c) comprises the heavy and light chains of SEQ ID NOs: 14 and 11, corresponding to SEQ ID NO: 14 and 11 of the instant claims. The antibody or antigen-binding fragment can have one of the following characteristics (a) binds to complement component C5 at pH 7.4 and 25°C with a dissociation constant (KD) ≤ 1 nM;(b) binds to C5 at pH 6.0 and 25°C with a KD≥10 nM;(c) wherein the [(KD of the antibody or antigen-binding fragment thereof for C5 at pH 6.0 and 25°C)/(KD of the antibody or antigen-binding fragment thereof for C5 at pH 7.4 and 25°C)] is greater than or equal to 25. (see entire document, in particular, Abstract, Summary of Invention, and Claims). The anti-C5 antibody can be administered intravenously (Para. 0146) and, in some embodiments, in combination with an anti-inflammatory agent to treat inflammatory disorders (Para. 0194).
Kulasekararaj further teaches that ravulizumab administered to patients having a complemented-associated disorder and previously treated with eculizumab resulted in immediate and complete inhibition of C5 activity that was sustained throughout the 26-week treatment period (~6 months) (Key Points, Abstract, Methods: Trial Oversight and Study Design, and Additional Secondary Endpoints: Figure 3 discussion). In particular, ravulizumab is administered at (a) a loading dose of 2400 mg for patients >40 kg to <60 kg, 2700 mg for patients >60 kg to <100 kg, 3000 mg for patients 2100 kg; and (b) a maintenance dose of: 3000 mg for patients >40 kg to <60 kg, 3300 mg for patients >60 kg to <100 kg, or 3600 mg for patients100 kg, two weeks after the loading dose and then once a week for 8 weeks (Methods: Trial Oversight and Study Design and Supplemental Appendix, Section 2-Suppmental Figure 1). Eculizumab-experienced patients received eculizumab at the labeled dose for ≥ 6 months prior to study entry (Methods: Patients).
Fenniche further teaches that the efficacy of vitiligo treatment is based on the percentage of repigmentation of the treated area as determined by comparing pre-and post-treatment photos. In particular, repigmentation is graded into one of four categories: excellent re-pigmentation (ER) (> 75% re-pigmentation), good repigmentation (GR) (50–75% repigmentation), moderate repigmentation (MR) (25–50% repigmentation), and poor repigmentation (PR) (< 25% repigmentation) (“Assessment of Treatment Efficacy” section on Page 128).
Batchelor further teaches that the Vitiligo Noticeability Scale (VNS) is a patient‐reported outcome measure that can be used to assess how ‘noticeable’ vitiligo patches are after treatment from the patient's perspective. The VNS is a better and more consistent indicator of global treatment success than percentage re-pigmentation, with VNS scores of 4 or 5 interpreted as representing treatment success (see Summary, Short Abstract, and Table 1).
It would have been obvious to one of ordinary skill in the art to intravenously administer the anti-C5 antibody of the issued claims (ravulizumab) to a patient having vitiligo—either alone or in combination with an anti-inflammatory agent—for a 6-month treatment period after the loading dose, wherein (a) the patient has been previously treated with eculizumab; (b) ravulizumab and eculizumab are administered according to the instantly recited dosing regimens; and (c) treatment efficacy is determined by measuring repigmentation based on pre-and post-treatment images of the treated area or the vitiligo noticeability scale (VNS). One of ordinary skill in the art would have been motivated to do so because terminal complement activation is involved in the pathogenesis of vitiligo as taught by Van den Wijngaard; and inhibition of C5 cleavage into C5a and C5b by C5 modulatory compounds, in particular, is useful for treating complement-mediated disorders, including vitiligo as taught by Arata. Since ravulizumab specifically binds to human C5 and inhibits the cleavage of C5 into C5a and C5b as taught by Andrien, it can be used to treat vitiligo. Moreover, ravulizumab administered according to the instantly claimed dosing regimen results in complete and sustained inhibition of C5 activity throughout a 26-week treatment period (~6 months) in patients with a complement-associated disorder and previously treated with labeled-dose eculizumab as taught by Kulasekararaj. Lastly, artisans would have been motivated either measure repigmentation based on the comparison of pre-and post-treatment images as taught by Fenniche or apply the Vitiligo Noticeability Scale (VNS) as taught by Batchelor in order to assess the efficacy of vitiligo treatment. Therefore, one of ordinary skill in the art would reasonably expect the anti-C5 antibody of the issued claims (ravulizumab)—either alone or in combination with an anti-inflammatory agent— to be able to treat vitiligo in a subject according to the regimen provided by Kulasekararaj, wherein the subject was previously administered labeled-dose eculizumab.
Claim 31 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 9079949B1 in view of Van Den Wijngaard, Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information, as applied to claims 1, 10, 23, 35, 39, 40, and 43 above, and further in view of Bodere et al ( Borderé, Alicia Cecile et al. “Current and emerging therapy for the management of vitiligo.” Clinical, cosmetic and investigational dermatology vol. 2 15-25. 12 Mar. 2009), hereinafter Bodere.
The teachings of the issued claims in view of Van Den Wijngaard, Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information have been discussed above and differ from the instantly claimed invention in that it is not taught that the anti-inflammatory agent include topical corticosteroids and/or phototherapy.
However, Bodere teaches that topical corticosteroids and photo(chemotherapy) can be used for the treatment of vitiligo (see Abstract).
It would have been obvious to one of ordinary skill in the art to modify the method of treating vitiligo disclosed by prior art such that the anti-inflammatory agent administered in combination with the anti-C5 antibody is a topical corticosteroid or photo(chemo)therapy. One of ordinary skill in the art would have been motivated to do so since topical corticosteroids and photo(chemo)therapy are both options for the treatment of vitiligo in a subject. Therefore, one of ordinary skill in the art would reasonably expect that the anti-C5 antibody of the issued claims (ravuliuzmab) administered in combination with a topical corticosteroid or phototherapy can effectively treat vitiligo in a subject.
Claim 41 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 9079949B1 in view of Van Den Wijngaard, Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information, as applied to claims 1, 10, 23, 35, 39, 40, and 43 above, and further in view of Kim et al (Kim, Hyun Jung et al. Acta dermato-venereologica vol. 98,2 (2018): 180-184. doi:10.2340/00015555-2836), hereinafter Kim.
The teachings of the issued claims in view of Van Den Wijngaard, Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that patient is refractory to topical treatment of vitiligo.
However, Kim teaches that the treatment of vitiligo is challenging and requires a multidisciplinary approach. Despite numerous available treatment options, including topical immune-suppressants, a high proportion of patients with vitiligo have resistant disease. Therefore, new therapeutic approaches are required to effectively treat refractory vitiligo in a patient (Abstract and first two paragraphs of Introduction).
It would have been obvious to one of ordinary skill in the art to modify the method of treating vitiligo as discussed previously such that the anti-C5 antibody of the issued claims (ravulizumab) is also administered to patients resistant (i.e. refractory) to existing treatment options, including topical therapy. One of ordinary skill in the art would have been motivated to do so because treatment of vitiligo requires multidisciplinary and novel therapeutic approaches given the high proportion of vitiligo patients refractory to available treatment options such as topical therapy as taught by Kim. Since terminal complement activation plays a role in vitiligo pathogenesis as taught by Van Den Wijngaard, blocking the cleavage of C5 into C5a and C5b using ravulizumab represents a therapeutic approach that would be beneficial in the treatment of vitiligo patients that are refractory to standard treatment options such as topical therapy. Therefore, one of ordinary skill in the art would reasonably expect that the anti-C5 antibody of the issued claims (ravulizumab) can be used to effectively treat patients having vitiligo that is refractory to topical treatment.
Claim 42 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 9079949B1 in view of Van Den Wijngaard, Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information, as applied to claim 1, 10, 23, 35, 39, 40, and 43 above, and further in view of Lee et al (Lee, Jong Wook et al. Blood vol. 133,6 (2019): 530-539. doi:10.1182/blood-2018-09-876136. Epub Date: 2018 Dec 3), hereinafter Lee.
The teachings of the issued claims in view of Van Den Wijngaard, Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that patient is naïve to anti-C5 therapy.
However, Lee teaches that ravulizumab results in immediate, complete, and sustained inhibition of C5 throughout the treatment period in C5 inhibitor–naive patients having a complement-mediated disorder (see Key Points, Abstract, and Figure 3).
It would have been obvious to one of ordinary skill in the art to modify the method of treating vitiligo as discussed previously such that anti-C5 antibody of the issued claims (ravulizumab) is administered to a patient naïve to anti-C5 therapy. One of ordinary skill in the art would have been motivated to do so since ravulizumab results in immediate, complete, and sustained inhibition of C5 throughout the treatment period in C5 inhibitor–naive patients having a complement-mediated disorder as taught by Lee. As such, subjects having a complement-related disease that is naïve to anti-C5 therapy is a recognized patient populations in which treatment with ravulizumab is therapeutically effective. Therefore, one of ordinary skill in the art would reasonably expect that the anti-C5 antibody of the issued claims (ravulizumab) can effectively treat vitiligo in a patient that is naïve to anti-C5 therapy.
Claims 1, 10, 23, 35, 39, 40, and 43 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 9107861B1 in view of Van den Wijngaard (van den Wijngaard, R M J G J et al. The British journal of dermatology vol. 146,1 (2002): 80-7. doi:10.1046/j.1365-2133.2002.04604, of record), Arata et al (WO2015191951A2), hereinafter Arata, Andrien et al (EP3594235A1, of record), hereinafter Andrien, Kulasekararaj et al (Kulasekararaj, Austin G et al. Blood vol. 133,6 (2019): 540-549. doi:10.1182/blood-2018-09-876805, Epub Date: 2018 Dec 3), hereinafter Kulasekararaj, Fenniche et al (Fenniche, Samy et al. Dermatology and therapy vol. 8,1 (2018): 127-135. doi:10.1007/s13555-017-0218-x), hereinafter Fenniche, and Batchelor et al (Batchelor, Jonathan et al. Trials vol. 16,Suppl 2 P68. 16 Nov. 2015, doi:10.1186/1745-6215-16-S2-P68), hereinafter Batchelor, as evidenced by Soliris® (eculizumab) prescribing information (Alexion Pharmaceuticals, Soliris® (eculizumab) Prescribing Information, revised 2017, OA.Appendix).
The issued claims recite a method of treating a C5 mediated disorder in a subject comprising administering an antibody or antigen binding fragment that
(a) binds to complement component human C5;
(b) inhibits the cleavage of C5 into fragments C5a and C5b;
(c) comprises heavy and light chains of SEQ ID NOs: 14 and 11, corresponding to SEQ ID NO: 14 and 11 of the instant claims (issued claims and 4). The antibody or antigen-binding fragment can have one of the characteristics recited in instant claim 10 (issued claims 6-8).
The issued claims do not teach administration of the anti-C5 antibody ravulizumab to treat vitiligo in a subject. Further, the dosage regimen of the anti-C5 antibody recited in the claims is not taught. Lastly, it is not taught that treatment efficacy is assessed by measuring repigmentation based on the comparison of pre-and post-treatment images or the Vitiligo Noticeability Scale (VNS).
However, Van Den Wijngaard teaches that under homeostatic conditions, self-cells are protected from classical and alternative pathways of complement activation by membrane embedded complement regulatory proteins which inhibit the formation of C3/C5 convertases of the classical and alternative pathways. Decreased expression of these molecules on melanocytes, in the presence of circulating antibodies against these cells, can contribute to complement‐mediated melanocyte loss in vitiligo (et al, see Summary and Introduction). Thus, terminal complement activation plays a role in the destruction of melanocytes, leading to the characteristic white patches of depigmentation seen in vitiligo.
Arata further teaches that inhibition of C5 cleavage into C5a and C5b by C5 modulatory compounds is useful for treating diseases in which C5 cleavage contributes to disease progression, including vitiligo (Abstract, Para. 0009, Para. 0015, Para. 0018, Para. 0020, Para. 0173, Para.0176, and Para. 0189).
Andrien further teaches an anti-C5 antibody which (a) binds to complement component human C5; (b) inhibits the cleavage of C5 into fragments C5a and C5b ; and (c) comprises the heavy and light chains of SEQ ID NOs: 14 and 11, corresponding to SEQ ID NO: 14 and 11 of the instant claims. The antibody or antigen-binding fragment can have one of the following characteristics (a) binds to complement component C5 at pH 7.4 and 25°C with a dissociation constant (KD) ≤ 1 nM;(b) binds to C5 at pH 6.0 and 25°C with a KD≥10 nM;(c) wherein the [(KD of the antibody or antigen-binding fragment thereof for C5 at pH 6.0 and 25°C)/(KD of the antibody or antigen-binding fragment thereof for C5 at pH 7.4 and 25°C)] is greater than or equal to 25. (see entire document, in particular, Abstract, Summary of Invention, and Claims). The anti-C5 antibody can be administered intravenously (Para. 0146) and, in some embodiments, in combination with an anti-inflammatory agent to treat inflammatory disorders (Para. 0194).
Kulasekararaj further teaches that ravulizumab administered to patients having a complemented-associated disorder and previously treated with eculizumab resulted in immediate and complete inhibition of C5 activity that was sustained throughout the 26-week treatment period (~6 months) (Key Points, Abstract, Methods: Trial Oversight and Study Design, and Additional Secondary Endpoints: Figure 3 discussion). In particular, ravulizumab is administered at (a) a loading dose of 2400 mg for patients >40 kg to <60 kg, 2700 mg for patients >60 kg to <100 kg, 3000 mg for patients 2100 kg; and (b) a maintenance dose of: 3000 mg for patients >40 kg to <60 kg, 3300 mg for patients >60 kg to <100 kg, or 3600 mg for patients100 kg, two weeks after the loading dose and then once a week for 8 weeks (Methods: Trial Oversight and Study Design and Supplemental Appendix, Section 2-Suppmental Figure 1). Eculizumab-experienced patients received eculizumab at the labeled dose for ≥ 6 months prior to study entry (Methods: Patients).
Fenniche further teaches that the efficacy of vitiligo treatment is based on the percentage of repigmentation of the treated area as determined by comparing pre-and post-treatment photos. In particular, repigmentation is graded into one of four categories: excellent re-pigmentation (ER) (> 75% re-pigmentation), good repigmentation (GR) (50–75% repigmentation), moderate repigmentation (MR) (25–50% repigmentation), and poor repigmentation (PR) (< 25% repigmentation) (“Assessment of Treatment Efficacy” section on Page 128).
Batchelor further teaches that the Vitiligo Noticeability Scale (VNS) is a patient‐reported outcome measure that can be used to assess how ‘noticeable’ vitiligo patches are after treatment from the patient's perspective. The VNS is a better and more consistent indicator of global treatment success than percentage re-pigmentation, with VNS scores of 4 or 5 interpreted as representing treatment success (see Summary, Short Abstract, and Table 1).
It would have been obvious to one of ordinary skill in the art to modify the method of the issued claims such that (a) the complement-associated disorder is vitiligo and the patient has been previously treated with eculizumab, (b) the anti-C5 antibody (ravulizumab) is intravenously administered either alone or in combination with an anti-inflammatory agent over a 6 month treatment period, (c) ravulizumab and eculizumab are administered according to the instantly recited dosing regimens; and (d) treatment efficacy is determined by measuring repigmentation based on pre-and post-treatment images of the treated area or the vitiligo noticeability scale (VNS). One of ordinary skill in the art would have been motivated to do so because terminal complement activation is involved in the pathogenesis of vitiligo as taught by Van den Wijngaard; and inhibition of C5 cleavage into C5a and C5b by C5 modulatory compounds, in particular, is useful for treating complement-mediated disorders, including vitiligo as taught by Arata. Since ravulizumab specifically binds to human C5 and inhibits the cleavage of C5 into C5a and C5b as taught by Andrien, it can be used to treat vitiligo. Moreover, ravulizumab administered according to the instantly claimed dosing regimen results in complete and sustained inhibition of C5 activity throughout a 26-week treatment period (~6 months) in patients with a complement-associated disorder and previously treated with labeled-dose eculizumab as taught by Kulasekararaj. Lastly, artisans would have been motivated either measure repigmentation based on the comparison of pre-and post-treatment images as taught by Fenniche or apply the Vitiligo Noticeability Scale (VNS) as taught by Batchelor in order to assess the efficacy of vitiligo treatment. Therefore, one of ordinary skill in the art would reasonably expect the anti-C5 antibody ravulizumab –either alone or in combination with an anti-inflammatory agent— to be able to treat vitiligo in a subject according to the regimen provided by Kulasekararaj, wherein the subject was previously administered labeled-dose eculizumab.
Claim 31 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 9107861B1 in view of Van Den Wijngaard, Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information, as applied to claims 1, 10, 23, 35, 39, 40, and 43 above, and further in view of Bodere et al ( Borderé, Alicia Cecile et al. “Current and emerging therapy for the management of vitiligo.” Clinical, cosmetic and investigational dermatology vol. 2 15-25. 12 Mar. 2009), hereinafter Bodere.
The teachings of the issued claims in view of Van Den Wijngaard, Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information have been discussed above and differ from the instantly claimed invention in that it is not taught that the anti-inflammatory agent include topical corticosteroids and/or phototherapy.
However, Bodere teaches that topical corticosteroids and photo(chemotherapy) can be used for the treatment of vitiligo (see Abstract).
It would have been obvious to one of ordinary skill in the art to modify the method of treating vitiligo disclosed by prior art such that the anti-inflammatory agent administered in combination with the anti-C5 antibody is a topical corticosteroid or photo(chemo)therapy. One of ordinary skill in the art would have been motivated to do so since topical corticosteroids and photo(chemo)therapy are both options for the treatment of vitiligo in a subject. Therefore, one of ordinary skill in the art would reasonably expect that the anti-C5 antibody of the issued claims (ravuliuzmab) administered in combination with a topical corticosteroid or phototherapy can effectively treat vitiligo in a subject.
Claim 41 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 9107861B1 in view of Van Den Wijngaard, Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information, as applied to claims 1, 10, 23, 35, 39, 40, and 43 above, and further in view of Kim et al (Kim, Hyun Jung et al. Acta dermato-venereologica vol. 98,2 (2018): 180-184. doi:10.2340/00015555-2836), hereinafter Kim.
The teachings of the issued claims in view of Van Den Wijngaard, Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that patient is refractory to topical treatment of vitiligo.
However, Kim teaches that the treatment of vitiligo is challenging and requires a multidisciplinary approach. Despite numerous available treatment options, including topical immune-suppressants, a high proportion of patients with vitiligo have resistant disease. Therefore, new therapeutic approaches are required to effectively treat refractory vitiligo in a patient (Abstract and first two paragraphs of Introduction).
It would have been obvious to one of ordinary skill in the art to modify the method of treating vitiligo as discussed previously such that the anti-C5 antibody ravulizumab is also administered to patients resistant (i.e. refractory) to existing treatment options, including topical therapy. One of ordinary skill in the art would have been motivated to do so because treatment of vitiligo requires multidisciplinary and novel therapeutic approaches given the high proportion of vitiligo patients refractory to available treatment options such as topical therapy as taught by Kim. Since terminal complement activation plays a role in vitiligo pathogenesis as taught by Van Den Wijngaard, blocking the cleavage of C5 into C5a and C5b using ravulizumab represents a therapeutic approach that would be beneficial in the treatment of vitiligo patients that are refractory to standard treatment options such as topical therapy. Therefore, one of ordinary skill in the art would reasonably expect that the anti-C5 antibody of the issued claims (ravulizumab) can be used to effectively treat patients having vitiligo that is refractory to topical treatment.
Claim 42 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 9107861B1 in view of Van Den Wijngaard, Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information, as applied to claim 1, 10, 23, 35, 39, 40, and 43 above, and further in view of Lee et al (Lee, Jong Wook et al. Blood vol. 133,6 (2019): 530-539. doi:10.1182/blood-2018-09-876136. Epub Date: 2018 Dec. 3), hereinafter Lee.
The teachings of the issued claims in view of Van Den Wijngaard, Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that patient is naïve to anti-C5 therapy.
However, Lee teaches that ravulizumab results in immediate, complete, and sustained inhibition of C5 throughout the treatment period in C5 inhibitor–naive patients having a complement-mediated disorder (see Key Points, Abstract, and Figure 3).
It would have been obvious to one of ordinary skill in the art to modify the method of treating vitiligo as discussed previously such that anti-C5 antibody of the issued claims (ravulizumab) is administered to a patient naïve to anti-C5 therapy. One of ordinary skill in the art would have been motivated to do so since ravulizumab results in immediate, complete, and sustained inhibition of C5 throughout the treatment period in C5 inhibitor–naive patients having a complement-mediated disorder as taught by Lee. As such, subjects having a complement-related disease that is naïve to anti-C5 therapy is a recognized patient populations in which treatment with ravulizumab is therapeutically effective. Therefore, one of ordinary skill in the art would reasonably expect that the anti-C5 antibody of the issued claims (ravulizumab) can effectively treat vitiligo in a patient that is naïve to anti-C5 therapy.
Claims 1, 10, 23, 35, 39, 40, and 43 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-36 of U.S. Patent No. 9206251B2 in view of Van den Wijngaard (van den Wijngaard, R M J G J et al. The British journal of dermatology vol. 146,1 (2002): 80-7. doi:10.1046/j.1365-2133.2002.04604, of record), Arata et al (WO2015191951A2), hereinafter Arata, Andrien et al (EP3594235A1, of record), hereinafter Andrien, Kulasekararaj et al (Kulasekararaj, Austin G et al. Blood vol. 133,6 (2019): 540-549. doi:10.1182/blood-2018-09-876805, Epub Date: 2018 Dec 3), hereinafter Kulasekararaj, Fenniche et al (Fenniche, Samy et al. Dermatology and therapy vol. 8,1 (2018): 127-135. doi:10.1007/s13555-017-0218-x), hereinafter Fenniche, and Batchelor et al (Batchelor, Jonathan et al. Trials vol. 16,Suppl 2 P68. 16 Nov. 2015, doi:10.1186/1745-6215-16-S2-P68), hereinafter Batchelor, as evidenced by Soliris® (eculizumab) prescribing information (Alexion Pharmaceuticals, Soliris® (eculizumab) Prescribing Information, revised 2017, OA.Appendix).
The issued claims recite a nucleic acid encoding an anti-C5 antibody having the amino acid sequences of SEQ ID NOs: 14 and 11, corresponding to SEQ ID NO: 14 and 11 of the instant claims (claims 1 and 6. The nucleic acid renders obvious the anti-C5 antibody.
The issued claims do not teach administration of the anti-C5 antibody ravulizumab to treat vitiligo in a subject. Further, the dosage regimen of the anti-C5 antibody recited in the claims is not taught. Lastly, it is not taught that treatment efficacy is assessed by measuring repigmentation based on the comparison of pre-and post-treatment images or the Vitiligo Noticeability Scale (VNS).
However, Van Den Wijngaard teaches that under homeostatic conditions, self-cells are protected from classical and alternative pathways of complement activation by membrane embedded complement regulatory proteins which inhibit the formation of C3/C5 convertases of the classical and alternative pathways. Decreased expression of these molecules on melanocytes, in the presence of circulating antibodies against these cells, can contribute to complement‐mediated melanocyte loss in vitiligo (et al, see Summary and Introduction). Thus, terminal complement activation plays a role in the destruction of melanocytes, leading to the characteristic white patches of depigmentation seen in vitiligo.
Arata further teaches that inhibition of C5 cleavage into C5a and C5b by C5 modulatory compounds is useful for treating diseases in which C5 cleavage contributes to disease progression, including vitiligo (Abstract, Para. 0009, Para. 0015, Para. 0018, Para. 0020, Para. 0173, Para. 0176, and Para. 0189).
Andrien further teaches an anti-C5 antibody which (a) binds to complement component human C5; (b) inhibits the cleavage of C5 into fragments C5a and C5b ; and (c) comprises the heavy and light chains of SEQ ID NOs: 14 and 11, corresponding to SEQ ID NO: 14 and 11 of the instant claims. The antibody or antigen-binding fragment can have one of the following characteristics (a) binds to complement component C5 at pH 7.4 and 25°C with a dissociation constant (KD) ≤ 1 nM;(b) binds to C5 at pH 6.0 and 25°C with a KD≥10 nM;(c) wherein the [(KD of the antibody or antigen-binding fragment thereof for C5 at pH 6.0 and 25°C)/(KD of the antibody or antigen-binding fragment thereof for C5 at pH 7.4 and 25°C)] is greater than or equal to 25. (see entire document, in particular, Abstract, Summary of Invention, and Claims). The anti-C5 antibody can be administered intravenously (Para. 0146) and, in some embodiments, in combination with an anti-inflammatory agent to treat inflammatory disorders (Para. 0194).
Kulasekararaj further teaches that ravulizumab administered to patients having a complemented-associated disorder and previously treated with eculizumab resulted in immediate and complete inhibition of C5 activity that was sustained throughout the 26-week treatment period (~6 months) (Key Points, Abstract, Methods: Trial Oversight and Study Design, and Additional Secondary Endpoints: Figure 3 discussion). In particular, ravulizumab is administered at (a) a loading dose of 2400 mg for patients >40 kg to <60 kg, 2700 mg for patients >60 kg to <100 kg, 3000 mg for patients 2100 kg; and (b) a maintenance dose of: 3000 mg for patients >40 kg to <60 kg, 3300 mg for patients >60 kg to <100 kg, or 3600 mg for patients100 kg, two weeks after the loading dose and then once a week for 8 weeks (Methods: Trial Oversight and Study Design and Supplemental Appendix, Section 2-Suppmental Figure 1). Eculizumab-experienced patients received eculizumab at the labeled dose for ≥ 6 months prior to study entry (Methods: Patients).
Fenniche further teaches that the efficacy of vitiligo treatment is based on the percentage of repigmentation of the treated area as determined by comparing pre-and post-treatment photos. In particular, repigmentation is graded into one of four categories: excellent re-pigmentation (ER) (> 75% re-pigmentation), good repigmentation (GR) (50–75% repigmentation), moderate repigmentation (MR) (25–50% repigmentation), and poor repigmentation (PR) (< 25% repigmentation) (“Assessment of Treatment Efficacy” section on Page 128).
Batchelor further teaches that the Vitiligo Noticeability Scale (VNS) is a patient‐reported outcome measure that can be used to assess how ‘noticeable’ vitiligo patches are after treatment from the patient's perspective. The VNS is a better and more consistent indicator of global treatment success than percentage re-pigmentation, with VNS scores of 4 or 5 interpreted as representing treatment success (see Summary, Short Abstract, and Table 1).
It would have been obvious to one of ordinary skill in the art to intravenously administer the anti-C5 antibody of the issued claims (ravulizumab) to a patient having vitiligo—either alone or in combination with an anti-inflammatory agent—for a 6-month treatment period after the loading dose, wherein (a) the patient has been previously treated with eculizumab; (b) ravulizumab and eculizumab are administered according to the instantly recited dosing regimens; and (c) treatment efficacy is determined by measuring repigmentation based on pre-and post-treatment images of the treated area or the vitiligo noticeability scale (VNS). One of ordinary skill in the art would have been motivated to do so because terminal complement activation is involved in the pathogenesis of vitiligo as taught by Van den Wijngaard; and inhibition of C5 cleavage into C5a and C5b by C5 modulatory compounds, in particular, is useful for treating complement-mediated disorders, including vitiligo as taught by Arata. Since ravulizumab specifically binds to human C5 and inhibits the cleavage of C5 into C5a and C5b as taught by Andrien, it can be used to treat vitiligo. Moreover, ravulizumab administered according to the instantly claimed dosing regimen results in complete and sustained inhibition of C5 activity throughout a 26-week treatment period (~6 months) in patients with a complement-associated disorder and previously treated with labeled-dose eculizumab as taught by Kulasekararaj. Lastly, artisans would have been motivated either measure repigmentation based on the comparison of pre-and post-treatment images as taught by Fenniche or apply the Vitiligo Noticeability Scale (VNS) as taught by Batchelor in order to assess the efficacy of vitiligo treatment. Therefore, one of ordinary skill in the art would reasonably expect the anti-C5 antibody of the issued claims (ravulizumab)—either alone or in combination with an anti-inflammatory agent— to be able to treat vitiligo in a subject according to the regimen provided by Kulasekararaj, wherein the subject was previously administered labeled-dose eculizumab.
Claim 31 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-36 of U.S. Patent No. 9206251B2 in view of Van Den Wijngaard, Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information, as applied to claims 1, 10, 23, 35, 39, 40, and 43 above, and further in view of Bodere et al ( Borderé, Alicia Cecile et al. “Current and emerging therapy for the management of vitiligo.” Clinical, cosmetic and investigational dermatology vol. 2 15-25. 12 Mar. 2009), hereinafter Bodere.
The teachings of the issued claims in view of Van Den Wijngaard, Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information have been discussed above and differ from the instantly claimed invention in that it is not taught that the anti-inflammatory agent include topical corticosteroids and/or phototherapy.
However, Bodere teaches that topical corticosteroids and photo(chemotherapy) can be used for the treatment of vitiligo (see Abstract).
It would have been obvious to one of ordinary skill in the art to modify the method of treating vitiligo disclosed by prior art such that the anti-inflammatory agent administered in combination with the anti-C5 antibody is a topical corticosteroid or photo(chemo)therapy. One of ordinary skill in the art would have been motivated to do so since topical corticosteroids and photo(chemo)therapy are both options for the treatment of vitiligo in a subject. Therefore, one of ordinary skill in the art would reasonably expect that the anti-C5 antibody of the issued claims (ravuliuzmab) administered in combination with a topical corticosteroid or phototherapy can effectively treat vitiligo in a subject.
Claim 41 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-36 of U.S. Patent No. 9206251B2 in view of Van Den Wijngaard, Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information, as applied to claims 1, 10, 23, 35, 39, 40, and 43 above, and further in view of Kim et al (Kim, Hyun Jung et al. Acta dermato-venereologica vol. 98,2 (2018): 180-184. doi:10.2340/00015555-2836), hereinafter Kim.
The teachings of the issued claims in view of Van Den Wijngaard, Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that patient is refractory to topical treatment of vitiligo.
However, Kim teaches that the treatment of vitiligo is challenging and requires a multidisciplinary approach. Despite numerous available treatment options, including topical immune-suppressants, a high proportion of patients with vitiligo have resistant disease. Therefore, new therapeutic approaches are required to effectively treat refractory vitiligo in a patient (Abstract and first two paragraphs of Introduction).
It would have been obvious to one of ordinary skill in the art to modify the method of treating vitiligo taught as discussed previously such that the anti-C5 antibody ravulizumab is also administered to patients resistant (i.e. refractory) to existing treatment options, including topical therapy. One of ordinary skill in the art would have been motivated to do so because treatment of vitiligo requires multidisciplinary and novel therapeutic approaches given the high proportion of vitiligo patients refractory to available treatment options such as topical therapy as taught by Kim. Since terminal complement activation plays a role in vitiligo pathogenesis as taught by Van Den Wijngaard, blocking the cleavage of C5 into C5a and C5b using ravulizumab represents a therapeutic approach that would be beneficial in the treatment of vitiligo patients that are refractory to standard treatment options such as topical therapy. Therefore, one of ordinary skill in the art would reasonably expect that the anti-C5 antibody of the issued claims (ravulizumab) can be used to effectively treat patients having vitiligo that is refractory to topical treatment.
Claim 42 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-36 of U.S. Patent No. 9206251B2 in view of Van Den Wijngaard, Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information, as applied to claim 1, 10, 23, 35, 39, 40, and 43 above, and further in view of Lee et al (Lee, Jong Wook et al. Blood vol. 133,6 (2019): 530-539. doi:10.1182/blood-2018-09-876136. Epub Date: 2018 Dec. 3), hereinafter Lee.
The teachings of the issued claims in view of Van Den Wijngaard, Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that patient is naïve to anti-C5 therapy.
However, Lee teaches that ravulizumab results in immediate, complete, and sustained inhibition of C5 throughout the treatment period in C5 inhibitor–naive patients having a complement-mediated disorder (see Key Points, Abstract, and Figure 3).
It would have been obvious to one of ordinary skill in the art to modify the method of treating vitiligo as discussed previously such that anti-C5 antibody of the issued claims (ravulizumab) is administered to a patient naïve to anti-C5 therapy. One of ordinary skill in the art would have been motivated to do so since ravulizumab results in immediate, complete, and sustained inhibition of C5 throughout the treatment period in C5 inhibitor–naive patients having a complement-mediated disorder as taught by Lee. As such, subjects having a complement-related disease that is naïve to anti-C5 therapy is a recognized patient populations in which treatment with ravulizumab is therapeutically effective. Therefore, one of ordinary skill in the art would reasonably expect that the anti-C5 antibody of the issued claims (ravulizumab) can effectively treat vitiligo in a patient that is naïve to anti-C5 therapy.
Claims 1, 10, 23, 35, 39, 40, and 43 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 9371377B2 in view of Van den Wijngaard (van den Wijngaard, R M J G J et al. The British journal of dermatology vol. 146,1 (2002): 80-7. doi:10.1046/j.1365-2133.2002.04604, of record), Arata et al (WO2015191951A2), hereinafter Arata, Andrien et al (EP3594235A1, of record), hereinafter Andrien, Kulasekararaj et al (Kulasekararaj, Austin G et al. Blood vol. 133,6 (2019): 540-549. doi:10.1182/blood-2018-09-876805, Epub Date: 2018 Dec 3), hereinafter Kulasekararaj, Fenniche et al (Fenniche, Samy et al. Dermatology and therapy vol. 8,1 (2018): 127-135. doi:10.1007/s13555-017-0218-x), hereinafter Fenniche, and Batchelor et al (Batchelor, Jonathan et al. Trials vol. 16,Suppl 2 P68. 16 Nov. 2015, doi:10.1186/1745-6215-16-S2-P68), hereinafter Batchelor, as evidenced by Soliris® (eculizumab) prescribing information (Alexion Pharmaceuticals, Soliris® (eculizumab) Prescribing Information, revised 2017, OA.Appendix).
The issued claims recite an antibody or antigen binding fragment that
(a) binds to complement component human C5;
(b) inhibits the cleavage of C5 into fragments C5a and C5b;
(c) comprises the antibody or antigen-binding fragment thereof can comprise the heavy and light chains of SEQ ID NOs: 14 and 11, corresponding to SEQ ID NO: 14 and 11 of the instant claims (issued claims 1 and 5). The antibody or antigen-binding fragment can have one of the characteristics recited in instant claim 10 (issued claims7-9).
The issued claims do not teach administration of the anti-C5 antibody ravulizumab to treat vitiligo in a subject. Further, the dosage regimen of the anti-C5 antibody recited in the claims is not taught. Lastly, it is not taught that treatment efficacy is assessed by measuring repigmentation based on the comparison of pre-and post-treatment images or the Vitiligo Noticeability Scale (VNS).
However, Van Den Wijngaard teaches that under homeostatic conditions, self-cells are protected from classical and alternative pathways of complement activation by membrane embedded complement regulatory proteins which inhibit the formation of C3/C5 convertases of the classical and alternative pathways. Decreased expression of these molecules on melanocytes, in the presence of circulating antibodies against these cells, can contribute to complement‐mediated melanocyte loss in vitiligo (et al, see Summary and Introduction). Thus, terminal complement activation plays a role in the destruction of melanocytes, leading to the characteristic white patches of depigmentation seen in vitiligo.
Arata further teaches that inhibition of C5 cleavage into C5a and C5b by C5 modulatory compounds is useful for treating diseases in which C5 cleavage contributes to disease progression, including vitiligo (Abstract, Para. 0009, Para. 0015, Para. 0018, Para. 0020, Para. 0173, Para. 0176, and Para. 0189).
Andrien further teaches an anti-C5 antibody which (a) binds to complement component human C5; (b) inhibits the cleavage of C5 into fragments C5a and C5b ; and (c) comprises the heavy and light chains of SEQ ID NOs: 14 and 11, corresponding to SEQ ID NO: 14 and 11 of the instant claims. The antibody or antigen-binding fragment can have one of the following characteristics (a) binds to complement component C5 at pH 7.4 and 25°C with a dissociation constant (KD) ≤ 1 nM;(b) binds to C5 at pH 6.0 and 25°C with a KD≥10 nM;(c) wherein the [(KD of the antibody or antigen-binding fragment thereof for C5 at pH 6.0 and 25°C)/(KD of the antibody or antigen-binding fragment thereof for C5 at pH 7.4 and 25°C)] is greater than or equal to 25. (see entire document, in particular, Abstract, Summary of Invention, and Claims). The anti-C5 antibody can be administered intravenously (Para. 0146) and, in some embodiments, in combination with an anti-inflammatory agent to treat inflammatory disorders (Para. 0194).
Kulasekararaj further teaches that ravulizumab administered to patients having a complemented-associated disorder and previously treated with eculizumab resulted in immediate and complete inhibition of C5 activity that was sustained throughout the 26-week treatment period (~6 months) (Key Points, Abstract, Methods: Trial Oversight and Study Design, and Additional Secondary Endpoints: Figure 3 discussion). In particular, ravulizumab is administered at (a) a loading dose of 2400 mg for patients >40 kg to <60 kg, 2700 mg for patients >60 kg to <100 kg, 3000 mg for patients 2100 kg; and (b) a maintenance dose of: 3000 mg for patients >40 kg to <60 kg, 3300 mg for patients >60 kg to <100 kg, or 3600 mg for patients100 kg, two weeks after the loading dose and then once a week for 8 weeks (Methods: Trial Oversight and Study Design and Supplemental Appendix, Section 2-Suppmental Figure 1). Eculizumab-experienced patients received eculizumab at the labeled dose for ≥ 6 months prior to study entry (Methods: Patients).
Fenniche further teaches that the efficacy of vitiligo treatment is based on the percentage of repigmentation of the treated area as determined by comparing pre-and post-treatment photos. In particular, repigmentation is graded into one of four categories: excellent re-pigmentation (ER) (> 75% re-pigmentation), good repigmentation (GR) (50–75% repigmentation), moderate repigmentation (MR) (25–50% repigmentation), and poor repigmentation (PR) (< 25% repigmentation) (“Assessment of Treatment Efficacy” section on Page 128).
Batchelor further teaches that the Vitiligo Noticeability Scale (VNS) is a patient‐reported outcome measure that can be used to assess how ‘noticeable’ vitiligo patches are after treatment from the patient's perspective. The VNS is a better and more consistent indicator of global treatment success than percentage re-pigmentation, with VNS scores of 4 or 5 interpreted as representing treatment success (see Summary, Short Abstract, and Table 1).
It would have been obvious to one of ordinary skill in the art to intravenously administer the anti-C5 antibody of the issued claims (ravulizumab) to a patient having vitiligo—either alone or in combination with an anti-inflammatory agent—for a 6-month treatment period after the loading dose, wherein (a) the patient has been previously treated with eculizumab; (b) ravulizumab and eculizumab are administered according to the instantly co regimens; and (c) treatment efficacy is determined by measuring repigmentation based on pre-and post-treatment images of the treated area or the vitiligo noticeability scale (VNS). One of ordinary skill in the art would have been motivated to do so because terminal complement activation is involved in the pathogenesis of vitiligo as taught by Van den Wijngaard; and inhibition of C5 cleavage into C5a and C5b by C5 modulatory compounds, in particular, is useful for treating complement-mediated disorders, including vitiligo as taught by Arata. Since ravulizumab specifically binds to human C5 and inhibits the cleavage of C5 into C5a and C5b as taught by Andrien, it can be used to treat vitiligo. Moreover, ravulizumab administered according to the instantly claimed dosing regimen results in complete and sustained inhibition of C5 activity throughout a 26-week treatment period (~6 months) in patients with a complement-associated disorder and previously treated with labeled-dose eculizumab as taught by Kulasekararaj. Lastly, artisans would have been motivated either measure repigmentation based on the comparison of pre-and post-treatment images as taught by Fenniche or apply the Vitiligo Noticeability Scale (VNS) as taught by Batchelor in order to assess the efficacy of vitiligo treatment. Therefore, one of ordinary skill in the art would reasonably expect the anti-C5 antibody of the issued claims (ravulizumab)—either alone or in combination with an anti-inflammatory agent— to be able to treat vitiligo in a subject according to the regimen provided by Kulasekararaj, wherein the subject was previously administered labeled-dose eculizumab.
Claim 31 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 9371377B2 in view of Van Den Wijngaard, Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information, as applied to claims 1, 10, 23, 35, 39, 40, and 43 above, and further in view of Bodere et al ( Borderé, Alicia Cecile et al. “Current and emerging therapy for the management of vitiligo.” Clinical, cosmetic and investigational dermatology vol. 2 15-25. 12 Mar. 2009), hereinafter Bodere.
The teachings of the issued claims in view of Van Den Wijngaard, Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information have been discussed above and differ from the instantly claimed invention in that it is not taught that the anti-inflammatory agent include topical corticosteroids and/or phototherapy.
However, Bodere teaches that topical corticosteroids and photo(chemotherapy) can be used for the treatment of vitiligo (see Abstract).
It would have been obvious to one of ordinary skill in the art to modify the method of treating vitiligo disclosed by prior art such that the anti-inflammatory agent administered in combination with the anti-C5 antibody is a topical corticosteroid or photo(chemo)therapy. One of ordinary skill in the art would have been motivated to do so since topical corticosteroids and photo(chemo)therapy are both options for the treatment of vitiligo in a subject. Therefore, one of ordinary skill in the art would reasonably expect that the anti-C5 antibody of the issued claims (ravuliuzmab) administered in combination with a topical corticosteroid or phototherapy can effectively treat vitiligo in a subject.
Claim 41 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 9371377B2 in view of Van Den Wijngaard, Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information, as applied to claims 1, 10, 23, 35, 39, 40, and 43 above, and further in view of Kim et al (Kim, Hyun Jung et al. Acta dermato-venereologica vol. 98,2 (2018): 180-184. doi:10.2340/00015555-2836), hereinafter Kim.
The teachings of the issued claims in view of Van Den Wijngaard, Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that patient is refractory to topical treatment of vitiligo.
However, Kim teaches that the treatment of vitiligo is challenging and requires a multidisciplinary approach. Despite numerous available treatment options, including topical immune-suppressants, a high proportion of patients with vitiligo have resistant disease. Therefore, new therapeutic approaches are required to effectively treat refractory vitiligo in a patient (Abstract and first two paragraphs of Introduction).
It would have been obvious to one of ordinary skill in the art to modify the method of treating vitiligo as discussed previously such that the anti-C5 antibody ravulizumab is also administered to patients resistant (i.e. refractory) to existing treatment options, including topical therapy. One of ordinary skill in the art would have been motivated to do so because treatment of vitiligo requires multidisciplinary and novel therapeutic approaches given the high proportion of vitiligo patients refractory to available treatment options such as topical therapy as taught by Kim. Since terminal complement activation plays a role in vitiligo pathogenesis as taught by Van Den Wijngaard, blocking the cleavage of C5 into C5a and C5b using ravulizumab represents a therapeutic approach that would be beneficial in the treatment of vitiligo patients that are refractory to standard treatment options such as topical therapy. Therefore, one of ordinary skill in the art would reasonably expect that the anti-C5 antibody of the issued claims (ravulizumab) can be used to effectively treat patients having vitiligo that is refractory to topical treatment.
Claim 42 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 9371377B2 in view of Van Den Wijngaard, Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information, as applied to claim 1, 10, 23, 35, 39, 40, and 43 above, and further in view of Lee et al (Lee, Jong Wook et al. Blood vol. 133,6 (2019): 530-539. doi:10.1182/blood-2018-09-876136. Epub Date: 2018 Dec. 18), hereinafter Lee.
The teachings of the issued claims in view of Van Den Wijngaard, Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that patient is naïve to anti-C5 therapy.
However, Lee teaches that ravulizumab results in immediate, complete, and sustained inhibition of C5 throughout the treatment period in C5 inhibitor–naive patients having a complement-mediated disorder (see Key Points, Abstract, and Figure 3).
It would have been obvious to one of ordinary skill in the art to modify the method of treating vitiligo as discussed previously such that anti-C5 antibody of the issued claims (ravulizumab) is administered to a patient naïve to anti-C5 therapy. One of ordinary skill in the art would have been motivated to do so since ravulizumab results in immediate, complete, and sustained inhibition of C5 throughout the treatment period in C5 inhibitor–naive patients having a complement-mediated disorder as taught by Lee. As such, subjects having a complement-related disease that is naïve to anti-C5 therapy is a recognized patient populations in which treatment with ravulizumab is therapeutically effective. Therefore, one of ordinary skill in the art would reasonably expect that the anti-C5 antibody of the issued claims (ravulizumab) can effectively treat vitiligo in a patient that is naïve to anti-C5 therapy.
Claims 1, 10, 23, 35, 39, 40, and 43 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 9663574B2 in view of Van den Wijngaard (van den Wijngaard, R M J G J et al. The British journal of dermatology vol. 146,1 (2002): 80-7. doi:10.1046/j.1365-2133.2002.04604, of record), Arata et al (WO2015191951A2), hereinafter Arata, Andrien et al (EP3594235A1, of record), hereinafter Andrien, Kulasekararaj et al (Kulasekararaj, Austin G et al. Blood vol. 133,6 (2019): 540-549. doi:10.1182/blood-2018-09-876805, Epub Date: 2018 Dec 3), hereinafter Kulasekararaj, Fenniche et al (Fenniche, Samy et al. Dermatology and therapy vol. 8,1 (2018): 127-135. doi:10.1007/s13555-017-0218-x), hereinafter Fenniche, and Batchelor et al (Batchelor, Jonathan et al. Trials vol. 16,Suppl 2 P68. 16 Nov. 2015, doi:10.1186/1745-6215-16-S2-P68), hereinafter Batchelor, as evidenced by Soliris® (eculizumab) prescribing information (Alexion Pharmaceuticals, Soliris® (eculizumab) Prescribing Information, revised 2017, OA.Appendix).
The issued claims recite an antibody or antigen binding fragment that
(a) binds to complement component human C5;
(b) inhibits the cleavage of C5 into fragments C5a and C5b;
(c) comprises the antibody or antigen-binding fragment thereof can comprise the heavy and light chains of SEQ ID NOs: 14 and 11, corresponding to SEQ ID NO: 14 and 11 of the instant claims (issued claims 1 and 5). The antibody has the characteristics recited in instant claim 10 (issued claims 6-8).
The issued claims do not teach administration of the anti-C5 antibody ravulizumab to treat vitiligo in a subject. Further, the dosage regimen of the anti-C5 antibody recited in the claims is not taught. Lastly, it is not taught that treatment efficacy is assessed by measuring repigmentation based on the comparison of pre-and post-treatment images or the Vitiligo Noticeability Scale (VNS).
However, Van Den Wijngaard teaches that under homeostatic conditions, self-cells are protected from classical and alternative pathways of complement activation by membrane embedded complement regulatory proteins which inhibit the formation of C3/C5 convertases of the classical and alternative pathways. Decreased expression of these molecules on melanocytes, in the presence of circulating antibodies against these cells, can contribute to complement‐mediated melanocyte loss in vitiligo (et al, see Summary and Introduction). Thus, terminal complement activation plays a role in the destruction of melanocytes, leading to the characteristic white patches of depigmentation seen in vitiligo.
Arata further teaches that inhibition of C5 cleavage into C5a and C5b by C5 modulatory compounds is useful for treating diseases in which C5 cleavage contributes to disease progression, including vitiligo (Abstract, Para. 0009, Para. 0015, Para. 0018, Para. 0020, Para. 0173, Para. 0176, and Para. 0189).
Andrien further teaches an anti-C5 antibody which (a) binds to complement component human C5; (b) inhibits the cleavage of C5 into fragments C5a and C5b ; and (c) comprises the heavy and light chains of SEQ ID NOs: 14 and 11, corresponding to SEQ ID NO: 14 and 11 of the instant claims. The antibody or antigen-binding fragment can have one of the following characteristics (a) binds to complement component C5 at pH 7.4 and 25°C with a dissociation constant (KD) ≤ 1 nM;(b) binds to C5 at pH 6.0 and 25°C with a KD≥10 nM;(c) wherein the [(KD of the antibody or antigen-binding fragment thereof for C5 at pH 6.0 and 25°C)/(KD of the antibody or antigen-binding fragment thereof for C5 at pH 7.4 and 25°C)] is greater than or equal to 25. (see entire document, in particular, Abstract, Summary of Invention, and Claims). The anti-C5 antibody can be administered intravenously (Para. 0146) and, in some embodiments, in combination with an anti-inflammatory agent to treat inflammatory disorders (Para. 0194).
Kulasekararaj further teaches that ravulizumab administered to patients having a complemented-associated disorder and previously treated with eculizumab resulted in immediate and complete inhibition of C5 activity that was sustained throughout the 26-week treatment period (~6 months) (Key Points, Abstract, Methods: Trial Oversight and Study Design, and Additional Secondary Endpoints: Figure 3 discussion). In particular, ravulizumab is administered at (a) a loading dose of 2400 mg for patients >40 kg to <60 kg, 2700 mg for patients >60 kg to <100 kg, 3000 mg for patients 2100 kg; and (b) a maintenance dose of: 3000 mg for patients >40 kg to <60 kg, 3300 mg for patients >60 kg to <100 kg, or 3600 mg for patients100 kg, two weeks after the loading dose and then once a week for 8 weeks (Methods: Trial Oversight and Study Design and Supplemental Appendix, Section 2-Suppmental Figure 1). Eculizumab-experienced patients received eculizumab at the labeled dose for ≥ 6 months prior to study entry (Methods: Patients).
Fenniche further teaches that the efficacy of vitiligo treatment is based on the percentage of repigmentation of the treated area as determined by comparing pre-and post-treatment photos. In particular, repigmentation is graded into one of four categories: excellent re-pigmentation (ER) (> 75% re-pigmentation), good repigmentation (GR) (50–75% repigmentation), moderate repigmentation (MR) (25–50% repigmentation), and poor repigmentation (PR) (< 25% repigmentation) (“Assessment of Treatment Efficacy” section on Page 128).
Batchelor further teaches that the Vitiligo Noticeability Scale (VNS) is a patient‐reported outcome measure that can be used to assess how ‘noticeable’ vitiligo patches are after treatment from the patient's perspective. The VNS is a better and more consistent indicator of global treatment success than percentage re-pigmentation, with VNS scores of 4 or 5 interpreted as representing treatment success (see Summary, Short Abstract, and Table 1).
It would have been obvious to one of ordinary skill in the art to intravenously administer the anti-C5 antibody of the issued claims (ravulizumab) to a patient having vitiligo—either alone or in combination with an anti-inflammatory agent—for a 6-month treatment period after the loading dose, wherein (a) the patient has been previously treated with eculizumab; (b) ravulizumab and eculizumab are administered according to the instantly recited dosing regimens; and (c) treatment efficacy is determined by measuring repigmentation based on pre-and post-treatment images of the treated area or the vitiligo noticeability scale (VNS). One of ordinary skill in the art would have been motivated to do so because terminal complement activation is involved in the pathogenesis of vitiligo as taught by Van den Wijngaard; and inhibition of C5 cleavage into C5a and C5b by C5 modulatory compounds, in particular, is useful for treating complement-mediated disorders, including vitiligo as taught by Arata. Since ravulizumab specifically binds to human C5 and inhibits the cleavage of C5 into C5a and C5b as taught by Andrien, it can be used to treat vitiligo. Moreover, ravulizumab administered according to the instantly claimed dosing regimen results in complete and sustained inhibition of C5 activity throughout a 26-week treatment period (~6 months) in patients with a complement-associated disorder and previously treated with labeled-dose eculizumab as taught by Kulasekararaj. Lastly, artisans would have been motivated either measure repigmentation based on the comparison of pre-and post-treatment images as taught by Fenniche or apply the Vitiligo Noticeability Scale (VNS) as taught by Batchelor in order to assess the efficacy of vitiligo treatment. Therefore, one of ordinary skill in the art would reasonably expect the anti-C5 antibody of the issued claims (ravulizumab)—either alone or in combination with an anti-inflammatory agent— to be able to treat vitiligo in a subject according to the regimen provided by Kulasekararaj, wherein the subject was previously administered labeled-dose eculizumab.
Claim 31 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 9663574B2 in view of Van Den Wijngaard, Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information, as applied to claims 11, 10, 23, 35, 39, 40, and 43 above, and further in view of Bodere et al ( Borderé, Alicia Cecile et al. “Current and emerging therapy for the management of vitiligo.” Clinical, cosmetic and investigational dermatology vol. 2 15-25. 12 Mar. 2009), hereinafter Bodere.
The teachings of the issued claims in view of Van Den Wijngaard, Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information have been discussed above and differ from the instantly claimed invention in that it is not taught that the anti-inflammatory agent include topical corticosteroids and/or phototherapy.
However, Bodere teaches that topical corticosteroids and photo(chemotherapy) can be used for the treatment of vitiligo (see Abstract).
It would have been obvious to one of ordinary skill in the art to modify the method of treating vitiligo disclosed by prior art such that the anti-inflammatory agent administered in combination with the anti-C5 antibody is a topical corticosteroid or photo(chemo)therapy. One of ordinary skill in the art would have been motivated to do so since topical corticosteroids and photo(chemo)therapy are both options for the treatment of vitiligo in a subject. Therefore, one of ordinary skill in the art would reasonably expect that the anti-C5 antibody of the issued claims (ravuliuzmab) administered in combination with a topical corticosteroid or phototherapy can effectively treat vitiligo in a subject.
Claim 41 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 9663574B2 in view of Van Den Wijngaard, Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information, as applied to claims 1, 10, 23, 35, 39, 40, and 43 above, and further in view of Kim et al (Kim, Hyun Jung et al. Acta dermato-venereologica vol. 98,2 (2018): 180-184. doi:10.2340/00015555-2836), hereinafter Kim.
The teachings of the issued claims in view of Van Den Wijngaard, Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that patient is refractory to topical treatment of vitiligo.
However, Kim teaches that the treatment of vitiligo is challenging and requires a multidisciplinary approach. Despite numerous available treatment options, including topical immune-suppressants, a high proportion of patients with vitiligo have resistant disease. Therefore, new therapeutic approaches are required to effectively treat refractory vitiligo in a patient (Abstract and first two paragraphs of Introduction).
It would have been obvious to one of ordinary skill in the art to modify the method of treating vitiligo as discussed previously such that the anti-C5 antibody ravulizumab is also administered to patients resistant (i.e. refractory) to existing treatment options, including topical therapy. One of ordinary skill in the art would have been motivated to do so because treatment of vitiligo requires multidisciplinary and novel therapeutic approaches given the high proportion of vitiligo patients refractory to available treatment options such as topical therapy as taught by Kim. Since terminal complement activation plays a role in vitiligo pathogenesis as taught by Van Den Wijngaard, blocking the cleavage of C5 into C5a and C5b using ravulizumab represents a therapeutic approach that would be beneficial in the treatment of vitiligo patients that are refractory to standard treatment options such as topical therapy. Therefore, one of ordinary skill in the art would reasonably expect that the anti-C5 antibody of the issued claims (ravulizumab) can be used to effectively treat patients having vitiligo that is refractory to topical treatment.
Claim 42 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 9663574B2 in view of Van Den Wijngaard, Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information, as applied to claim 1, 10, 23, 35, 39, 40, and 43 above, and further in view of Lee et al (Lee, Jong Wook et al. Blood vol. 133,6 (2019): 530-539. doi:10.1182/blood-2018-09-876136. Epub Date: 2018 Dec. 3), hereinafter Lee.
The teachings of the issued claims in view of Van Den Wijngaard, Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that patient is naïve to anti-C5 therapy.
However, Lee teaches that ravulizumab results in immediate, complete, and sustained inhibition of C5 throughout the treatment period in C5 inhibitor–naive patients having a complement-mediated disorder (see Key Points, Abstract, and Figure 3).
It would have been obvious to one of ordinary skill in the art to modify the method of treating vitiligo as discussed previously such that anti-C5 antibody of the issued claims (ravulizumab) is administered to a patient naïve to anti-C5 therapy. One of ordinary skill in the art would have been motivated to do so since ravulizumab results in immediate, complete, and sustained inhibition of C5 throughout the treatment period in C5 inhibitor–naive patients having a complement-mediated disorder as taught by Lee. As such, subjects having a complement-related disease that is naïve to anti-C5 therapy is a recognized patient populations in which treatment with ravulizumab is therapeutically effective. Therefore, one of ordinary skill in the art would reasonably expect that the anti-C5 antibody of the issued claims (ravulizumab) can effectively treat vitiligo in a patient that is naïve to anti-C5 therapy.
Claims 1, 10, 23, 35, 39, 40, and 43 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 11434280B2 in view of Van den Wijngaard (van den Wijngaard, R M J G J et al. The British journal of dermatology vol. 146,1 (2002): 80-7. doi:10.1046/j.1365-2133.2002.04604, of record), Arata et al (WO2015191951A2), hereinafter Arata, Andrien et al (EP3594235A1, of record), hereinafter Andrien, Kulasekararaj et al (Kulasekararaj, Austin G et al. Blood vol. 133,6 (2019): 540-549. doi:10.1182/blood-2018-09-876805, Epub Date: 2018 Dec 3), hereinafter Kulasekararaj, Fenniche et al (Fenniche, Samy et al. Dermatology and therapy vol. 8,1 (2018): 127-135. doi:10.1007/s13555-017-0218-x), hereinafter Fenniche, and Batchelor et al (Batchelor, Jonathan et al. Trials vol. 16,Suppl 2 P68. 16 Nov. 2015, doi:10.1186/1745-6215-16-S2-P68), hereinafter Batchelor, as evidenced by Soliris® (eculizumab) prescribing information (Alexion Pharmaceuticals, Soliris® (eculizumab) Prescribing Information, revised 2017, OA.Appendix).
The issued claims recite an antibody or antigen binding fragment that
(a) binds to complement component human C5;
(b) inhibits the cleavage of C5 into fragments C5a and C5b;
(c) comprises the heavy and light chains of SEQ ID NOs: 14 and 11, corresponding to SEQ ID NO: 14 and 11 of the instant claims. The antibody or antigen-binding fragment can have one of the characteristics recited in instant claim 10. (issued claims 1, 17, and 18).
The issued claims do not teach administration of the anti-C5 antibody ravulizumab to treat vitiligo in a subject. Further, the dosage regimen of the anti-C5 antibody recited in the claims is not taught. Lastly, it is not taught that treatment efficacy is assessed by measuring repigmentation based on the comparison of pre-and post-treatment images or the Vitiligo Noticeability Scale (VNS).
However, Van Den Wijngaard teaches that under homeostatic conditions, self-cells are protected from classical and alternative pathways of complement activation by membrane embedded complement regulatory proteins which inhibit the formation of C3/C5 convertases of the classical and alternative pathways. Decreased expression of these molecules on melanocytes, in the presence of circulating antibodies against these cells, can contribute to complement‐mediated melanocyte loss in vitiligo (et al, see Summary and Introduction). Thus, terminal complement activation plays a role in the destruction of melanocytes, leading to the characteristic white patches of depigmentation seen in vitiligo.
Arata further teaches that inhibition of C5 cleavage into C5a and C5b by C5 modulatory compounds is useful for treating diseases in which C5 cleavage contributes to disease progression, including vitiligo (Abstract, Para. 0009, Para. 0015, Para. 0018, Para. 0020, Para. 0173, Para. 0176, and Para. 0189).
Andrien further teaches an anti-C5 antibody which (a) binds to complement component human C5; (b) inhibits the cleavage of C5 into fragments C5a and C5b ; and (c) comprises the heavy and light chains of SEQ ID NOs: 14 and 11, corresponding to SEQ ID NO: 14 and 11 of the instant claims. The antibody or antigen-binding fragment can have one of the following characteristics (a) binds to complement component C5 at pH 7.4 and 25°C with a dissociation constant (KD) ≤ 1 nM;(b) binds to C5 at pH 6.0 and 25°C with a KD≥10 nM;(c) wherein the [(KD of the antibody or antigen-binding fragment thereof for C5 at pH 6.0 and 25°C)/(KD of the antibody or antigen-binding fragment thereof for C5 at pH 7.4 and 25°C)] is greater than or equal to 25. (see entire document, in particular, Abstract, Summary of Invention, and Claims). The anti-C5 antibody can be administered intravenously (Para. 0146) and, in some embodiments, in combination with an anti-inflammatory agent to treat inflammatory disorders (Para. 0194).
Kulasekararaj further teaches that ravulizumab administered to patients having a complemented-associated disorder and previously treated with eculizumab resulted in immediate and complete inhibition of C5 activity that was sustained throughout the 26-week treatment period (~6 months) (Key Points, Abstract, Methods: Trial Oversight and Study Design, and Additional Secondary Endpoints: Figure 3 discussion). In particular, ravulizumab is administered at (a) a loading dose of 2400 mg for patients >40 kg to <60 kg, 2700 mg for patients >60 kg to <100 kg, 3000 mg for patients 2100 kg; and (b) a maintenance dose of: 3000 mg for patients >40 kg to <60 kg, 3300 mg for patients >60 kg to <100 kg, or 3600 mg for patients100 kg, two weeks after the loading dose and then once a week for 8 weeks (Methods: Trial Oversight and Study Design and Supplemental Appendix, Section 2-Suppmental Figure 1). Eculizumab-experienced patients received eculizumab at the labeled dose for ≥ 6 months prior to study entry (Methods: Patients).
Fenniche further teaches that the efficacy of vitiligo treatment is based on the percentage of repigmentation of the treated area as determined by comparing pre-and post-treatment photos. In particular, repigmentation is graded into one of four categories: excellent re-pigmentation (ER) (> 75% re-pigmentation), good repigmentation (GR) (50–75% repigmentation), moderate repigmentation (MR) (25–50% repigmentation), and poor repigmentation (PR) (< 25% repigmentation) (“Assessment of Treatment Efficacy” section on Page 128).
Batchelor further teaches that the Vitiligo Noticeability Scale (VNS) is a patient‐reported outcome measure that can be used to assess how ‘noticeable’ vitiligo patches are after treatment from the patient's perspective. The VNS is a better and more consistent indicator of global treatment success than percentage re-pigmentation, with VNS scores of 4 or 5 interpreted as representing treatment success (see Summary, Short Abstract, and Table 1).
It would have been obvious to one of ordinary skill in the art to intravenously administer the anti-C5 antibody of the issued claims (ravulizumab) to a patient having vitiligo—either alone or in combination with an anti-inflammatory agent—for a 6-month treatment period after the loading dose, wherein (a) the patient has been previously treated with eculizumab; (b) ravulizumab and eculizumab are administered according to the instantly recited dosing regimens; and (c) treatment efficacy is determined by measuring repigmentation based on pre-and post-treatment images of the treated area or the vitiligo noticeability scale (VNS). One of ordinary skill in the art would have been motivated to do so because terminal complement activation is involved in the pathogenesis of vitiligo as taught by Van den Wijngaard; and inhibition of C5 cleavage into C5a and C5b by C5 modulatory compounds, in particular, is useful for treating complement-mediated disorders, including vitiligo as taught by Arata. Since ravulizumab specifically binds to human C5 and inhibits the cleavage of C5 into C5a and C5b as taught by Andrien, it can be used to treat vitiligo. Moreover, ravulizumab administered according to the instantly claimed dosing regimen results in complete and sustained inhibition of C5 activity throughout a 26-week treatment period (~6 months) in patients with a complement-associated disorder and previously treated with labeled-dose eculizumab as taught by Kulasekararaj. Lastly, artisans would have been motivated either measure repigmentation based on the comparison of pre-and post-treatment images as taught by Fenniche or apply the Vitiligo Noticeability Scale (VNS) as taught by Batchelor in order to assess the efficacy of vitiligo treatment. Therefore, one of ordinary skill in the art would reasonably expect the anti-C5 antibody of the issued claims (ravulizumab)—either alone or in combination with an anti-inflammatory agent— to be able to treat vitiligo in a subject according to the regimen provided by Kulasekararaj, wherein the subject was previously administered labeled-dose eculizumab.
Claim 31 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 11434280B2 in view of Van Den Wijngaard, Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information, as applied to claims 1, 10, 23, 35, 39, 40, and 43 above, and further in view of Bodere et al ( Borderé, Alicia Cecile et al. “Current and emerging therapy for the management of vitiligo.” Clinical, cosmetic and investigational dermatology vol. 2 15-25. 12 Mar. 2009), hereinafter Bodere.
The teachings of the issued claims in view of Van Den Wijngaard, Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information have been discussed above and differ from the instantly claimed invention in that it is not taught that the anti-inflammatory agent include topical corticosteroids and/or phototherapy.
However, Bodere teaches that topical corticosteroids and photo(chemotherapy) can be used for the treatment of vitiligo (see Abstract).
It would have been obvious to one of ordinary skill in the art to modify the method of treating vitiligo disclosed by prior art such that the anti-inflammatory agent administered in combination with the anti-C5 antibody is a topical corticosteroid or photo(chemo)therapy. One of ordinary skill in the art would have been motivated to do so since topical corticosteroids and photo(chemo)therapy are both options for the treatment of vitiligo in a subject. Therefore, one of ordinary skill in the art would reasonably expect that the anti-C5 antibody of the issued claims (ravuliuzmab) administered in combination with a topical corticosteroid or phototherapy can effectively treat vitiligo in a subject.
Claim 41 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 11434280B2 in view of Van Den Wijngaard, Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information, as applied to claims 1, 10, 23, 35, 39, 40, and 43 above, and further in view of Kim et al (Kim, Hyun Jung et al. Acta dermato-venereologica vol. 98,2 (2018): 180-184. doi:10.2340/00015555-2836), hereinafter Kim.
The teachings of the issued claims in view of Van Den Wijngaard, Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that patient is refractory to topical treatment of vitiligo.
However, Kim teaches that the treatment of vitiligo is challenging and requires a multidisciplinary approach. Despite numerous available treatment options, including topical immune-suppressants, a high proportion of patients with vitiligo have resistant disease. Therefore, new therapeutic approaches are required to effectively treat refractory vitiligo in a patient (Abstract and first two paragraphs of Introduction).
It would have been obvious to one of ordinary skill in the art to modify the method of treating vitiligo taught as discussed previously such that the anti-C5 antibody ravulizumab is also administered to patients resistant (i.e. refractory) to existing treatment options, including topical therapy. One of ordinary skill in the art would have been motivated to do so because treatment of vitiligo requires multidisciplinary and novel therapeutic approaches given the high proportion of vitiligo patients refractory to available treatment options such as topical therapy as taught by Kim. Since terminal complement activation plays a role in vitiligo pathogenesis as taught by Van Den Wijngaard, blocking the cleavage of C5 into C5a and C5b using ravulizumab represents a therapeutic approach that would be beneficial in the treatment of vitiligo patients that are refractory to standard treatment options such as topical therapy. Therefore, one of ordinary skill in the art would reasonably expect that the anti-C5 antibody of the issued claims (ravulizumab) can be used to effectively treat patients having vitiligo that is refractory to topical treatment.
Claim 42 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 11434280B2 in view of Van Den Wijngaard, Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information, as applied to claim 1, 10, 23, 35, 39, 40, and 43 above, and further in view of Lee et al (Lee, Jong Wook et al. Blood vol. 133,6 (2019): 530-539. doi:10.1182/blood-2018-09-876136. Epub Date: 2018 Dec. 3), hereinafter Lee.
The teachings of the issued claims in view of Van Den Wijngaard, Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that patient is naïve to anti-C5 therapy.
However, Lee teaches that ravulizumab results in immediate, complete, and sustained inhibition of C5 throughout the treatment period in C5 inhibitor–naive patients having a complement-mediated disorder (see Key Points, Abstract, and Figure 3).
It would have been obvious to one of ordinary skill in the art to modify the method of treating vitiligo as discussed previously such that anti-C5 antibody of the issued claims (ravulizumab) is administered to a patient naïve to anti-C5 therapy. One of ordinary skill in the art would have been motivated to do so since ravulizumab results in immediate, complete, and sustained inhibition of C5 throughout the treatment period in C5 inhibitor–naive patients having a complement-mediated disorder as taught by Lee. As such, subjects having a complement-related disease that is naïve to anti-C5 therapy is a recognized patient populations in which treatment with ravulizumab is therapeutically effective. Therefore, one of ordinary skill in the art would reasonably expect that the anti-C5 antibody of the issued claims (ravulizumab) can effectively treat vitiligo in a patient that is naïve to anti-C5 therapy.
Claims 1, 10, 23, 35, 39, 40, and 43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6-11, 15, 18-19, and 27-33 of co-pending Application No. 17057867 in view of Van den Wijngaard (van den Wijngaard, R M J G J et al. The British journal of dermatology vol. 146,1 (2002): 80-7. doi:10.1046/j.1365-2133.2002.04604, of record), Arata et al (WO2015191951A2), hereinafter Arata, Andrien et al (EP3594235A1, of record), hereinafter Andrien, Kulasekararaj et al (Kulasekararaj, Austin G et al. Blood vol. 133,6 (2019): 540-549. doi:10.1182/blood-2018-09-876805, Epub Date: 2018 Dec 3), hereinafter Kulasekararaj, Fenniche et al (Fenniche, Samy et al. Dermatology and therapy vol. 8,1 (2018): 127-135. doi:10.1007/s13555-017-0218-x), hereinafter Fenniche, and Batchelor et al (Batchelor, Jonathan et al. Trials vol. 16,Suppl 2 P68. 16 Nov. 2015, doi:10.1186/1745-6215-16-S2-P68), hereinafter Batchelor, as evidenced by Soliris® (eculizumab) prescribing information (Alexion Pharmaceuticals, Soliris® (eculizumab) Prescribing Information, revised 2017, OA.Appendix).This is a provisional nonstatutory double patenting rejection.
The co-pending claims recite a kit comprising an (a) anti-C5 antibody ravulizumab having the heavy and light chains of SEQ ID NOs: 14 and 11, respectively (corresponding to SEQ ID NOs: 14 and 11 of the instant claims (co-pending claim 28-30 and 32-33).
The co-pending claims do not teach administration of the anti-C5 antibody (ravulizumab) to treat vitiligo in a subject. Further, the dosage regimen of the anti-C5 antibody recited in the claims is not taught. Lastly, it is not taught that treatment efficacy is assessed by measuring repigmentation based on the comparison of pre-and post-treatment images or the Vitiligo Noticeability Scale (VNS).
However, Van Den Wijngaard teaches that under homeostatic conditions, self-cells are protected from classical and alternative pathways of complement activation by membrane embedded complement regulatory proteins which inhibit the formation of C3/C5 convertases of the classical and alternative pathways. Decreased expression of these molecules on melanocytes, in the presence of circulating antibodies against these cells, can contribute to complement‐mediated melanocyte loss in vitiligo (et al, see Summary and Introduction). Thus, terminal complement activation plays a role in the destruction of melanocytes, leading to the characteristic white patches of depigmentation seen in vitiligo.
Arata further teaches that inhibition of C5 cleavage into C5a and C5b by C5 modulatory compounds is useful for treating diseases in which C5 cleavage contributes to disease progression, including vitiligo (Abstract, Para. 0009, Para. 0015, Para. 0018, Para. 0020, Para. 0173, Para. 0176, and Para. 0189).
Andrien further teaches an anti-C5 antibody which (a) binds to complement component human C5; (b) inhibits the cleavage of C5 into fragments C5a and C5b ; and (c) comprises the heavy and light chains of SEQ ID NOs: 14 and 11, corresponding to SEQ ID NO: 14 and 11 of the instant claims. The antibody or antigen-binding fragment can have one of the following characteristics (a) binds to complement component C5 at pH 7.4 and 25°C with a dissociation constant (KD) ≤ 1 nM;(b) binds to C5 at pH 6.0 and 25°C with a KD≥10 nM;(c) wherein the [(KD of the antibody or antigen-binding fragment thereof for C5 at pH 6.0 and 25°C)/(KD of the antibody or antigen-binding fragment thereof for C5 at pH 7.4 and 25°C)] is greater than or equal to 25. (see entire document, in particular, Abstract, Summary of Invention, and Claims). The anti-C5 antibody can be administered intravenously (Para. 0146) and, in some embodiments, in combination with an anti-inflammatory agent to treat inflammatory disorders (Para. 0194).
Kulasekararaj further teaches that ravulizumab administered to patients having a complemented-associated disorder and previously treated with eculizumab resulted in immediate and complete inhibition of C5 activity that was sustained throughout the 26-week treatment period (~6 months) (Key Points, Abstract, Methods: Trial Oversight and Study Design, and Additional Secondary Endpoints: Figure 3 discussion). In particular, ravulizumab is administered at (a) a loading dose of 2400 mg for patients >40 kg to <60 kg, 2700 mg for patients >60 kg to <100 kg, 3000 mg for patients 2100 kg; and (b) a maintenance dose of: 3000 mg for patients >40 kg to <60 kg, 3300 mg for patients >60 kg to <100 kg, or 3600 mg for patients100 kg, two weeks after the loading dose and then once a week for 8 weeks (Methods: Trial Oversight and Study Design and Supplemental Appendix, Section 2-Suppmental Figure 1). Eculizumab-experienced patients received eculizumab at the labeled dose for ≥ 6 months prior to study entry (Methods: Patients).
Fenniche further teaches that the efficacy of vitiligo treatment is based on the percentage of repigmentation of the treated area as determined by comparing pre-and post-treatment photos. In particular, repigmentation is graded into one of four categories: excellent re-pigmentation (ER) (> 75% re-pigmentation), good repigmentation (GR) (50–75% repigmentation), moderate repigmentation (MR) (25–50% repigmentation), and poor repigmentation (PR) (< 25% repigmentation) (“Assessment of Treatment Efficacy” section on Page 128).
Batchelor further teaches that the Vitiligo Noticeability Scale (VNS) is a patient‐reported outcome measure that can be used to assess how ‘noticeable’ vitiligo patches are after treatment from the patient's perspective. The VNS is a better and more consistent indicator of global treatment success than percentage re-pigmentation, with VNS scores of 4 or 5 interpreted as representing treatment success (see Summary, Short Abstract, and Table 1).
It would have been obvious to one of ordinary skill in the art to intravenously administer the anti-C5 antibody of the co-pending claims (ravulizumab) to a patient having vitiligo—either alone or in combination with an anti-inflammatory agent—for a 6-month treatment period after the loading dose, wherein (a) the patient has been previously treated with eculizumab; (b) ravulizumab and eculizumab are administered according to the instantly recited dosing regimens; and (c) treatment efficacy is determined by measuring repigmentation based on pre-and post-treatment images of the treated area or the vitiligo noticeability scale (VNS). One of ordinary skill in the art would have been motivated to do so because terminal complement activation is involved in the pathogenesis of vitiligo as taught by Van den Wijngaard; and inhibition of C5 cleavage into C5a and C5b by C5 modulatory compounds, in particular, is useful for treating complement-mediated disorders, including vitiligo as taught by Arata. Since ravulizumab specifically binds to human C5 and inhibits the cleavage of C5 into C5a and C5b as taught by Andrien, it can be used to treat vitiligo. Moreover, ravulizumab administered according to the instantly claimed dosing regimen results in complete and sustained inhibition of C5 activity throughout a 26-week treatment period (~6 months) in patients with a complement-associated disorder and previously treated with labeled-dose eculizumab as taught by Kulasekararaj. Lastly, artisans would have been motivated either measure repigmentation based on the comparison of pre-and post-treatment images as taught by Fenniche or apply the Vitiligo Noticeability Scale (VNS) as taught by Batchelor in order to assess the efficacy of vitiligo treatment. Therefore, one of ordinary skill in the art would reasonably expect the anti-C5 antibody of the copending claims (ravulizumab)—either alone or in combination with an anti-inflammatory agent— to be able to treat vitiligo in a subject according to the regimen provided by Kulasekararaj, wherein the subject was previously administered labeled-dose eculizumab.
Claim 31 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6-13, 15, 17-19, 22-23, 25, 32, and 35 of co-pending Application No. 17057867 in view of Van Den Wijngaard, Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information, as applied to claims 1, 10, 23, 35, 39, 40, and 43 above, and further in view of Bodere et al (Borderé, Alicia Cecile et al. “Current and emerging therapy for the management of vitiligo.” Clinical, cosmetic and investigational dermatology vol. 2 15-25. 12 Mar. 2009, of record), hereinafter Bodere.
This is a provisional nonstatutory double patenting rejection.
The teachings of the co-pending claims in view of Van Den Wijngaard, Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information have been discussed above and differ from the instantly claimed invention in that it is not taught that the anti-inflammatory agent include topical corticosteroids and/or phototherapy.
However, Bodere teaches that topical corticosteroids and photo(chemotherapy) can be used for the treatment of vitiligo (see Abstract).
It would have been obvious to one of ordinary skill in the art to modify the method of treating vitiligo disclosed by prior art such that the anti-inflammatory agent administered in combination with the anti-C5 antibody is a topical corticosteroid or photo(chemo)therapy. One of ordinary skill in the art would have been motivated to do so since topical corticosteroids and photo(chemo)therapy are both options for the treatment of vitiligo in a subject. Therefore, one of ordinary skill in the art would reasonably expect that the anti-C5 antibody of the co-pending claims (ravuliuzmab) administered in combination with a topical corticosteroid or phototherapy can effectively treat vitiligo in a subject.
Claim 41 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6-13, 15, 17-19, 22-23, 25, 32, and 35 of co-pending Application No. 17057867 in view of Van Den Wijngaard, Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information, as applied to claims 1, 10, 23, 35, 39, 40, and 43 above, and further in view of Kim et al (Kim, Hyun Jung et al. Acta dermato-venereologica vol. 98,2 (2018): 180-184. doi:10.2340/00015555-2836), hereinafter Kim.
This is a provisional nonstatutory double patenting rejection.
The teachings of the co-pending claims in view of Van Den Wijngaard, Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that patient is refractory to topical treatment of vitiligo.
However, Kim teaches that the treatment of vitiligo is challenging and requires a multidisciplinary approach. Despite numerous available treatment options, including topical immune-suppressants, a high proportion of patients with vitiligo have resistant disease. Therefore, new therapeutic approaches are required to effectively treat refractory vitiligo in a patient (Abstract and first two paragraphs of Introduction).
It would have been obvious to one of ordinary skill in the art to modify the method of treating vitiligo taught as discussed previously such that the anti-C5 antibody ravulizumab is also administered to patients resistant (i.e. refractory) to existing treatment options, including topical therapy. One of ordinary skill in the art would have been motivated to do so because treatment of vitiligo requires multidisciplinary and novel therapeutic approaches given the high proportion of vitiligo patients refractory to available treatment options such as topical therapy as taught by Kim. Since terminal complement activation plays a role in vitiligo pathogenesis as taught by Van Den Wijngaard, blocking the cleavage of C5 into C5a and C5b using ravulizumab represents a therapeutic approach that would be beneficial in the treatment of vitiligo patients that are refractory to standard treatment options such as topical therapy. Therefore, one of ordinary skill in the art would reasonably expect that the anti-C5 antibody of the co-pending claims (ravulizumab) can be used to effectively treat patients having vitiligo that is refractory to topical treatment.
Claim 42 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6-13, 15, 17-19, 22-23, 25, 32, and 35 of co-pending Application No. 17057867 view of Van Den Wijngaard, Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information, as applied to claim 1, 10, 23, 35, 39, 40, and 43 above, and further in view of Lee et al (Lee, Jong Wook et al. “Blood vol. 133,6 (2019): 530-539. doi:10.1182/blood-2018-09-876136. Epub Date: 2018 Dec. 3), hereinafter Lee.
This is a provisional nonstatutory double patenting rejection.
The teachings of the co-pending claims in view of Van Den Wijngaard, Arata, Andrien, Kulasekararaj, Fenniche, Batchelor, as evidenced by Soliris® (eculizumab) prescribing information have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that patient is naïve to anti-C5 therapy.
However, Lee teaches that ravulizumab results in immediate, complete, and sustained inhibition of C5 throughout the treatment period in C5 inhibitor–naive patients having a complement-mediated disorder (see Key Points, Abstract, and Figure 3).
It would have been obvious to one of ordinary skill in the art to modify the method of treating vitiligo as discussed previously such that anti-C5 antibody of the co-pending claims (ravulizumab) is administered to a patient naïve to anti-C5 therapy. One of ordinary skill in the art would have been motivated to do so since ravulizumab results in immediate, complete, and sustained inhibition of C5 throughout the treatment period in C5 inhibitor–naive patients having a complement-mediated disorder as taught by Lee. As such, subjects having a complement-related disease that is naïve to anti-C5 therapy is a recognized patient populations in which treatment with ravulizumab is therapeutically effective. Therefore, one of ordinary skill in the art would reasonably expect that the anti-C5 antibody of the co-pending claims (ravulizumab) can effectively treat vitiligo in a patient that is naïve to anti-C5 therapy.
Response to Arguments
Applicant's arguments filed 03/09/2026 have been fully considered but they are not persuasive.
With respect to the rejections made under 35 USC 103, Applicant argues the following points;
The combination of cited references including Colley fail to teach or suggest all of the elements of the amended claims.
the primary reference Colley generally discloses that antibodies against C5/C5a/C5adesR may be useful for preventing or treating C5/C5a/C5adesR-mediated conditions. However, Colley exemplifies only mAbl to mAb9 and mAb12, all of which bind to a different target (i.e., C5a) than the antibody recited in the present claims (i.e., C5). The antibodies disclosed in Colley are thus unrelated to ravulizumab because they bind to C5a, an anaphylatoxin, which has little, if any, effect in the terminal complex pathway and formation of MAC (C5b9).
According to Colley the aforementioned species of antibodies (specifically, anti-C5a antibodies selected from mAbl to mAb9 and mAb12) are useful for treating a laundry list of inflammatory, autoimmune indications, and cancers, of which vitiligo is mentioned; however, Colley does not provide any scientific rationale or guidance to artisans that vitiligo could be treated with anti-C5a antibodies.
Colley teaches away from the presently claimed invention. Specifically, Example 19 of Colley discloses that an anti- C5 mAb (Eculizumab) which blocks cleavage of C5 to C5a and C5b, was less efficient at blocking C5a-mediated neutrophil activation when it is added to whole blood at the same time as E. coli. This indicated that blocking pre-existing C5a together with C5 has an advantage over blocking the generation of C5a. mAb9 binds to the C5a portion of C5 and thus neutralizes C5a before it is formed upon C5 cleavage when complement cascade is activated."
The data in Example 1 of the present application describes the surprising effect of anti-C5 antibody therapy in vitiligo patients. Specifically, six months after starting anti-C5 antibody therapy, the patient "unexpectedly noticed macules of repigmentation on his face and hands... and he never had such an improvement in his vitiligo [when treated with topical drugs] before starting eculizumab." These findings support the inventiveness of the presently claimed methods and could not have been predicted or expected from the combined teachings of the cited references.
Andrien, does not cure deficiencies of Colley because Andrien does not teach or suggest that anti-C5a antibodies and anti-C5 antibodies are interchangeable and that the same effects can be expected by interchanging the two, as the Office appears to imply, much less that ravulizumab can be used to treat vitiligo.
In response to Applicant’s arguments, the Examiner notes that the rejections in the present Office Action do not rely upon the teachings of Colley. Nevertheless, the Examiner maintains the positions previously set forth in the Response to Arguments of the Final Rejection mailed. Specifically, the Examiner notes that 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). Further, disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). Additionally, “[a] known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use.” In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994) (see MPEP 2163). Colley broadly teaches antibodies that target C5, C5a, and/or C5adesr as well as methods of treating autoimmune or inflammatory disorders such as vitiligo using such antibodies. Thus, the disclosure of Colley encompasses antibodies that target C5 such as ravulizumab (as taught by Andrien) and the methods are not limited only to the use of anti-C5a antibodies contrary to Applicant’s assertion.
Further, the prior art teaches that in homeostasis, self-cells are protected from classical and alternative pathways of complement activation by membrane embedded complement regulatory proteins that inhibit different steps of complement activation, which inhibit the formation of C3/C5 convertases of the classical and alternative pathways. And, it has been suggested that decreased expression of these molecules on melanocytes, in the presence of circulating antibodies against these cells, may contribute to complement‐mediated melanocyte loss in vitiligo (Van Den Wijngaard et al, see Summary and Introduction). Thus, it was known in the art that terminal complement activation plays a role in the destruction of melanocytes, leading to the characteristic white patches of depigmentation seen in vitiligo. As such, artisans would reasonably expect that an anti-C5 antibody that inhibits terminal complement activation such as ravulizumab to be able to effectively treat vitiligo by blocking complement-mediated destruction of melanocytes so that re-pigmentation can occur. Therefore, it is not unexpected for an anti-C5 antibody that inhibits terminal complement activation such as ravulizumab to promote re-pigmentation in a subject having vitiligo contrary to Applicant’s assertion.
Applicant has set forth similar arguments with respect to double patenting rejections concerning the deficiencies of the cited prior art in rendering obvious the instantly claimed invention. As such, the Examiner maintains the double patenting rejections for the same reasons set forth above for the rejections made under 35 U.S.C. 103 with the exception of the non-statutory double patenting rejection over U.S. Patent No. 9803007B1 directed to methods of treating PNH patients.
Conclusion
No claims are allowable.
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/LIA E TAYLOR/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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