DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Information Disclosure Statement
Four information disclosure statement (IDS) submitted: one on 1/03/2023; one on 04/11/2025; one on 10/24/2025; and one on 02/02/2026. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Specification
The incorporation of essential material in the specification by reference to an unpublished U.S. application (see two provisional applications in page 5, line 14 of the instant specification), foreign application or patent, or to a publication is improper. Applicant is required to amend the disclosure to include the material incorporated by reference, if the material is relied upon to overcome any objection, rejection, or other requirement imposed by the Office. The amendment must be accompanied by a statement executed by the applicant, or a practitioner representing the applicant, stating that the material being inserted is the material previously incorporated by reference and that the amendment contains no new matter. 37 CFR 1.57(g).
Status of the Claims
Claims 1-2 and 5-20 are pending in this application. Claims 3-4 have been cancelled by applicant.
Claim Interpretation
Complete TMA response is defined as simultaneous hematologic and renal improvement in patients with TMA, with platelets and LDH being the most frequent variables used for evaluating response in patients with aHUS (specification, page 60, lines 7-15).
The term “baseline” is not specifically defined in the specification. For the purposes of applying art, “baseline” will be interpreted as the respective parameter value in a subject with aHUS prior to administration of any treatment, in accordance with the guidance in the specification (e.g. page 16, lines 7-10).
Examiner Notes
Claim 16 is free of the prior art, but stands rejected under several obviousness-type non-statutory double patenting rejections.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-2 and 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over Adams et al. (WO 2015/009616 A1 – Cited in IDS).
Regarding claims 1-2, Adams discloses their compounds of Formula I below, as inhibitors of the complement alternative pathway and Factor B (abstract). Adams specifically discloses Iptacopan (page 175) and iptacopan HCl (page 176). Adams discloses that their invention provides methods of treating a complement related disease or disorder, such as atypical hemolytic uremic syndrome (aHUS), comprising administration of an effective amount of one of their compounds (para. bridging pages 50-51).
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Therefore, regarding claims 1-2, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to administer iptacopan HCl to a subject suffering from aHUS. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Adam’s disclosure of their compounds of Formula I, specifically their disclosure of iptacopan HCl, as inhibitors of the complement alternative pathway and Factor B; further in view of their teaching that their compounds can be administered as part of a method of treatment for aHUS.
Regarding claim 14, Adams discloses methods of treating glomerulonephritis by administering their compounds, which would be expected to improve reduced glomerular filtration rates (GRF) (page 51, para. 2, lines 9-12). Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to expect an improvement in GRF after treatment with Adam’s iptacopan HCl. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Adam’s teachings above.
Regarding claim 15, Adams teaches that compounds in their invention may inherently or by design form solvates with solvents (including water); and that it is intended that their invention embrace both solvated and unsolvated forms, such as hydrates (page 30, lines 11-17). Furthermore, Adams discloses their iptacopan HCl is prepared from a water/ acetonitrile medium (see page 176). While Adams doesn’t specifically disclose a monohydrate salt of their iptacopan HCl, a person with ordinary skill has good reason to pursue known options within his or her technical grasp. Note: MPEP 2143(E) KSR, 550 U.S. at 421, 82 USPQ2d at 1397.
Claims 5-13 and 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Adams et al. (WO 2015/009616 A1 – Cited in IDS); as applied to claims 1-2 and 14-15; in view of Fakhouri et al. (Am. J. Kidney Dis. 2016, 68: 84-93) (“Fakhouri”).
The teachings of Adams are disclosed above and incorporated herein.
While Adams does not specifically teach: (i) wherein treatment comprises achieving complete thrombotic microangiopathy (TMS) response, or normalization of lactate hydrogenase (LDH) to below the upper limit of normal (claims 7-8, 10-11, and 20); (iv) wherein TMA response comprises improving kidney function and reducing serum creatinine by about 10% or more as compared to a baseline (claim 12); (v) wherein treatment increases hemoglobin by about 0.5 g/dL or more (claim 13); (vi) wherein treatment stabilizes or improves eGFR (claim 14); the teachings of Fakhouri are relied upon for these disclosures.
Fakhouri teaches aHUS is a rare genetic life-threatening disease of chronic uncontrolled complement activation leading to thrombotic microangiopathy (TMA) and severe end-organ damage. Fakhouri discloses a study of eculizumab for aHUS; patients 18 years or older with aHUS (platelet count ≥ 150 x 103/ µL,hemoglobin ≤ lower limit of normal, lactate dehydrogenase ≥ 1.5 x upper limit of normal [ULN], and serum creatinine ≥ ULN) were included in this multicenter multinational study. Fakhouri discloses their primary end point was complete TMA response within 26 weeks, defined by hematologic normalization (platelet count ≥ 150 x 103/ µL and LDH ≤ ULN) and preservation of kidney function (< 25% serum creatine increase from baseline) (abstract). Fakhouri teaches 73% of their subjects were included during their first TMA manifestation – reading on treatment naïve subjects (abstract – Results). Fakhouri teaches complete TMA response was also characterized by improvement in hemoglobin levels by ≥ 2 g/dL (page 85, col. 2, End Points). Fakhouri also discloses aHUS patient reported gene mutations, which include C3, CFH, MCP, etc. (Table 1, page 87).
Regarding claim 5, Fakhouri teaches 73% of their subjects were included during their first TMA manifestation – reading on treatment naïve subjects (abstract – Results).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to administer Adams’ iptacopan HCl to a subject with aHUS who is naïve to complement inhibitor therapy. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Adams discloses iptacopan HCl as a complement inhibitor effective for the treatment of aHUS; further because Fakhouri teaches treatment of subjects with their first TMA manifestations, all of whom achieved complete TMA response.
Regarding claim 6, Fakhouri discloses that their patients were required to have been vaccinated against Neisseria meningitidis (page 85, col. 2, para. 1).
Therefore, it would have been prima facie obvious to vaccinate an aHUS patient against Neisseria meningitidis prior to administration of Adams’ complement inhibitor, in view of Fakhouri. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Adams teaches their iptacopan HCl as a complement inhibitor; and Fakhouri teaches their subjects were required to be vaccinated against Neisseria meningitidis at least 2 weeks prior to complement inhibitor administration; and even after vaccination, they report two cases of meningococcal infections (abstract – results).
Regarding claims 7-8, 10-12, and 20, it would have been prima facie obvious to one of ordinary skill prior to the effective filing of the claimed invention to administer Adams’ treatment until complete thrombotic microangiopathy (TMA) response was observed in terms of: (i) normalization of platelet count (claims 7-8 and 20), (ii) level of LDH being reduced to below ULN (claims 7, 10-11, and 20), (iii) reducing creating levels by about 10% or more compared to baseline (claims 7, 12, and 20). One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Adams discloses their alternative and complement pathway inhibitor, iptacopan HCl, as effective for the treatment of aHUS; further because Fakhouri discloses their primary end point for treating aHUS (to ensure improvement in hematologic, renal, and quality of life of subjects) was complete TMA response, which they define by hematologic normalization (platelet count ≥ 150 x 103/ µL (reading on claims 7-8 and 20) and LDH ≤ ULN (reading on claims 7, 10-11, and 20)) and preservation of kidney function (< 25% serum creatine increase from baseline (reading on claims 7, 12, and 20)).
Regarding claims 9 and 19, Fakhouri teaches hematologic normalization of platelet count to ≥ 150 x 103/ µL to ensure improvement in hematologic, renal, and quality of life of subjects (abstract).
Regarding claim 13, Fakhouri teaches complete TMA response was also characterized by improvement in hemoglobin levels by ≥ 2 g/dL (page 85, col. 2, End Points) – reading on about 0.5 g/dL or more.
Regarding the claimed ranges of platelet counts, LDH levels, creatine levels, and hemoglobin levels, as recited in claims 7-13 and 19-20, Applicant is advised that the courts have stated where the claimed ranges overlap or lie inside the ranges disclosed by the prior art and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists. See In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990); Titanium Metals Corp. of America v. Banner, 778 F2d 775. 227 USPQ 773 (Fed. Cir. 1985) (see MPEP 2144.05.01). The courts have also found that where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05-II.
Therefore, the claimed ranges merely represent an obvious variant and/or routine optimization of the values of the cited prior art.
Regarding claim 18, Fakhouri discloses aHUS patient reported gene mutations, which include C3, CFH, MCP, etc. (Table 1, page 87). Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to treat a subject with aHUS that has been determined to have the claimed mutations. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of the teachings of Adams and Fakhouri.
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Adams et al. (WO 2015/009616 A1 – Cited in IDS); in view of Fakhouri et al. (Am. J. Kidney Dis. 2016, 68: 84-93) (“Fakhouri”); as applied to claims 5-13 and 18-20; further in view of Zhang et al. (Hematology Reports, 2017; 9:7053) (“Zhang”).
The teachings of Adams and Fakhouri are disclosed above and incorporated herein.
While Adams in view of Fakhouri does not specifically teach: (i) wherein the subject is has been or is currently being treated with complement inhibitor therapy, immunosuppressive therapy, or other therapy for aHUS (claim 17); the teachings of Zhang are relied upon for these disclosures.
Zhang teaches 16 patients with aHUS with eculizumab-induced remission stopped treatment after a median of 4.3 months and home monitoring ensued. Five patients experienced relapse within 6 months of discontinuation and remission was successfully reinduced with immediate return to eculizumab therapy (page 65, col. 1, lines 12-19). Zhang teaches that eculizumab is expensive, and predisposes patients to meningococcal infections (page 64, col. 2, last para.).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to administer Adams in view of Fakhouri’s complement pathway inhibitor to an aHUS patient who has previously received treatment for aHUS, such as eculizumab, in view of Zhang. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Adams in view of Fakhouri teach iptacopan HCl for the treatment of aHUS; further because Zhang discloses that after complete remission due to eculizumab, patients experienced relapse after 6 months and were able to achieve remission after returning to treatment. One would have been further motivated to find alternative treatment options to eculizumab because Zhang teaches that eculizumab treatment is expensive, and predisposes patients to meningococcal infections.
Claims 5-6, 9, and 17-19 are rejected under 35 U.S.C. 103 as being unpatentable over Adams et al. (WO 2015/009616 A1 – Cited in IDS); as applied to claims 1-2 and 14-15; in view of Zhang et al. (Hematology Reports, 2017; 9:7053) (“Zhang”).
The teachings of Adams are disclosed above and incorporated herein.
While Adams does not specifically teach: (i) treatment of a subject who is naïve to complement inhibitor therapy (claim 5); (ii) wherein the subject has been vaccinated against Haemophilus influenzae infections (claim 6); (iii) wherein the platelet count is normalized to the claimed range (claims 9 and 19); (iv) wherein the subject is has been or is currently being treated with complement inhibitor therapy, immunosuppressive therapy, or other therapy for aHUS (claim 17); or (iv) a genetic mutation (claim 18); the teachings of Zhang are relied upon for these disclosures.
Zhang teaches ongoing complement activity in atypical HUS results from a failure of complement regulation. Complement regulatory proteins may be impaired in their action by loss-of-function mutations (CFH, CFI, CD46, and THBD) or acquired antibodies (specifically to complement factor H). Conversely, potentiation may be augmented by gain-of-function mutations in CFB or C3 (reading on claim 18) (page 62, col. 2, para. 2). Zhang discloses aHUS involves the following features: i) MAHA with hemoglobin levels below 10 g/dL, elevation of serum lactate dehydrogenase (LDH) level, notable decrease of serum haptoglobin level, and the presence of schistocytes on a peripheral blood smear; ii) thrombocytopenia with platelet counts less than 150 K/mcL and; iii) acute kidney injury (AKI) (defined as serum creatinine levels at least 1.5 times the upper limit of the age- and sex-specific pediatric reference range (page 63, col. 1, para. 1). The first-line treatment of patients with aHUS is eculizumab, by interdicting with the hemolytic process and rescuing native kidney function hence dramatically changing the prognosis of this potentially fatal syndrome (page 64, col. 1-2, last para.). Zhang discloses that treated patients experienced improvements in renal function, such as increase in GFR (page 64, col. 2); and teaches that treatment with eculizumab is expensive, and predisposes patients to meningococcal infections; that eculizumab carries a black box warning, advising vaccination against Neisseria meningitidis, and in non-immune individuals, consideration could also be
given to vaccination against Haemophilus influenzae (page 64, col. 3). Zhang teaches relapse is common after discontinuation of treatment, and that early detection of TMA recurrence and
prompt retreatment with eculizumab seem to be efficient in controlling of TMA and restoration of kidney functions. Zhang discloses initial treatment of aHUS with a course of therapeutic plasma exchange is reasonable while awaiting ADAMTS-13 activity level results in a new patient (reading on treatment naïve) (conclusions).
Regarding claim 5, Zhang teaches initial treatment with a course of therapeutic plasma exchange is reasonable while awaiting ADAMTS-13 activity level results in a new patient (reading on treatment naïve) to diagnose TPP or aHUS (conclusions). Zhang teaches eculizumab as the first-line treatment of patients with aHUS (page 64, col. 1-2, last para.); and discloses that eculizumab is expensive, and predisposes patients to meningococcal infections; and teaches relapse is common after discontinuation of treatment.
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to administer Adams’ iptacopan HCl to a subject with aHUS who is naïve to complement inhibitor therapy. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Adams discloses iptacopan HCl as a complement inhibitor effective for the treatment of aHUS; further because Zhang teaches that in new patients (treatment naïve), plasma exchange is reasonable while awaiting ADAMTS-13 activity level; further because Zhang discloses that while eculizumab has become a first-line treatment for patients with aHUS, considerable work remains to be done, and points to emerging complement-directed therapeutics as alternatives for the future.
Regarding claim 6, Zhang teaches that late-complement-inhibition has predisposed subjects to meningococcal infections, advising vaccination against Neisseria meningitidis, and in non-immune individuals, consideration could also be given to vaccination against Haemophilus influenzae (page 64, col. 3). Therefore, it would have been prima facie obvious to vaccinate an aHUS patient against Neisseria meningitidis and Haemophilus influenzae prior to administration of Adams’ complement inhibitor, in view of Zhang. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Adams teaches their iptacopan HCl as a complement inhibitor; and Zhang teaches late-complement-inhibition has predisposed subjects to meningococcal infections.
Regarding claims 9 and 19, Zhang teaches that aHUS involves platelet counts less than 150 k/ µL (= 150 x 109 /L) (page 63, col. 1, line 11). Zhang also teaches that treatment with a complement inhibitor normalized hemolytic markers and platelet count in 90% of patients with aHUS refractory to plasma exchange (page 64, col. 2). Therefore, Adam in view of Zhang suggests that treatment with Adams’ complement inhibitor will result in platelet counts higher than 150 x 109 /L, reading on the instantly claimed range.
Applicant is advised that the courts have stated where the claimed ranges overlap or lie inside the ranges disclosed by the prior art and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists. See In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990); Titanium Metals Corp. of America v. Banner, 778 F2d 775. 227 USPQ 773 (Fed. Cir. 1985) (see MPEP 2144.05.01). The courts have also found that where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05-II.
Therefore, the claimed ranges merely represent an obvious variant and/or routine optimization of the values of the cited prior art.
Regarding claim 17, Zhang teaches 16 patients with aHUS with eculizumab-induced remission stopped treatment after a median of 4.3 months and home monitoring ensued. Five patients experienced relapse within 6 months of discontinuation and remission was successfully reinduced with immediate return to eculizumab therapy (page 65, col. 1, lines 12-19); and that that eculizumab is expensive, and predisposes patients to meningococcal infections.
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to administer Adams’s complement pathway inhibitor to an aHUS patient who has previously received treatment for aHUS, such as eculizumab. One of ordinary skill would have been motivated to do so because Zhang discloses that after complete remission due to eculizumab, patients experienced relapse after 6 months and were able to achieve remission after returning to treatment. Further because Adams discloses their complement inhibitor compound, effective for the treatment of aHUS; and Zhang teaches that eculizumab is expensive, and predisposes patients to meningococcal infections.
Regarding claim 18, Zhang teaches ongoing complement activity in atypical HUS results from a failure of complement regulation. Complement regulatory proteins may be impaired in their action by loss-of-function mutations (CFH, CFI, CD46, and THBD) or acquired antibodies (specifically to complement factor H). Conversely, potentiation may be augmented by gain-of-function mutations in CFB or C3 (page 62, col. 2, para. 2). Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to treat a subject with aHUS that has been determined to have the claimed mutations. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of the teachings of Adams and Zhang.
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 1-2 and 14-16 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 11,603,363 B2 (US ‘363); in view of Adams et al. (WO 2015/009616 A1 – Cited in IDS).
Regarding claims 1-2 and 14-16, US ‘363 claims a crystalline hydrate form of iptacopan HCl (instantly claimed as Form HB – claim 16), wherein the hydrate is a monohydrate (US ‘363’s claims 1 and 7). US ‘363 discloses their compound as a complement inhibitor (abstract)
While US ‘363 does not claim their compound in a method of treating aHUS; the teachings of Adams are relied upon for these disclosures.
Adams discloses iptacopan HCl, as an inhibitor of the complement alternative pathway and Factor B (abstract). Adams discloses that their invention provides methods of treating a complement related disease or disorder, such as atypical hemolytic uremic syndrome (aHUS), comprising administration of an effective amount of one of their compounds (para. bridging pages 50-51).
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Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to administer US ‘363’s iptacopan HCl hydrate form to a subject suffering from aHUS. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of US ‘363’s disclosure of their complement inhibitor compound and pharmaceutical compositions thereof; further in view of Adam’s disclosure that iptacopan HCl can be administered as part of a method of treatment for aHUS.
Claims 5-13 and 18-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 11,603,363 B2 (US ‘363); in view of Adams et al. (WO 2015/009616 A1 – Cited in IDS); as applied to claims 1-2 and 14-16; further in view of Fakhouri et al. (Am. J. Kidney Dis. 2016, 68: 84-93) (“Fakhouri”).
The teachings of US ‘363 and Adams are disclosed above and incorporated herein.
While US ‘363 and Adams do not specifically teach: (i) wherein treatment comprises achieving complete thrombotic microangiopathy (TMS) response, or normalization of lactate hydrogenase (LDH) to below the upper limit of normal (claims 7-8, 10-11, and 20); (iv) wherein TMA response comprises improving kidney function and reducing serum creatinine by about 10% or more as compared to a baseline (claim 12); (v) wherein treatment increases hemoglobin by about 0.5 g/dL or more (claim 13); (vi) wherein treatment stabilizes or improves eGFR (claim 14); the teachings of Fakhouri are relied upon for these disclosures.
Fakhouri teaches HUS is a rare genetic life-threatening disease of chronic uncontrolled complement activation leading to thrombotic microangiopathy (TMA) and severe end-organ damage. Fakhouri discloses a study of eculizumab for aHUS; patients 18 years or older with aHUS (platelet count ≥ 150 x 103/ µL,hemoglobin ≤ lower limit of normal, lactate dehydrogenase ≥ 1.5 x upper limit of normal [ULN], and serum creatinine ≥ ULN) were included in this multicenter multinational study. Fakhouri discloses their primary end point was complete TMA response within 26 weeks, defined by hematologic normalization (platelet count ≥ 150 x 103/ µL and LDH ≤ ULN) and preservation of kidney function (< 25% serum creatine increase from baseline) (abstract). Fakhouri teaches 73% of their subjects were included during their first TMA manifestation – reading on treatment naïve subjects (abstract – Results). Fakhouri teaches complete TMA response was also characterized by improvement in hemoglobin levels by ≥ 2 g/dL (page 85, col. 2, End Points). Fakhouri also discloses aHUS patient reported gene mutations, which include C3, CFH, MCP, etc. (Table 1, page 87).
Regarding claim 5, Fakhouri teaches 73% of their subjects were included during their first TMA manifestation – reading on treatment naïve subjects (abstract – Results).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to administer US ‘363 and Adams’ iptacopan HCl to a subject with aHUS who is naïve to complement inhibitor therapy. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because US ‘363 and Adams disclose iptacopan HCl and pharmaceutical compositions thereof as a complement inhibitor effective for the treatment of aHUS; further because Fakhouri teaches treatment of subjects with their first TMA manifestations, all of whom achieved complete TMA response.
Regarding claim 6, Fakhouri discloses that their patients were required to have been vaccinated against Neisseria meningitidis (page 85, col. 2, para. 1).
Therefore, it would have been prima facie obvious to vaccinate an aHUS patient against Neisseria meningitidis prior to administration of US ‘363 and Adams’ complement inhibitor, in view of Fakhouri. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because US ‘363 and Adams teach their iptacopan HCl as a complement inhibitor; and Fakhouri teaches their subjects were required to be vaccinated against Neisseria meningitidis at least 2 weeks prior to complement inhibitor administration; and even after vaccination, they report two cases of meningococcal infections (abstract – results).
Regarding claims 7-8, 10-12, and 20, it would have been prima facie obvious to one of ordinary skill prior to the effective filing of the claimed invention to administer US ‘363 and Adams’ treatment until complete thrombotic microangiopathy (TMA) response was observed in terms of: (i) normalization of platelet count (claims 7-8 and 20), (ii) level of LDH being reduced to below ULN (claims 7, 10-11, and 20), (iii) reducing creating levels by about 10% or more compared to baseline (claims 7, 12, and 20). One of ordinary skill would have been motivated to do so with a reasonable expectation of success because US ‘363 and Adams disclose their alternative and complement pathway inhibitor, iptacopan HCl, as effective for the treatment of aHUS; further because Fakhouri discloses their primary end point for treating aHUS (to ensure improvement in hematologic, renal, and quality of life of subjects) was complete TMA response, which they define by hematologic normalization (platelet count ≥ 150 x 103/ µL (reading on claims 7-8 and 20) and LDH ≤ ULN (reading on claims 7, 10-11, and 20)) and preservation of kidney function (< 25% serum creatine increase from baseline (reading on claims 7, 12, and 20)).
Regarding claims 9 and 19, Fakhouri teaches hematologic normalization of platelet count to ≥ 150 x 103/ µL to ensure improvement in hematologic, renal, and quality of life of subjects (abstract).
Regarding claim 13, Fakhouri teaches complete TMA response was also characterized by improvement in hemoglobin levels by ≥ 2 g/dL (page 85, col. 2, End Points) – reading on about 0.5 g/dL or more.
Regarding the claimed ranges of platelet counts, LDH levels, creatine levels, and hemoglobin levels, as recited in claims 7-13 and 19-20, Applicant is advised that the courts have stated where the claimed ranges overlap or lie inside the ranges disclosed by the prior art and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists. See In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990); Titanium Metals Corp. of America v. Banner, 778 F2d 775. 227 USPQ 773 (Fed. Cir. 1985) (see MPEP 2144.05.01). The courts have also found that where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05-II.
Therefore, the claimed ranges merely represent an obvious variant and/or routine optimization of the values of the cited prior art.
Regarding claim 18, Fakhouri discloses aHUS patient reported gene mutations, which include C3, CFH, MCP, etc. (Table 1, page 87). Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to treat a subject with aHUS that has been determined to have the claimed mutations. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of the teachings of US ‘363, Adams and Fakhouri.
Claim 17 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 11,603,363 B2 (US ‘363); in view of Adams et al. (WO 2015/009616 A1 – Cited in IDS); as applied to claims 1-2 and 14-16; further in view of Zhang et al. (Hematology Reports, 2017; 9:7053) (“Zhang”).
The teachings of US ‘363 and Adams are disclosed above and incorporated herein.
While US ‘363 and Adams do not specifically teach: (i) wherein the subject is has been or is currently being treated with complement inhibitor therapy, immunosuppressive therapy, or other therapy for aHUS (claim 17); the teachings of Zhang are relied upon for these disclosures.
Zhang teaches 16 patients with aHUS with eculizumab-induced remission stopped treatment after a median of 4.3 months and home monitoring ensued. Five patients experienced relapse within 6 months of discontinuation and remission was successfully reinduced with immediate return to eculizumab therapy (page 65, col. 1, lines 12-19). Zhang teaches that eculizumab is expensive, and predisposes patients to meningococcal infections (page 64, col. 2, last para.).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to administer US ‘363 and Adams’s complement pathway inhibitor to an aHUS patient who has previously received treatment for aHUS, such as eculizumab, in view of Zhang. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because US ‘363 and Adams teach iptacopan HCl for the treatment of aHUS; further because Zhang discloses that after complete remission due to eculizumab, patients experienced relapse after 6 months and were able to achieve remission after returning to treatment. One would have been further motivated to find alternative treatment options to eculizumab because Zhang teaches that eculizumab treatment is expensive, and predisposes patients to meningococcal infections.
Claims 1-2, 6, and 13-15 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-49 of U.S. Patent No. 12,453,726 B2 (US ‘726); in view of Adams et al. (WO 2015/009616 A1 – Cited in IDS).
Regarding claims 1-2 and 14-15, US ‘726 claims a method of treating intravascular hemolysis in a subject, comprising administration of iptacopan benzoate (US ‘726’s claim 1). US ‘726 discloses their compound as a complement inhibitor (abstract).
Regarding instant claim 6, US ‘726 claims their method wherein the subject has been vaccinated against Neisseria meningitidis (US ‘726 claim 24).
Regarding instant claim 13, US ‘726 discloses their method, wherein treatment normalizes hemoglobin levels by about 2 g/dL (US ‘726 claim 2), and wherein treatment efficacy is determinded based on hemoglobin levels compared to a baseline (US ‘726 claim 25).
While US ‘726 does not claim: (i) their method for the treatment of aHUS; the teachings of Adams are relied upon for these disclosures.
Adams discloses iptacopan HCl, as an inhibitor of the complement alternative pathway and Factor B (abstract). Adams discloses that their invention provides methods of treating a complement related disease or disorder, such as atypical hemolytic uremic syndrome (aHUS), comprising administration of an effective amount of one of their compounds (para. bridging pages 50-51).
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Therefore, regarding claims 1, 6, and 13-15, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to administer US ‘726’s iptacopan benzoate (or Adams’ iptacopan HCl) to a subject suffering from aHUS. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of US ‘726’s disclosure of their complement inhibitor compound; further in view of Adam’s disclosure that iptacopan HCl can be administered as part of a method of treatment for aHUS.
Claims 5, 7-12, and 18-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-49 of U.S. Patent No. 12,453,726 B2 (US ‘726); in view of Adams et al. (WO 2015/009616 A1 – Cited in IDS); as applied to claims 1-2, 6, and 13-15; further in view of Fakhouri et al. (Am. J. Kidney Dis. 2016, 68: 84-93) (“Fakhouri”).
The teachings of US ‘726 and Adams are disclosed above and incorporated herein.
Regarding instant claims 10-11 and 20, US ‘726 claims wherein their method reduced levels of LDH (US ‘726 claim 8-9).
While US ‘726 and Adams don’t specifically teach: (i) wherein treatment comprises achieving complete thrombotic microangiopathy (TMS) response, or normalization of platelet count (claims 7-8 and 20); (iv) wherein TMA response comprises improving kidney function and reducing serum creatinine by about 10% or more as compared to a baseline (claim 12).
Fakhouri teaches HUS is a rare genetic life-threatening disease of chronic uncontrolled complement activation leading to thrombotic microangiopathy (TMA) and severe end-organ damage. Fakhouri discloses a study of eculizumab for aHUS; patients 18 years or older with aHUS (platelet count ≥ 150 x 103/ µL,hemoglobin ≤ lower limit of normal, lactate dehydrogenase ≥ 1.5 x upper limit of normal [ULN], and serum creatinine ≥ ULN) were included in this multicenter multinational study. Fakhouri discloses their primary end point was complete TMA response within 26 weeks, defined by hematologic normalization (platelet count ≥ 150 x 103/ µL and LDH ≤ ULN) and preservation of kidney function (< 25% serum creatine increase from baseline) (abstract). Fakhouri teaches 73% of their subjects were included during their first TMA manifestation – reading on treatment naïve subjects (abstract – Results). Fakhouri teaches complete TMA response was also characterized by improvement in hemoglobin levels by ≥ 2 g/dL (page 85, col. 2, End Points). Fakhouri also discloses aHUS patient reported gene mutations, which include C3, CFH, MCP, etc. (Table 1, page 87).
Regarding claim 5, Fakhouri teaches 73% of their subjects were included during their first TMA manifestation – reading on treatment naïve subjects (abstract – Results).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to administer US ‘726 and Adams’ iptacopan to a subject with aHUS who is naïve to complement inhibitor therapy. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because US ‘726 and Adams disclose iptacopan as a complement inhibitor effective for the treatment of aHUS; further because Fakhouri teaches treatment of subjects with their first TMA manifestations, all of whom achieved complete TMA response.
Regarding claims 7-8, 10-12, and 20, it would have been prima facie obvious to one of ordinary skill prior to the effective filing of the claimed invention to administer US ‘726 and Adams’ treatment until complete thrombotic microangiopathy (TMA) response was observed in terms of: (i) normalization of platelet count (claims 7-8 and 20), (ii) level of LDH being reduced to below ULN (claims 7, 10-11, and 20), (iii) reducing creating levels by about 10% or more compared to baseline (claims 7, 12, and 20). One of ordinary skill would have been motivated to do so with a reasonable expectation of success because US ‘726 and Adams disclose their alternative and complement pathway inhibitor, iptacopan, as effective for the treatment of aHUS; further because Fakhouri discloses their primary end point for treating aHUS (to ensure improvement in hematologic, renal, and quality of life of subjects) was complete TMA response, which they define by hematologic normalization (platelet count ≥ 150 x 103/ µL (reading on claims 7-8 and 20) and LDH ≤ ULN (reading on claims 7, 10-11, and 20)) and preservation of kidney function (< 25% serum creatine increase from baseline (reading on claims 7, 12, and 20)).
Regarding claims 9 and 19, Fakhouri teaches hematologic normalization of platelet count to ≥ 150 x 103/ µL to ensure improvement in hematologic, renal, and quality of life of subjects (abstract).
Regarding the claimed ranges of platelet counts, LDH levels, creatine levels, and hemoglobin levels, as recited in claims 7-13 and 19-20, Applicant is advised that the courts have stated where the claimed ranges overlap or lie inside the ranges disclosed by the prior art and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists The courts have also found that where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.
Therefore, the claimed ranges merely represent an obvious variant and/or routine optimization of the values of the cited prior art.
Regarding claim 18, Fakhouri discloses aHUS patient reported gene mutations, which include C3, CFH, MCP, etc. (Table 1, page 87). Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to treat a subject with aHUS that has been determined to have the claimed mutations. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of the teachings of US ‘726, Adams and Fakhouri.
Claim 17 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-49 of U.S. Patent No. 12,453,726 B2 (US ‘726); in view of Adams et al. (WO 2015/009616 A1 – Cited in IDS); as applied to claims 1-2 and 14-16; further in view of Zhang et al. (Hematology Reports, 2017; 9:7053) (“Zhang”).
The teachings of US ‘726 and Adams are disclosed above and incorporated herein.
While US ‘726 and Adams do not specifically teach: (i) wherein the subject is has been or is currently being treated with complement inhibitor therapy, immunosuppressive therapy, or other therapy for aHUS (claim 17); the teachings of Zhang are relied upon for these disclosures.
Zhang teaches 16 patients with aHUS with eculizumab-induced remission stopped treatment after a median of 4.3 months and home monitoring ensued. Five patients experienced relapse within 6 months of discontinuation and remission was successfully reinduced with immediate return to eculizumab therapy (page 65, col. 1, lines 12-19). Zhang teaches that eculizumab is expensive, and predisposes patients to meningococcal infections (page 64, col. 2, last para.).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to administer US ‘726 and Adams’s complement pathway inhibitor to an aHUS patient who has previously received treatment for aHUS, such as eculizumab, in view of Zhang. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because US ‘726 and Adams teach iptacopan for the treatment of aHUS; further because Zhang discloses that after complete remission due to eculizumab, patients experienced relapse after 6 months and were able to achieve remission after returning to treatment. One would have been further motivated to find alternative treatment options to eculizumab because Zhang teaches that eculizumab treatment is expensive, and predisposes patients to meningococcal infections.
Claims 1-2 and 14-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 4 of copending Application No. 18/569,432 (Copending ‘432); in view of Adams et al. (WO 2015/009616 A1 – Cited in IDS).
Regarding instant claims 1-2 and 15-16, Copending ‘432 claims a method of treating autoimmune hematological conditions (reading on aHUS), comprising administration of an iptacopan salt thereof, specifically claiming Form HB (Copending ‘432 claims 1 and 4).
While Copending ‘432 does not claim their compound in a method of treating aHUS; the teachings of Adams are relied upon for these disclosures.
Adams discloses iptacopan HCl, as an inhibitor of the complement alternative pathway and Factor B (abstract). Adams discloses that their invention provides methods of treating a complement related disease or disorder, such as atypical hemolytic uremic syndrome (aHUS), comprising administration of an effective amount of one of their compounds (para. bridging pages 50-51).
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Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to administer Copending ‘432’s iptacopan HCl hydrate form to a subject suffering from aHUS. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Copending ‘432’s disclosure of their complement inhibitor compound and pharmaceutical compositions thereof; further in view of Adam’s disclosure that iptacopan HCl can be administered as part of a method of treatment for aHUS.
This is a provisional nonstatutory double patenting rejection.
Claims 5-13 and 18-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 and 4 of copending Application No. 18/569,432 (Copending ‘432); in view of Adams et al. (WO 2015/009616 A1 – Cited in IDS); as applied to claims 1-2 and 14-16; further in view of Fakhouri et al. (Am. J. Kidney Dis. 2016, 68: 84-93) (“Fakhouri”).
The teachings of Copending ‘432 and Adams are disclosed above and incorporated herein.
While Copending ‘432 and Adams do not specifically teach: (i) wherein treatment comprises achieving complete thrombotic microangiopathy (TMS) response, or normalization of lactate hydrogenase (LDH) to below the upper limit of normal (claims 7-8, 10-11, and 20); (iv) wherein TMA response comprises improving kidney function and reducing serum creatinine by about 10% or more as compared to a baseline (claim 12); (v) wherein treatment increases hemoglobin by about 0.5 g/dL or more (claim 13); (vi) wherein treatment stabilizes or improves eGFR (claim 14); the teachings of Fakhouri are relied upon for these disclosures.
Fakhouri teaches HUS is a rare genetic life-threatening disease of chronic uncontrolled complement activation leading to thrombotic microangiopathy (TMA) and severe end-organ damage. Fakhouri discloses a study of eculizumab for aHUS; patients 18 years or older with aHUS (platelet count ≥ 150 x 103/ µL,hemoglobin ≤ lower limit of normal, lactate dehydrogenase ≥ 1.5 x upper limit of normal [ULN], and serum creatinine ≥ ULN) were included in this multicenter multinational study. Fakhouri discloses their primary end point was complete TMA response within 26 weeks, defined by hematologic normalization (platelet count ≥ 150 x 103/ µL and LDH ≤ ULN) and preservation of kidney function (< 25% serum creatine increase from baseline) (abstract). Fakhouri teaches 73% of their subjects were included during their first TMA manifestation – reading on treatment naïve subjects (abstract – Results). Fakhouri teaches complete TMA response was also characterized by improvement in hemoglobin levels by ≥ 2 g/dL (page 85, col. 2, End Points). Fakhouri also discloses aHUS patient reported gene mutations, which include C3, CFH, MCP, etc. (Table 1, page 87).
Regarding claim 5, Fakhouri teaches 73% of their subjects were included during their first TMA manifestation – reading on treatment naïve subjects (abstract – Results).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to administer Copending ‘432 and Adams’ iptacopan HCl to a subject with aHUS who is naïve to complement inhibitor therapy. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Copending ‘432 and Adams disclose iptacopan HCl and pharmaceutical compositions thereof as a complement inhibitor effective for the treatment of aHUS; further because Fakhouri teaches treatment of subjects with their first TMA manifestations, all of whom achieved complete TMA response.
Regarding claim 6, Fakhouri discloses that their patients were required to have been vaccinated against Neisseria meningitidis (page 85, col. 2, para. 1).
Therefore, it would have been prima facie obvious to vaccinate an aHUS patient against Neisseria meningitidis prior to administration of Copending ‘432 and Adams’ complement inhibitor, in view of Fakhouri. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Copending ‘432 and Adams teache their iptacopan HCl as a complement inhibitor; and Fakhouri teaches their subjects were required to be vaccinated against Neisseria meningitidis at least 2 weeks prior to complement inhibitor administration; and even after vaccination, they report two cases of meningococcal infections (abstract – results).
Regarding claims 7-8, 10-12, and 20, it would have been prima facie obvious to one of ordinary skill prior to the effective filing of the claimed invention to administer Copending ‘432 and Adams’ treatment until complete thrombotic microangiopathy (TMA) response was observed in terms of: (i) normalization of platelet count (claims 7-8 and 20), (ii) level of LDH being reduced to below ULN (claims 7, 10-11, and 20), (iii) reducing creating levels by about 10% or more compared to baseline (claims 7, 12, and 20). One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Copending ‘432 and Adams disclose their alternative and complement pathway inhibitor, iptacopan HCl, as effective for the treatment of aHUS; further because Fakhouri discloses their primary end point for treating aHUS (to ensure improvement in hematologic, renal, and quality of life of subjects) was complete TMA response, which they define by hematologic normalization (platelet count ≥ 150 x 103/ µL (reading on claims 7-8 and 20) and LDH ≤ ULN (reading on claims 7, 10-11, and 20)) and preservation of kidney function (< 25% serum creatine increase from baseline (reading on claims 7, 12, and 20)).
Regarding claims 9 and 19, Fakhouri teaches hematologic normalization of platelet count to ≥ 150 x 103/ µL to ensure improvement in hematologic, renal, and quality of life of subjects (abstract).
Regarding claim 13, Fakhouri teaches complete TMA response was also characterized by improvement in hemoglobin levels by ≥ 2 g/dL (page 85, col. 2, End Points) – reading on about 0.5 g/dL or more.
Regarding the claimed ranges of platelet counts, LDH levels, creatine levels, and hemoglobin levels, as recited in claims 7-13 and 19-20, Applicant is reminded that the courts have stated where the claimed ranges overlap or lie inside the ranges disclosed by the prior art and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists. The courts have also found that where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.
Therefore, the claimed ranges merely represent an obvious variant and/or routine optimization of the values of the cited prior art.
Regarding claim 18, Fakhouri discloses aHUS patient reported gene mutations, which include C3, CFH, MCP, etc. (Table 1, page 87). Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to treat a subject with aHUS that has been determined to have the claimed mutations. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of the teachings of Copending ‘432, Adams and Fakhouri.
This is a provisional nonstatutory double patenting rejection.
Claims 17 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 and 4 of copending Application No. 18/569,432 (Copending ‘432); in view of Adams et al. (WO 2015/009616 A1 – Cited in IDS); as applied to claims 1-2 and 14-16; further in view of Zhang et al. (Hematology Reports, 2017; 9:7053) (“Zhang”).
The teachings of Copending ‘432 and Adams are disclosed above and incorporated herein.
While Copending ‘432 and Adams do not specifically teach: (i) wherein the subject is has been or is currently being treated with complement inhibitor therapy, immunosuppressive therapy, or other therapy for aHUS (claim 17); the teachings of Zhang are relied upon for these disclosures.
Zhang teaches 16 patients with aHUS with eculizumab-induced remission stopped treatment after a median of 4.3 months and home monitoring ensued. Five patients experienced relapse within 6 months of discontinuation and remission was successfully reinduced with immediate return to eculizumab therapy (page 65, col. 1, lines 12-19). Zhang teaches that eculizumab is expensive, and predisposes patients to meningococcal infections (page 64, col. 2, last para.).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to administer Copending ‘432 and Adams’s complement pathway inhibitor to an aHUS patient who has previously received treatment for aHUS, such as eculizumab, in view of Zhang. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Copending ‘432 and Adams teach iptacopan HCl for the treatment of aHUS; further because Zhang discloses that after complete remission due to eculizumab, patients experienced relapse after 6 months and were able to achieve remission after returning to treatment. One would have been further motivated to find alternative treatment options to eculizumab because Zhang teaches that eculizumab treatment is expensive, and predisposes patients to meningococcal infections.
This is a provisional nonstatutory double patenting rejection.
Claims 1-2 and 14-15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 18/689,933 (Copending ‘933); in view of Adams et al. (WO 2015/009616 A1 – Cited in IDS).
Regarding instant claims 1-2 and 15-16, Copending ‘933 claims a method of treating AMD, comprising administration of an iptacopan salt thereof (Copending ‘933 claim 1).
While Copending ‘933 does not claim their compound in a method of treating aHUS; the teachings of Adams are relied upon for these disclosures.
Adams discloses iptacopan HCl, as an inhibitor of the complement alternative pathway and Factor B (abstract). Adams discloses that their invention provides methods of treating a complement related disease or disorder, such as atypical hemolytic uremic syndrome (aHUS), comprising administration of an effective amount of one of their compounds (para. bridging pages 50-51).
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Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to administer Copending ‘933’s iptacopan HCl hydrate form to a subject suffering from aHUS. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Copending ‘933’s disclosure of their complement inhibitor compound and pharmaceutical compositions thereof; further in view of Adam’s disclosure that iptacopan HCl can be administered as part of a method of treatment for aHUS.
This is a provisional nonstatutory double patenting rejection.
Claims 5-13 and 18-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 18/689,933 (Copending ‘933); in view of Adams et al. (WO 2015/009616 A1 – Cited in IDS); as applied to claims 1-2 and 14-15; further in view of Fakhouri et al. (Am. J. Kidney Dis. 2016, 68: 84-93) (“Fakhouri”).
The teachings of Copending ‘933 and Adams are disclosed above and incorporated herein.
While Copending ‘933 and Adams do not specifically teach: (i) wherein treatment comprises achieving complete thrombotic microangiopathy (TMS) response, or normalization of lactate hydrogenase (LDH) to below the upper limit of normal (claims 7-8, 10-11, and 20); (iv) wherein TMA response comprises improving kidney function and reducing serum creatinine by about 10% or more as compared to a baseline (claim 12); (v) wherein treatment increases hemoglobin by about 0.5 g/dL or more (claim 13); (vi) wherein treatment stabilizes or improves eGFR (claim 14); the teachings of Fakhouri are relied upon for these disclosures.
Fakhouri teaches HUS is a rare genetic life-threatening disease of chronic uncontrolled complement activation leading to thrombotic microangiopathy (TMA) and severe end-organ damage. Fakhouri discloses a study of eculizumab for aHUS; patients 18 years or older with aHUS (platelet count ≥ 150 x 103/ µL,hemoglobin ≤ lower limit of normal, lactate dehydrogenase ≥ 1.5 x upper limit of normal [ULN], and serum creatinine ≥ ULN) were included in this multicenter multinational study. Fakhouri discloses their primary end point was complete TMA response within 26 weeks, defined by hematologic normalization (platelet count ≥ 150 x 103/ µL and LDH ≤ ULN) and preservation of kidney function (< 25% serum creatine increase from baseline) (abstract). Fakhouri teaches 73% of their subjects were included during their first TMA manifestation – reading on treatment naïve subjects (abstract – Results). Fakhouri teaches complete TMA response was also characterized by improvement in hemoglobin levels by ≥ 2 g/dL (page 85, col. 2, End Points). Fakhouri also discloses aHUS patient reported gene mutations, which include C3, CFH, MCP, etc. (Table 1, page 87).
Regarding claim 5, Fakhouri teaches 73% of their subjects were included during their first TMA manifestation – reading on treatment naïve subjects (abstract – Results).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to administer Copending ‘933 and Adams’ iptacopan HCl to a subject with aHUS who is naïve to complement inhibitor therapy. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Copending ‘933 and Adams disclose iptacopan HCl and pharmaceutical compositions thereof as a complement inhibitor effective for the treatment of aHUS; further because Fakhouri teaches treatment of subjects with their first TMA manifestations, all of whom achieved complete TMA response.
Regarding claim 6, Fakhouri discloses that their patients were required to have been vaccinated against Neisseria meningitidis (page 85, col. 2, para. 1).
Therefore, it would have been prima facie obvious to vaccinate an aHUS patient against Neisseria meningitidis prior to administration of Copending ‘933 and Adams’ complement inhibitor, in view of Fakhouri. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Copending ‘933 and Adams teache their iptacopan HCl as a complement inhibitor; and Fakhouri teaches their subjects were required to be vaccinated against Neisseria meningitidis at least 2 weeks prior to complement inhibitor administration; and even after vaccination, they report two cases of meningococcal infections (abstract – results).
Regarding claims 7-8, 10-12, and 20, it would have been prima facie obvious to one of ordinary skill prior to the effective filing of the claimed invention to administer Copending ‘933 and Adams’ treatment until complete thrombotic microangiopathy (TMA) response was observed in terms of: (i) normalization of platelet count (claims 7-8 and 20), (ii) level of LDH being reduced to below ULN (claims 7, 10-11, and 20), (iii) reducing creating levels by about 10% or more compared to baseline (claims 7, 12, and 20). One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Copending ‘933 and Adams disclose their alternative and complement pathway inhibitor, iptacopan HCl, as effective for the treatment of aHUS; further because Fakhouri discloses their primary end point for treating aHUS (to ensure improvement in hematologic, renal, and quality of life of subjects) was complete TMA response, which they define by hematologic normalization (platelet count ≥ 150 x 103/ µL (reading on claims 7-8 and 20) and LDH ≤ ULN (reading on claims 7, 10-11, and 20)) and preservation of kidney function (< 25% serum creatine increase from baseline (reading on claims 7, 12, and 20)).
Regarding claims 9 and 19, Fakhouri teaches hematologic normalization of platelet count to ≥ 150 x 103/ µL to ensure improvement in hematologic, renal, and quality of life of subjects (abstract).
Regarding claim 13, Fakhouri teaches complete TMA response was also characterized by improvement in hemoglobin levels by ≥ 2 g/dL (page 85, col. 2, End Points) – reading on about 0.5 g/dL or more.
Regarding the claimed ranges of platelet counts, LDH levels, creatine levels, and hemoglobin levels, as recited in claims 7-13 and 19-20, Applicant is reminded that the courts have stated where the claimed ranges overlap or lie inside the ranges disclosed by the prior art and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists. The courts have also found that where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.
Therefore, the claimed ranges merely represent an obvious variant and/or routine optimization of the values of the cited prior art.
Regarding claim 18, Fakhouri discloses aHUS patient reported gene mutations, which include C3, CFH, MCP, etc. (Table 1, page 87). Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to treat a subject with aHUS that has been determined to have the claimed mutations. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of the teachings of Copending ‘933, Adams and Fakhouri.
This is a provisional nonstatutory double patenting rejection.
Claims 17 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 18/689,933 (Copending ‘933); in view of Adams et al. (WO 2015/009616 A1 – Cited in IDS); as applied to claims 1-2 and 14-16; further in view of Zhang et al. (Hematology Reports, 2017; 9:7053) (“Zhang”).
The teachings of Copending ‘933 and Adams are disclosed above and incorporated herein.
While Copending ‘933 and Adams do not specifically teach: (i) wherein the subject is has been or is currently being treated with complement inhibitor therapy, immunosuppressive therapy, or other therapy for aHUS (claim 17); the teachings of Zhang are relied upon for these disclosures.
Zhang teaches 16 patients with aHUS with eculizumab-induced remission stopped treatment after a median of 4.3 months and home monitoring ensued. Five patients experienced relapse within 6 months of discontinuation and remission was successfully reinduced with immediate return to eculizumab therapy (page 65, col. 1, lines 12-19). Zhang teaches that eculizumab is expensive, and predisposes patients to meningococcal infections (page 64, col. 2, last para.).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to administer Copending ‘933 and Adams’s complement pathway inhibitor to an aHUS patient who has previously received treatment for aHUS, such as eculizumab, in view of Zhang. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Copending ‘933 and Adams teach iptacopan HCl for the treatment of aHUS; further because Zhang discloses that after complete remission due to eculizumab, patients experienced relapse after 6 months and were able to achieve remission after returning to treatment. One would have been further motivated to find alternative treatment options to eculizumab because Zhang teaches that eculizumab treatment is expensive, and predisposes patients to meningococcal infections.
This is a provisional nonstatutory double patenting rejection.
Claims 1-2 and 14-15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 18/843,599 (Copending ‘599); in view of Adams et al. (WO 2015/009616 A1 – Cited in IDS).
Regarding instant claims 1-2 and 15-16, Copending ‘599 claims a method of treating AMD, comprising administration of an iptacopan salt thereof (Copending ‘599 claim 1).
While Copending ‘599 does not claim their compound in a method of treating aHUS; the teachings of Adams are relied upon for these disclosures.
Adams discloses iptacopan HCl, as an inhibitor of the complement alternative pathway and Factor B (abstract). Adams discloses that their invention provides methods of treating a complement related disease or disorder, such as atypical hemolytic uremic syndrome (aHUS), comprising administration of an effective amount of one of their compounds (para. bridging pages 50-51).
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Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to administer Copending ‘599’s iptacopan HCl hydrate form to a subject suffering from aHUS. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Copending ‘599’s disclosure of their complement inhibitor compound and pharmaceutical compositions thereof; further in view of Adam’s disclosure that iptacopan HCl can be administered as part of a method of treatment for aHUS.
This is a provisional nonstatutory double patenting rejection.
Claims 5-13 and 18-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 18/843,599 (Copending ‘599); in view of Adams et al. (WO 2015/009616 A1 – Cited in IDS); as applied to claims 1-2 and 14-15; further in view of Fakhouri et al. (Am. J. Kidney Dis. 2016, 68: 84-93) (“Fakhouri”).
The teachings of Copending ‘599 and Adams are disclosed above and incorporated herein.
While Copending ‘599 and Adams do not specifically teach: (i) wherein treatment comprises achieving complete thrombotic microangiopathy (TMS) response, or normalization of lactate hydrogenase (LDH) to below the upper limit of normal (claims 7-8, 10-11, and 20); (iv) wherein TMA response comprises improving kidney function and reducing serum creatinine by about 10% or more as compared to a baseline (claim 12); (v) wherein treatment increases hemoglobin by about 0.5 g/dL or more (claim 13); (vi) wherein treatment stabilizes or improves eGFR (claim 14); the teachings of Fakhouri are relied upon for these disclosures.
Fakhouri teaches HUS is a rare genetic life-threatening disease of chronic uncontrolled complement activation leading to thrombotic microangiopathy (TMA) and severe end-organ damage. Fakhouri discloses a study of eculizumab for aHUS; patients 18 years or older with aHUS (platelet count ≥ 150 x 103/ µL,hemoglobin ≤ lower limit of normal, lactate dehydrogenase ≥ 1.5 x upper limit of normal [ULN], and serum creatinine ≥ ULN) were included in this multicenter multinational study. Fakhouri discloses their primary end point was complete TMA response within 26 weeks, defined by hematologic normalization (platelet count ≥ 150 x 103/ µL and LDH ≤ ULN) and preservation of kidney function (< 25% serum creatine increase from baseline) (abstract). Fakhouri teaches 73% of their subjects were included during their first TMA manifestation – reading on treatment naïve subjects (abstract – Results). Fakhouri teaches complete TMA response was also characterized by improvement in hemoglobin levels by ≥ 2 g/dL (page 85, col. 2, End Points). Fakhouri also discloses aHUS patient reported gene mutations, which include C3, CFH, MCP, etc. (Table 1, page 87).
Regarding claim 5, Fakhouri teaches 73% of their subjects were included during their first TMA manifestation – reading on treatment naïve subjects (abstract – Results).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to administer Copending ‘599 and Adams’ iptacopan HCl to a subject with aHUS who is naïve to complement inhibitor therapy. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Copending ‘599 and Adams disclose iptacopan HCl and pharmaceutical compositions thereof as a complement inhibitor effective for the treatment of aHUS; further because Fakhouri teaches treatment of subjects with their first TMA manifestations, all of whom achieved complete TMA response.
Regarding claim 6, Fakhouri discloses that their patients were required to have been vaccinated against Neisseria meningitidis (page 85, col. 2, para. 1).
Therefore, it would have been prima facie obvious to vaccinate an aHUS patient against Neisseria meningitidis prior to administration of Copending ‘599 and Adams’ complement inhibitor, in view of Fakhouri. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Copending ‘599 and Adams teach their iptacopan HCl as a complement inhibitor; and Fakhouri teaches their subjects were required to be vaccinated against Neisseria meningitidis at least 2 weeks prior to complement inhibitor administration; and even after vaccination, they report two cases of meningococcal infections (abstract – results).
Regarding claims 7-8, 10-12, and 20, it would have been prima facie obvious to one of ordinary skill prior to the effective filing of the claimed invention to administer Copending ‘599 and Adams’ treatment until complete thrombotic microangiopathy (TMA) response was observed in terms of: (i) normalization of platelet count (claims 7-8 and 20), (ii) level of LDH being reduced to below ULN (claims 7, 10-11, and 20), (iii) reducing creating levels by about 10% or more compared to baseline (claims 7, 12, and 20). One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Copending ‘599 and Adams disclose their alternative and complement pathway inhibitor, iptacopan HCl, as effective for the treatment of aHUS; further because Fakhouri discloses their primary end point for treating aHUS (to ensure improvement in hematologic, renal, and quality of life of subjects) was complete TMA response, which they define by hematologic normalization (platelet count ≥ 150 x 103/ µL (reading on claims 7-8 and 20) and LDH ≤ ULN (reading on claims 7, 10-11, and 20)) and preservation of kidney function (< 25% serum creatine increase from baseline (reading on claims 7, 12, and 20)).
Regarding claims 9 and 19, Fakhouri teaches hematologic normalization of platelet count to ≥ 150 x 103/ µL to ensure improvement in hematologic, renal, and quality of life of subjects (abstract).
Regarding claim 13, Fakhouri teaches complete TMA response was also characterized by improvement in hemoglobin levels by ≥ 2 g/dL (page 85, col. 2, End Points) – reading on about 0.5 g/dL or more.
Regarding the claimed ranges of platelet counts, LDH levels, creatine levels, and hemoglobin levels, as recited in claims 7-13 and 19-20, Applicant is reminded that the courts have stated where the claimed ranges overlap or lie inside the ranges disclosed by the prior art and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists. The courts have also found that where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.
Therefore, the claimed ranges merely represent an obvious variant and/or routine optimization of the values of the cited prior art.
Regarding claim 18, Fakhouri discloses aHUS patient reported gene mutations, which include C3, CFH, MCP, etc. (Table 1, page 87). Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to treat a subject with aHUS that has been determined to have the claimed mutations. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of the teachings of Copending ‘599, Adams and Fakhouri.
This is a provisional nonstatutory double patenting rejection.
Claims 17 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 18/843,599 (Copending ‘599); in view of Adams et al. (WO 2015/009616 A1 – Cited in IDS); as applied to claims 1-2 and 14-16; further in view of Zhang et al. (Hematology Reports, 2017; 9:7053) (“Zhang”).
The teachings of Copending ‘599 and Adams are disclosed above and incorporated herein.
While Copending ‘599 and Adams do not specifically teach: (i) wherein the subject is has been or is currently being treated with complement inhibitor therapy, immunosuppressive therapy, or other therapy for aHUS (claim 17); the teachings of Zhang are relied upon for these disclosures.
Zhang teaches 16 patients with aHUS with eculizumab-induced remission stopped treatment after a median of 4.3 months and home monitoring ensued. Five patients experienced relapse within 6 months of discontinuation and remission was successfully reinduced with immediate return to eculizumab therapy (page 65, col. 1, lines 12-19). Zhang teaches that eculizumab is expensive, and predisposes patients to meningococcal infections (page 64, col. 2, last para.).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to administer Copending ‘599 and Adams’s complement pathway inhibitor to an aHUS patient who has previously received treatment for aHUS, such as eculizumab, in view of Zhang. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Copending ‘599 and Adams teach iptacopan HCl for the treatment of aHUS; further because Zhang discloses that after complete remission due to eculizumab, patients experienced relapse after 6 months and were able to achieve remission after returning to treatment. One would have been further motivated to find alternative treatment options to eculizumab because Zhang teaches that eculizumab treatment is expensive, and predisposes patients to meningococcal infections.
This is a provisional nonstatutory double patenting rejection.
Conclusion
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/JACKSON J HERNANDEZ/Examiner, Art Unit 1627
/SARAH PIHONAK/Primary Examiner, Art Unit 1627