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 . 1
Status of Claims
Claims 38, 51 and 57-58 are pending.
Response to Arguments
Applicant’s arguments and amendment of claim 38, filed January 22, 2026, with respect to Claims 38, 48, 51, 57, 58, 59 and 62 are rejected under 35 U.S.C. 103 as being unpatentable over Fan (U.S. Publication 2011/0275639) of record in view of O’Reilly (Urinary Soluble CD163 IN Active Renal Vasculitis, J Am Soc Nephrol. 2016 Sep; 27(9): 2906–2916), have been fully considered. Applicant’s amendment of claim 38 has necessitated a new rejection of claims 38, 51 and 57-58 over the same cited prior art and Walpole as detailed below.
Applicant’s arguments and amendment of claim 38, filed January 22, 2026 with respect to Claims 38, 48, 49, 51, 57, 58, 59, 60, and 62 rejected under 35 U.S.C. § 103 over Fan in view of Walpole et al., BMC Public Health 2012, 12:439 pp. 1-6 and O'Reilly have been fully considered. Applicant’s amendment of claim 38 has necessitated a new rejection of claims 38, 51 and 57-58 over the same cited prior as detailed below.
Applicant’s arguments and amendment of claim 38, filed January 22, 2026 with respect to Claims 38, 48, 51, 57, 58, 59, 61, and 62 rejected under 35 U.S.C. § 103 over Fan in view of O'Reilly and further in view of Jayne, J Am Soc Nephrol, April 2017, 28(9), 2756-2767 have been fully considered. Applicant’s amendment of claim 38 has necessitated a new rejection of claims 38, 51 and 57-58 over the same cited prior as detailed below.
Applicant’s arguments and amendment of claim 38, filed January 22, 2026 with respect to Claims 38, 48, 49, 51, 57, 58, 59, 60, 61, and 62 rejected under 35 U.S.C. § 103 over Jayne in view of O'Reilly have been fully considered. Applicant’s amendment of claim 38 has necessitated a new rejection of claims 38, 51 and 57-58 over the same cited prior as detailed below.
New Claim Rejections - 35 USC § 103 Necessitated by Amendment
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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 38, 51 and 57-58 are rejected under 35 U.S.C. 103 as being unpatentable over Fan (U.S. Publication 2011/0275639) as evidenced by Walpole et al. “The weight of nations: an estimation of adult human biomass,” BMC Public Health 2012, 12:439 pp. 1-6, in view of O’Reilly (Urinary Soluble CD163 IN Active Renal Vasculitis, J Am Soc Nephrol. 2016 Sep; 27(9): 2906–2916). These references have been previously cited by the Examiner.
Amended Claim 38 is a method for treating renal inflammation in an individual with ANCA2-associated vasculitis (AAV) comprising
administering avacopan to the individual, wherein the method comprises measuring soluble CD163 (sCD163) to creatinine ratio from the individual prior and subsequent to administration of avacopan;
wherein the individual has an elevated urinary soluble CD163 (sCD163) to creatinine ratio compared to individuals without AAV prior to administration of avacopan;
wherein 30 mg of avacopan is administered orally twice daily; and
wherein the administration of avacopan improves kidney inflammation within about 8 days of starting treatment.
In terms of claim interpretation, the specification notes renal/kidney inflammation is correlated with renal function parameters such as eGFR, UACR, MCP-1/creatinine (Cr) ratio and sCD163/Cr ratio, as well as improvement in AAV signs and symptoms. See paragraphs 86 and 103. Accordingly, prior art teaching a subject treated with the claimed avacopan compound who demonstrates improvements of said renal function markers or AAV symptoms will teach the claimed subject in need suffering from renal/kidney inflammation.
Claim 38 recites the functionally descriptive language “wherein the administration of avacopan improves kidney inflammation within about 8 days of starting treatment,” which occurs upon administration of avacopan to a subject in need. While Fan does not necessarily recite this limitation, prior art reciting the treatment of AAV in a subject with avacopan with kidney/renal inflammation would necessarily entail the improvement of kidney inflammation within about 8 days of starting treatment, whether explicitly recited in the art or not.
Fan U.S. Pub 639 teaches the claimed compound avacopan, i.e., (2R,3S)-2-(4-Cyclopentylaminophenyl)-1-(2-fluoro-6-methylbenzoyl)piperidine-3-carboxylic acid (4-methyl-3-trifluoromethylphenyl)amide. See paragraphs 174-175.3
The avacopan compound is taught as a compound of choice as it is individually claimed in claim 27 of Fan.
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This compound is disclosed as having an intended use of Inhibiting C5a binding to C5a receptor. See paragraphs 94, 95, 99 and 110.
Per claim 38 and the ANCA-associated vasculitis (AAV) subject in need suffering from renal inflammation, Fan4 teaches the claimed subject in its Example 1c), “Mouse Model of ANCA Induced Vasculitis”, where its compounds were used to test and treat these subjects in need as required by claim 38. See paragraphs 223-224. Fan teaches analysis of the kidney (renal) sections of the treated mice “can show significantly reduced number and severity of crescentic and necrotic lesions in the glomeruli when compared to vehicle (placebo) treated subjects.” See paragraph 224.
Fan’s teaching of reducing crescentic and necrotic lesion in mice renal sections necessarily entails a treatment of glomeruli (kidney) inflammation, where improvements of kidney inflammation in AAV symptoms occurred with avacopan treatment. As defined by the Applicant’s specification, paragraph 103.
With regard to the dose limitation of wherein 30 mg of avacopan is administered orally twice daily, Fan teaches twice daily dosing of its claimed compounds is more/particularly preferred. See paragraphs 110 and 112. Regarding the limitation of 30 mg dosing (total of 60 mg), Fan teaches dosage levels from between 0.5 mg to about 7 grams per human patient per day and dosage forms are from about 1 mg to about 500 mg of active ingredient, See paragraph 111. Given that Fan teaches 0.1 mg/kg to about 140 mg/kg is administered to a patient per day, including a dose of 1 mg/kg mg/kg in that range. Id at paragraph 111.
Walpole teaches that average weight of adults around the world, including Asia, Africa, Europe and North America are 57.7, 60.8, 70.8 and 80.7. See Table 3, page 3 of 6. Given a subject of 60 kg in mass, based off a dose 1 mg/kg as per Fan, one would arrive at a dose of 60 mg per day, which is taught by Fan can be administered twice a day. (60 kg per adult) * (1 mg/kg) = 60 mg per adult.
While Fan discloses the claim elements of claim 38 requiring a method of treating renal inflammation in an ANCA5-associated vasculitis (AAV) in a patient in need with the C5a inhibitor avacopan, it does not disclose the aspect of testing a population of patients for the biomarker sCD163, and/or measuring the sCD163 (biomarker) to creatinine ratio to diagnose the subject in need of avacopan treatment, and “wherein the individual has an elevated urinary soluble CD163 (sCD163) to creatinine ratio compared to individuals without AAV prior to administration of avacopan.”
To address these deficiencies, O’Reilly states “Our key finding was elevated urinary sCD163 levels in patients with active renal vasculitis compared with vasculitis patients in remission, disease controls, and healthy controls,“ (page 2912). O’Reilly concludes its data indicate that urinary sCD163 level associates very tightly with active renal vasculitis, and assessing this level may be a noninvasive method for diagnosing renal flare in the setting of a known diagnosis of small vessel vasculitis, see abstract.
With regard to the ratio of sCD163 to creatinine ratio, O’Reilly teaches “In order to account for differences in the concentration of urine between individuals, all sCD163 values were normalized to urinary creatinine.” See page 2907, column 2.
With regard to where the individual has an elevated urinary soluble CD163 (sCD163) to creatinine ratio compared to individuals without AAV prior to administration of avacopan, O’Reilly’s teaching of elevated urinary sCD163:creatinine ratio prior administration of avacopan would be evident to a PHOSITA, as measurement of elevated ratios for a patient in need of treatment of avacopan would be routine when such ratio is higher than patient not in need of treatment, i.e. a healthy patient without AAV.
Thus O’Reilly establishes the need to measure the biomarker sCD163 in the context of diagnosing (noninvasively) renal vasculitis so as to distinguish the subject from those suffering from other renal disorders, where levels of sCD163 are normalized (i.e. measured in ratio) to creatinine, i.e., a healthy patient.
A person having ordinary skill in the art (PHOSITA), armed with the knowledge of Fan treating renal inflammation in an ANCA AAV in a patient in need with the C5a inhibitor avacopan in the taught doses (mg,/kg) as evidenced by Walpole (teaching weight of patients in kg) would find it prima facie obvious to measure the sCD163:creatine ratio, where such ratio is increased in patients with AAV prior to dosing of avacopan, as taught by O’Reilly.
The rationale to support the prima facie case are the prior art findings of Fan (treatment of patients in need with avacopan as explained above in claimed doses as evidenced by Walpole) in combination with known method (measurement of sCD163 normalized to creatinine, i.e. a ratio, where elevated compared to a healthy patient) to predictably arrive at the claimed invention with a reasonable expectation of success as spelled out above.
Regarding claim 51 limited to a human subject, Fan teaches a method of treating a mammal suffering from C5a modulated diseases by administering its claimed compounds, which include avacopan. See claims 27 and 31. Fan defines typical patients for treatment include mammals, especially humans. See paragraph 109.
Regarding claim 57, it is noted that Fan and O’Reilly do not explicitly recite measurements of urinary sCD163 decreased by at least 25% within about 8 days of starting treatment with avacopan. However, as claim 57 merely describes a function of administering avacopan to the patient in need per Fan, the resulting sCD163 decrease of at least 25% within 8 days of starting avacopan treatment would naturally occur in the patient of Fan.
Regarding claim 58 and the limitation of wherein the soluble CD163 (sCD 163) to creatinine ratio is measured in a urinary sample. O’Reilly states “Our key finding was elevated urinary sCD163 levels in patients with active renal vasculitis compared with vasculitis patients in remission, disease controls, and healthy controls,“ (page 2912).
Further, with regard to the ratio of sCD163 to creatinine ratio, O’Reilly teaches “In order to account for differences in the concentration of urine between individuals, all sCD163 values were normalized to urinary creatinine.” See page 2907, column 2.
Thus O’Reilly establishes the need to measure the biomarker sCD163 in the context of diagnosing (noninvasively) renal vasculitis so as to distinguish the subject from those suffering from other renal disorders, where levels of sCD163 are normalized (i.e. measure in ratio) to creatinine.
Claims 38, 51 and 57-58 are rejected under 35 U.S.C. 103 as being unpatentable Jayne (Randomized Trial of C5a Receptor Inhibitor Avacopan in ANCA-Associated Vasculitis, J. Am Soc Nephrol, April 2017, 28(9), 2756-2767) as applied to claims 38, 48, 49 and 51 in view of O’Reilly (Urinary Soluble CD163 IN Active Renal Vasculitis, J Am Soc Nephrol. 2016 Sep; 27(9): 2906–2916), of record. The prior art has all been cited by the Examiner.
Claim 38 recites the functionally descriptive language “wherein the administration of avacopan improves kidney inflammation within about 8 days of starting treatment,” which inherently occurs upon administration of avacopan to a subject in need. Prior art reciting the treatment of AAV in a subject with avacopan with kidney inflammation would necessarily entail the improvement of kidney inflammation within about 8 days of starting treating , whether explicitly recited in the art or not.
Regarding claim 38 and the administration of avacopan wherein 30 mg of avacopan is administered orally twice daily Jayne teaches that “adults with newly diagnosed or relapsing vasculitis received placebo plus prednisone starting at 60 mg daily (control group), avacopan (30 mg, twice daily) plus reduced-dose prednisone (20 mg daily), or avacopan (30 mg, twice daily) without prednisone.” See Abstract. 6
With regard to claim 38 and the required AAV subject in need of treatment for renal inflammation, Jayne teaches a study to treat AAV with avacopan, where the study7 teaches renal inflammation improved rapidly and to a greater extent with avacopan compared with control. See page 4.
While Jayne discloses the claim elements of claim 38 requiring a method of treating renal inflammation in an ANCA AAV in a patient in need with the C5a inhibitor avacopan, it does not disclose the aspect of testing a population of patients for the biomarker sCD163, and/or measuring the sCD163 (biomarker) to creatinine ratio to diagnose the subject in need of avacopan treatment, and wherein the individual has an elevated urinary soluble CD163 (sCD163) to creatinine ratio compared to individuals without AAV prior to administration of avacopan;
To address these deficiencies, O’Reilly states “Our key finding was elevated urinary sCD163 levels in patients with active renal vasculitis compared with vasculitis patients in remission, disease controls, and healthy controls,“ (page 2912). O’Reilly concludes its data indicate that urinary sCD163 level associates very tightly with active renal vasculitis, and assessing this level may be a noninvasive method for diagnosing renal flare in the setting of a known diagnosis of small vessel vasculitis, see abstract.
With regard to the ratio of sCD163 to creatinine ratio, O’Reilly teaches “In order to account for differences in the concentration of urine between individuals, all sCD163 values were normalized to urinary creatinine.” See page 2907, column 2.
Thus O’Reilly establishes the need to measure the biomarker sCD163 in the context of diagnosing (noninvasively) renal vasculitis so as to distinguish the subject from those suffering from other renal disorders, where levels of sCD163 are normalized (i.e. measured in ratio) to creatinine. Note, with regard to where the individual has an elevated urinary soluble CD163 (sCD163) to creatinine ratio compared to individuals without AAV prior to administration of avacopan, O’Reilly’s teaching of elevated urinary sCD163:creatinine ratio prior administration of avacopan would be evident to a PHOSITA, as measurement of elevated ratios for a patient in need of treatment of avacopan would be routine when such ratio is higher than patient not in need of treatment, i.e. a healthy patient without AAV.
Thus O’Reilly establishes the need to measure the biomarker sCD163 in the context of diagnosing (noninvasively) renal vasculitis so as to distinguish the subject from those suffering from other renal disorders, where levels of sCD163 are normalized (i.e. measured in ratio) to creatinine, i.e., a healthy patient.
A PHOSITA, armed with the knowledge of Jayne treating renal inflammation in an ANCA AAV in a patient in need with the C5a inhibitor avacopan would find it prima facie obvious to measure soluble sCD163:creatine ratio, where the ratio would be elevated in AAV patients prior to Avacopan treatment, taught by O’Reilly. The rationale to support the prima facie case are the prior art findings of Jayne (treatment of patients in need with avacopan and doses as explained above) in combination with known method (measurement of sCD163 normalized to creatinine, i.e. a ratio) to predictably arrive treatment of subjects with avacopan while monitoring the subjects via measurement of sCD163: creatine ratio.
Regarding claim 51, Jayne teaches its study subjects are human. See Figure 1 noting the screening of 87 human patients, where 67 are enrolled
Regarding claim 57, it is noted that O’Reilly does not explicitly recite measurements of urinary sCD163 decreased by at least 25% within about 8 days of starting treatment with avacopan. However, as claim 57 merely describes a function of administering avacopan to the patient in need per Jayne, the resulting sCD163 decrease of at least 25% within 8 days of starting avacopan treatment would naturally occur in the patient of Jayne.
Regarding claim 58 and the limitation of wherein the soluble CD163 (sCD 163) to creatinine ratio is measured in a urinary sample. O’Reilly states “Our key finding was elevated urinary sCD163 levels in patients with active renal vasculitis compared with vasculitis patients in remission, disease controls, and healthy controls,“ (page 2912).
Further, with regard to the ratio of sCD163 to creatinine ratio, O’Reilly teaches “In order to account for differences in the concentration of urine between individuals, all sCD163 values were normalized to urinary creatinine.” See page 2907, column 2.
Thus O’Reilly establishes the need to measure the biomarker sCD163 in the context of diagnosing (noninvasively) renal vasculitis so as to distinguish the subject from those suffering from other renal disorders, where levels of sCD163 are normalized (i.e. measure in ratio) to creatinine.
RESPONSE TO ATTORNEY ARGUMENTS:
The Attorney response states that the Office continues to overly generalize the teachings of O'Reilly while disregarding the unpredictability in the art. The Attorney response states there is no basis cited by the Office for the proposition that any teaching of O'Reilly, including the use of CD 163 as a biomarker, could be generalized to all possible treatments for ANCA associated vasculitis (AAV), much less treatment the claimed avacopan treatment in the claimed time frame.
In response, while Applicant argues unpredictability in the art (as demonstrated by the state of the art treatment prednisone failing to show similar changes in CD163 levels as claimed), per MPEP 21458, [a]bsolute predictability is not a necessary prerequisite to a case of obviousness, Id. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient, Id. The Federal Circuit concluded that “[g]ood science and useful contributions do not necessarily result in patentability.” Id. at 1364, 83 USPQ2d at 1304.
As detailed above, the teachings of Fan, Walpole, O’Reilly and/or Jayne demonstrate what is known in the art, changes in CD163, with regard to ratios with creatinine, and measured in terms of albumin and MCP-1 ratios, are known in the art as indicative of kidney vasculitis health when treated with avacopan.
The Attorney response states Applicant's specification and clinical results show the Office's over-generalization of the O'Reilly teachings is inconsistent with the actual state of the art, noting Table 2 at paragraph 94.
The Attorney response states per Table 2 shows that prednisone therapy alone (i.e., a standard of care glucocorticoid therapy) could not achieve the same rapid effect regarding sCD163 levels and kidney inflammation (i.e., within 8 days of administration) in the selected patient population having elevated sCD163 and receiving therapy comprising avacopan, in contrast to prednisone only therapy
The Attorney response states per Table 2 reduction of sCD163 and reduction of kidney inflammation, was observed only at day 57 for patients receiving the standard of care, prednisone-only therapy, (sCD163 reductions at day 57 vs. day 8 for avacopan, 7 week difference).
The Attorney response concludes the state of the art and the specification’s clinical trial beneficial results with avacopan provide substantial evidence to show that O'Reilly does not provide a reasonable expectation of success to rebut the Action.
In response, as stated above, a person having ordinary skill in the art (PHOSITA), armed with the knowledge of Fan treating renal inflammation in an ANCA AAV in a patient in need with the C5a inhibitor avacopan in the taught doses (mg,/kg) as evidenced by Walpole (teaching weight of patients in kg) would find it prima facie obvious to measure the sCD163:creatine ratio, where such ratio is increased in patients with AAV prior to dosing of avacopan, as taught by O’Reilly.
The rationale to support the prima facie case are the prior art findings of Fan (treatment of patients in need with avacopan as explained above in claimed doses as evidenced by Walpole) in combination with known method (measurement of sCD163 normalized to creatinine, i.e. a ratio, where elevated compared to a healthy patient) to predictably arrive at the claimed invention with a reasonable expectation of success as spelled out above.
In response, as stated above, a person having ordinary skill in the art (PHOSITA), armed with the knowledge of Fan treating renal inflammation in an ANCA AAV in a patient in need with the C5a inhibitor avacopan in the taught doses (mg,/kg) as evidenced by Walpole (teaching weight of patients in kg) would find it prima facie obvious to measure the sCD163:creatine ratio, where such ratio is increased in patients with AAV prior to dosing of avacopan, as taught by O’Reilly.
The rationale to support the prima facie case are the prior art findings of Fan (treatment of patients in need with avacopan as explained above in claimed doses as evidenced by Walpole) in combination with known method (measurement of sCD163 normalized to creatinine, i.e. a ratio, where elevated compared to a healthy patient) to predictably arrive at the claimed invention with a reasonable expectation of success as spelled out above.
With regard to the Attorney arguments regarding the comparative data of Tables 1 and 2 comparing unexpected results demonstrating the 8 day efficacy to treat AAV ( noted by sCD163 ratio and reduction of renal inflammation) when compared to prednisone therapy ( 57 days to take effect), it is pointed out that a demonstration of unexpected results necessary to overcome a prima facie case of obviousness requires not only a showing that a weighing of expected and unexpected results per MPEP 716.02(c), commensurate in scope with claimed invention per MPEP 716.02(d), but said unexpected results must be a comparison with the closest prior art MPEP 716.02(d).
The above unexpected results comparing avacopan’s 8 day efficacy to predinisone’s 57 day efficacy do not necessarily rebut the prima facie case as the obviousness rejection does not rely upon teachings regarding prednisone as a basis of the rejection. See above. As detailed above, the rejections rely on the known teachings in the art regarding avacopan to treat AAV (per Fan and Jayne) where sCD163 to creatinine ratio elevated levels were noted in acute renal vasculitis patients versus those in remission, disease AND healthy controls.
The Attorney response states impermissible hindsight, Applicant submits that the Office has not identified any basis in the references of record that would have led the person of ordinary skill to arrive at the instantly claimed invention using a particular therapy (avacopan) and biomarker (CD163) for achieving beneficial changes in renal inflammation within eight days of commencing treatment.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
RESPONSE TO ATTORNEY ARGUMENTS:
Note, the ODP rejections of the claims other than claims 38, 51 and 57-58 are now rendered moot due their cancellation. The Attorney response argues that the remaining pending claims are nonobvious over the cited ODP rejections, as the amended claims are patentable over Jayne and O’Reilly, and the Office has failed to show that the reference claims of the '756 patent and the '266 application remedy the deficiencies of Jayne and O'Reilly, where other references also fail to remedy the primary references.
In response, new ODP rejections of the examined claims are detailed below.
Claims 38, 51 and 57-58 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 11,191,756 in view of Jayne (Randomized Trial of C5a Receptor Inhibitor Avacopan in ANCA-Associated Vasculitis, J. Am Soc Nephrol, April 2017, 28(9), 2756-2767 and O’Reilly (Urinary Soluble CD163 IN Active Renal Vasculitis, J Am Soc Nephrol. 2016 Sep; 27(9): 2906–2916).
Claim 38 has been amended to include the following below limitations:
wherein the individual has an elevated urinary soluble CD163 (sCD163) to creatinine ratio compared to individuals without AAV prior to administration of avacopan;
wherein 30 mg of avacopan is administered orally twice daily.
Reference patent Claim 1 is directed to treating ANCA-associated vasculitis in a human having a reduced ability to fight infections, the method comprising administering to the human a therapeutically effective amount of avacopan.
With regard to claim 38 and the functionally descriptive language “wherein the administration of avacopan improves kidney inflammation within about 8 days of starting treatment,” which occurs upon administration of avacopan to a subject in need. Prior art reciting the treatment of AAV in a subject with avacopan with kidney aka renal inflammation would necessarily entail the improvement of kidney inflammation within about 8 days of starting treating, upon the administration of the AAV afflicted patient. Reference patent claims 3-4 disclose administering 30 mg of avacopan, twice daily.
It is noted that reference patent claim 1 discloses claim elements of claim 38 requiring a method of treating ANCA AAV in a patient in need with the claimed C5a inhibitor avacopan, it doesn’t recite the limitation of treating renal inflammation in patients in need afflicted with ANCA AAV.
To address this deficiency, Jayne teaches a study to treat AAV with avacopan, where the study9 teaches renal inflammation improved rapidly and to a greater extent with avacopan compared with control. See page 4.
While the reference patent discloses the claim elements of claim 38 requiring a method of treating renal inflammation in an ANCA AAV in a patient in need with the C5a inhibitor avacopan, it does not disclose the aspect of testing a population of patients for the biomarker sCD163, and/or measuring the sCD163 (biomarker) to creatinine ratio to diagnose the subject in need of avacopan treatment.
To address this deficiency, the testing, sampling and measurement of sCD163 (biomarker) to assess efficacy of avacopan treatment of ANCA associated vasculitis (AAV) is well-known in the art per O’Reilly.
O’Reilly states “Our key finding was elevated urinary sCD163 levels in patients with active renal vasculitis compared with vasculitis patients in remission, disease controls, and healthy controls,“ (page 2912). O’Reilly concludes its data indicate that urinary sCD163 level associates very tightly with active renal vasculitis, and assessing this level may be a noninvasive method for diagnosing renal flare in the setting of a known diagnosis of small vessel vasculitis, see abstract.
With regard to the ratio of sCD163 to creatinine ratio, O’Reilly teaches “In order to account for differences in the concentration of urine between individuals, all sCD163 values were normalized to urinary creatinine.” See page 2907, column 2.
Thus O’Reilly establishes the need to measure the biomarker sCD163 in the context of diagnosing (noninvasively) renal vasculitis so as to distinguish the subject from those suffering from other renal disorders, where levels of sCD163 are normalized (i.e. measured in ratio) to creatinine. Also note the teachings of Jayne with regard to use of avacopan for the treatment of renal vasculitis (such as AAV) as already established. Note, with regard to where the individual has an elevated urinary soluble CD163 (sCD163) to creatinine ratio compared to individuals without AAV prior to administration of avacopan, O’Reilly’s teaching of elevated urinary sCD163:creatinine ratio prior administration of avacopan would be evident to a PHOSITA, as measurement of elevated ratios for a patient in need of treatment of avacopan would be routine when such ratio is higher than patient not in need of treatment, i.e. a healthy patient without AAV.
Thus O’Reilly establishes the need to measure the biomarker sCD163 in the context of diagnosing (noninvasively) renal vasculitis so as to distinguish the subject from those suffering from other renal disorders, where levels of sCD163 are normalized (i.e. measured in ratio) to creatinine, i.e., a healthy patient.
A PHOSITA, armed with the knowledge of the reference patent for treating renal inflammation in an ANCA AAV in a patient in need with the C5a inhibitor avacopan would find it prima facie obvious to combine this with the teachings of Jayne and O’Reilly treatment of renal inflammation with avacopan and to measure soluble sCD163 in subjects as compared to creatinine in these treated patients, where the ratio would be elevated in AAV patients prior to Avacopan treatment, taught by O’Reilly. The rationale to support the prima facie case are the prior art findings of the reference patent and O’Reilly and Jayne to predictably arrive at the claimed invention.
Regarding claim 51, Jayne teaches its study subjects are human. See Figure 1 noting the screening of 87 human patients, where 67 are enrolled.
Regarding claim 57, it is noted that O’Reilly does not necessarily recite measurements of urinary sCD163 decreased by at least 25% within about 8 days of starting treatment with avacopan. However, as claim 57 merely describes a function of the administration avacopan to the patient in need per Jayne, where the result of decrease by at least 25% within 8 days post starting treatment as a result of the administration, this property would naturally occur in the patient of Jayne, whether recited or not.
Regarding claim 58 and the limitation of wherein the soluble CD163 (sCD 163) to creatinine ratio is measured in a urinary sample. O’Reilly states “Our key finding was elevated urinary sCD163 levels in patients with active renal vasculitis compared with vasculitis patients in remission, disease controls, and healthy controls,“ (page 2912).
Further, with regard to the ratio of sCD163 to creatinine ratio, O’Reilly teaches “In order to account for differences in the concentration of urine between individuals, all sCD163 values were normalized to urinary creatinine.” See page 2907, column 2.
Thus O’Reilly establishes the need to measure the biomarker sCD163 in the context of diagnosing (noninvasively) renal vasculitis so as to distinguish the subject from those suffering from other renal disorders, where levels of sCD163 are normalized (i.e. measure in ratio) to creatinine.
Claims 38, 51 and 57-58 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 34-45 of copending Application No. 17/519266 (reference application) in view of Jayne (Randomized Trial of C5a Receptor Inhibitor Avacopan in ANCA-Associated Vasculitis, J. Am Soc Nephrol, April 2017, 28(9), 2756-2767) and O’Reilly (Urinary Soluble CD163 IN Active Renal Vasculitis, J Am Soc Nephrol. 2016 Sep; 27(9): 2906–2916.
With regard to examined claim 38 and the functionally descriptive language “wherein the administration of avacopan improves kidney inflammation within about 8 days of starting treatment,” which occurs upon a mere administration of avacopan to a subject in need. Prior art reciting the treatment of AAV in a subject with avacopan with kidney aka renal inflammation would necessarily entail the improvement of kidney inflammation within about 8 days of starting treating, upon the administration of the AAV afflicted patient, whether explicitly recited in the art or not.
Reference application claim 34 is directed to a method of treating AAV in a human having reduced ability to fight infections, the method comprising administering to the human a therapeutically effect amount of avacopan, or pharmaceutically acceptable salt, such that the level of plasma complement factor C5b-9 and C5a does not significantly change in the human upon treatment.
Reference patent claims 35-37 disclose oral administration of 30 mg of avacopan, twice daily.
Although the claims at issue are not identical, they are not patentably distinct from each other because both applications recited a method of treating ANCA-associated vasculitis with the administration of avacopan.
It is noted that reference application claim 34 discloses claim elements of claim 38 requiring a method of treating ANCA AAV in a patient in need with the claimed C5a inhibitor avacopan, it doesn’t recite the limitation of treating renal inflammation in patients in need afflicted with ANCA AAV.
To address this, Jayne teaches a study to treat AAV with avacopan, where the study teaches renal inflammation improved rapidly and to a greater extent with avacopan compared with control. See page 4.
While the reference application discloses the claim elements of claim 38 requiring a method of treating renal inflammation in an ANCA AAV in a patient in need with the C5a inhibitor avacopan, it does not disclose the aspect of testing a population of patients for the biomarker sCD163, and/or measuring the sCD163 (biomarker) to creatinine ratio to diagnose the subject in need of avacopan treatment.
To address this deficiency, the testing, sampling and measurement of sCD163 (biomarker) to assess efficacy of avacopan treatment of ANCA associated vasculitis (AAV) is well-known in the art per O’Reilly.
O’Reilly states “Our key finding was elevated urinary sCD163 levels in patients with active renal vasculitis compared with vasculitis patients in remission, disease controls, and healthy controls,“ (page 2912). O’Reilly concludes its data indicate that urinary sCD163 level associates very tightly with active renal vasculitis, and assessing this level may be a noninvasive method for diagnosing renal flare in the setting of a known diagnosis of small vessel vasculitis, see abstract.
With regard to the ratio of sCD163 to creatinine ratio, O’Reilly teaches “In order to account for differences in the concentration of urine between individuals, all sCD163 values were normalized to urinary creatinine.” See page 2907, column 2.
Thus O’Reilly establishes the need to measure the biomarker sCD163 in the context of diagnosing (noninvasively) renal vasculitis so as to distinguish the subject from those suffering from other renal disorders, where levels of sCD163 are normalized (i.e. measured in ratio) to creatinine. Also note the teachings of Jayne with regard to use of avacopan for the treatment of renal vasculitis (such as AAV) as already established. Note, with regard to where the individual has an elevated urinary soluble CD163 (sCD163) to creatinine ratio compared to individuals without AAV prior to administration of avacopan, O’Reilly’s teaching of elevated urinary sCD163:creatinine ratio prior administration of avacopan would be evident to a PHOSITA, as measurement of elevated ratios for a patient in need of treatment of avacopan would be routine when such ratio is higher than patient not in need of treatment, i.e. a healthy patient without AAV. Thus O’Reilly establishes the need to measure the biomarker sCD163 in the context of diagnosing (noninvasively) renal vasculitis so as to distinguish the subject from those suffering from other renal disorders, where levels of sCD163 are normalized (i.e. measured in ratio) to creatinine, i.e., a healthy patient.
A PHOSITA, armed with the knowledge of the reference application for treating renal inflammation in an ANCA AAV in a patient in need with the C5a inhibitor avacopan would find it prima facie obvious to combine this with the teachings of Jayne and O’Reilly, treatment of renal inflammation with avacopan and to measure soluble sCD163 in subjects as compared to creatinine in these treated patients, where the ratio would be elevated in AAV patients prior to Avacopan treatment, taught by O’Reilly. The rationale to support the prima facie case are the prior art findings of the reference patent and O’Reilly and Jayne to predictably arrive at the claimed invention.
Regarding claim 51, Jayne teaches its study subjects are human. See Figure 1 noting the screening of 87 human patients, where 67 are enrolled.
Regarding claim 57, it is noted that O’Reilly does not necessarily recite measurements of urinary sCD163 decreased by at least 25% within about 8 days of starting treatment with avacopan. However, as claim 57 merely describes a function of the administration avacopan to the patient in need per Jayne, where the result of decrease by at least 25% within 8 days post starting treatment as a result of the administration, this property would naturally occur in the patient of Jayne, whether recited or not.
Regarding claim 58 and the limitation of wherein the soluble CD163 (sCD 163) to creatinine ratio is measured in a urinary sample. O’Reilly states “Our key finding was elevated urinary sCD163 levels in patients with active renal vasculitis compared with vasculitis patients in remission, disease controls, and healthy controls,“ (page 2912).
Conclusion and Correspondence
No claims are allowed. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to WILLIAM LEE whose telephone number is (571)270-3876. The examiner can normally be reached M-F.
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/WILLIAM Y LEE/Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623
1 This application claims earliest domestic priority to 62/579,716 filed 10/31/2017.
2 Anti-neutrophil cytoplasmic antibodies, see paragraph 4 of specification
3 The previous SciFinder search that accompanied the non-final office action identified the claimed compound, avacopan, is disclosed in Fan US Pub 639.
4 As way of background, Fan US Pub 639 discloses a method comprising administering therapeutically effective amount of its compounds or treating patients suffering from conditions that are responsive to C5a receptor modulation. See paragraph 99. Fan teaches these diseases include autoimmune disorders such as inflammatory disorders and vasculitis. See paragraphs 101 and 103. Fan US Pub 639 discloses in the background that C5a receptors play an important roles in inflammation and tissue injury. See paragraph 0011. Fan US Pub 639 discloses that vasculitic diseases are characterized by inflammation of the vessels (paragraph 103).
5 Anti-neutrophil cytoplasmic antibodies
6 Per Jayne, avacopan, previously called CCX168, is an orally administered small-molecule C5aR antagonist that blocks the effects of C5a,21 and prevented the development of GN induced by anti-myeloperoxidase antibodies in a murine model of AAV. See page 2 of Jayne.
7 The study ran from Oct 12 2011 to Jan 18 2016, noting the success of the avacopan therapy in its ANCA associated vasculitis patients. See abstract. This success is evidenced by the clinical response at week 12 that was noted in 19 of 22 (86.4%) patients in the avacopan plus reduced-dose prednisone group (difference from control 16.4%; two-sided 90% confidence limit, -4.3% to 37.1 %; P=0.002 for noninferiority), and 17 of 21 (81.0%) patients in the avacopan without prednisone group (difference from control I 1.0%; two-sided 90% confidence limit, -11.0% to 32.9%; P=0.01 for noninferiority). See abstract. See also page 5 noting the double-blind, placebo controlled trial at 32 centers in Europe to reduce or replace glucocorticoid treatment with avacopan in AAV.
8 MPEP 2145, Citing to PharmaStem Therapeutics, Inc. v. Viacell, Inc., 491 F.3d 1342, 83 USPQ2d 1289 (Fed. Cir. 2007).
9 The study ran from Oct 12 2011 to Jan 18 2016, noting the success of the avacopan therapy in its ANCA associated vasculitis patients. See abstract. This success is evidenced by the clinical response at week 12 that was noted in 19 of 22 (86.4%) patients in the avacopan plus reduced-dose prednisone group (difference from control 16.4%; two-sided 90% confidence limit, -4.3% to 37.1 %; P=0.002 for noninferiority), and 17 of 21 (81.0%) patients in the avacopan without prednisone group (difference from control I 1.0%; two-sided 90% confidence limit, -11.0% to 32.9%; P=0.01 for noninferiority). See abstract. See also page 5 noting the double-blind, placebo controlled trial at 32 centers in Europe to reduce or replace glucocorticoid treatment with avacopan in AAV.
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