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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 4/30/26 has been entered.
Status of Claims
Applicant’s 4/30/26 claim listing adds new claims 19-21. No other claims were amended, canceled, or added. Claims 1-17 and 19-21 are pending and under examination.
Drawings
A renewed petition to include color drawings was granted on 6/3/26. The objection to the drawings is withdrawn.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-8, 12-15, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (2016, Pediatric Nephrology 31: 67-72; reference U) taken in view of Marcinkiewicz (US 20030186334) and Zallocchi et al. (2013, American Journal of Pathology 183: 1269-1280; on 4/26/23 IDS).
Zhang teaches that ACE inhibitors and ARBs are administered to treat Alport syndrome. (Abstract; page 67, column 2.) Regarding claims 7 and 8, Zhang teaches that a patient receives a diagnosis of Alport syndrome proven by at least two methods including kidney biopsy, skin biopsy, and/or mutation analysis. (Page 68, column 1.)
Regarding claim 15, Zhang teaches that the ACE inhibitor may be enalapril. (Page 67, column 2.)
Regarding claim 17, Zhang teaches that the ARB may be losartan. (Page 67, column 2.)
Zhang does not teach coadministering an [Symbol font/0x61]1 integrin blocking agent (claims 1-6), for example an [Symbol font/0x61]1 integrin blocking agent comprising obtustatin or one that prevents signaling through the [Symbol font/0x61]1b1 integrin receptor (claims 12-14). Zhang does not address all of the outcomes in claims 3-6.
Marcinkiewicz teaches that obtustatin is a peptide that is a potent, specific inhibitor of [Symbol font/0x61]1b1 integrin and can be administered as a pharmaceutical. (Abstract; paragraphs 16, 19, 108.)
Regarding claims 1-3, 5, and 6, Zallocchi teaches that Alport syndrome is characterized by delayed-onset progressive glomerulonephritis mediated by progressive accumulation of laminin 211 in the glomerular basement membrane (GBM), which is caused by [Symbol font/0x61]1b1-integrin-mediated mesangial-cell-process invasion of the glomerular capillary loop. (Page 1269, column 1; page 1270, column 1; page 1278, column 2.) Regarding claim 4, Zallocchi further teaches that Alport syndrome is characterized by glomerular injury due to biomechanical strain. (Page 1270, column 1; page 1278, column 2.) Zallocchi teaches that integrin [Symbol font/0x61]1-null mouse models of Alport syndrome show no mesangial-cell-process invasion and slowed accumulation of laminin 211. (Page 1270, column 1.) Zallocchi teaches that Alport patients have functional GBM for the first several years of life and only develop symptoms later. (Page 1269, column 2.) Zallocchi teaches that Alport syndrome is caused by mutations in type IV collagen genes (COL4A5, COL4A3, and COL4A4). (Page 1269, column 1.)
The person of ordinary skill in the art would have found it obvious to add Marcinkiewicz’s obtustatin to Zhang’s ACE inhibitor/ARB treatment regimen because Marcinkiewicz teaches that obtustatin inhibits [Symbol font/0x61]1b1 integrin and Zallocchi teaches that increased [Symbol font/0x61]1b1 integrin signaling results in mesangial invasion of glomerular capillaries, thereby initiating Alport syndrome symptoms. Zallocchi teaches the progression to symptomatic Alport syndrome is inhibited by the knockout of integrin [Symbol font/0x61]1. The person of ordinary skill in the art would therefore have understood that inhibiting [Symbol font/0x61]1b1 integrin would have achieved the outcomes in claims 1-6 because Zallocchi teaches that the “key aspect of Alport glomerular disease initiation”—mesangial-cell-process invasion—is blocked when [Symbol font/0x61]1b1 integrin signaling is blocked.
Regarding claims 12-14, Marcinkiewicz teaches that obtustatin is a small peptide that is a potent, specific inhibitor of [Symbol font/0x61]1b1 integrin. (Abstract, e.g.)
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang in view of Marcinkiewicz and Zallocchi as applied to claims 1-8, 12-15, and 17 above and further in view of Greinwald, Jr. (US 20040166495).
The teachings of Zhang, Marcinkiewicz, and Zallocchi are relied upon as above. In addition, Zallocchi teaches that in Alport-syndrome patients, the GBM is functional for the first few years of life, only deteriorating later. (Page 1269, column 2.)
Zhang, Marcinkiewicz, and Zallocchi do not teach determining that a subject is at risk for developing Alport glomerular disease before the onset of proteinuria prior to administering the [Symbol font/0x61]1 integrin blocking agent and ACE inhibitor and/or ARB.
Greinwald teaches diagnostic assays for predicting an individual’s risk for Alport syndrome based on screening for linked mutations. (Abstract; paragraphs 20, 23.) Regarding claim 9, Greinwald teaches that detecting a risk of hearing loss is beneficial in infants before their hearing loss can begin. (Paragraphs 3-5.)
The person of ordinary skill in the art would have found it obvious to determine that a subject is at risk for developing Alport glomerular disease before administering Marcinkiewicz’s [Symbol font/0x61]1 integrin blocking agent and Zhang’s ACE inhibitor and/or ARB. This is so because the skilled artisan would have understood based on Zallocchi that blocking [Symbol font/0x61]1 integrin activation prevents the GBM deterioration characteristic of Alport syndrome. The skilled artisan would have predicted that Greinwald’s risk-assessment method in view of Zhang would identify subjects who would benefit from the treatment regimen combining Marcinkiewicz’s [Symbol font/0x61]1 integrin blocking agent and Zhang’s ACE inhibitor and/or ARB.
The skilled artisan would have found it obvious to carry out Greinwald’s risk-assessment method in view of Zhang before proteinuria (or any Alport syndrome symptoms) begin in order to achieve Greinwald’s goal of early intervention. The skilled artisan would have understood based on Zallocchi that GBM is functional in Alport-syndrome patients for the first few years of their lives, so it would have been obvious to screen for Alport-syndrome risk at an early age.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang in view of Marcinkiewicz and Zallocchi as applied to claims 1-8, 12-15, and 17 above and further in view of Cosgrove (US 20150175695; on 4/26/23 IDS).
The teachings of Zhang, Marcinkiewicz, and Zallocchi are relied upon as above.
Zhang, Marcinkiewicz, and Zallocchi do not teach delaying and/or treating one or more sensory and/or hearing loss associated with Alport syndrome.
Cosgrove ’695 teaches that the symptoms of Alport syndrome are characterized by abnormalities in the basement membranes of the glomerulus (leading to hematuria, glomerulosclerosis, and end-stage kidney disease (ESRD)), cochlea (causing deafness), and eye (resulting in lenticonus and perimacular flecks). (Paragraph 3.)
The person of ordinary skill in the art would have found it obvious that the combination of Marcinkiewicz’s [Symbol font/0x61]1b1 integrin-inhibiting obtustatin and Zhang’s ACE inhibitors/ARBs would delay and/or treat the sensory and/or hearing losses Cosgrove ’695 teaches are associated with Alport syndrome. This is so because Zallocchi teaches that [Symbol font/0x61]1b1 integrin inhibition restores type IV collagen architecture and Cosgrove ’695 teaches that Alport-associated deafness, lenticonus, and perimacular flecks are caused by type IV collagen defects in the basement membranes of the cochlea and eye.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang in view of Marcinkiewicz and Zallocchi as applied to claims 1-8, 12-15, and 17 above and further in view of Kagami et al. (2002, Laboratory Investigation 82: 1219-1227; on 4/26/23 IDS).
The teachings of Zhang, Marcinkiewicz, and Zallocchi are relied upon as above.
Zhang, Marcinkiewicz, and Zallocchi do not teach that the [Symbol font/0x61]1 integrin blocking agent comprises an [Symbol font/0x61]1 integrin neutralizing antibody.
Kagami teaches a function-blocking [Symbol font/0x61]1 integrin antibody. (Abstract.) Kagami teaches that administering the antibody to a model of glomerulonephritis suppressed mesangial-cell proliferation and collagen accumulation, leading to mesangial ECM expansion. (Page 1221; page 1222, column 1.) Kagami concludes that the modulation of [Symbol font/0x61]1b1 integrin expression by activated mesangial cells in nephritic glomeruli may provide a new therapeutic approach for regulating abnormal mesangial remodeling leading to glomerulosclerosis. (Page 1225, column 1.)
It would have been obvious to the person of ordinary skill in the art to substitute Kagami’s function-blocking [Symbol font/0x61]1 integrin antibody for Marcinkiewicz’s [Symbol font/0x61]1b1 integrin-inhibiting obtustatin in the method of Zhang in view of Marcinkiewicz and Zallocchi because both agents inhibit [Symbol font/0x61]1 integrin upon administration to a subject. See MPEP 2143(I)(B) (simple substitution of known elements for each other to obtain predictable results is obvious); MPEP 2144.06 (substitution of art-recognized equivalents for same purpose is prima facie obvious).
Claims 16 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang in view of Marcinkiewicz and Zallocchi as applied to claims 1-8, 12-15, and 17 above and further in view of Cosgrove (WO 2014/028059; on 4/26/23 IDS).
The teachings of Zhang, Marcinkiewicz, and Zallocchi are relied upon as above.
Zhang, Marcinkiewicz, and Zallocchi do not teach that the ACE inhibitor is ramipril.
Cosgrove ’059 teaches that Alport syndrome may be treated with the ACE inhibitor ramipril, an agent known in the art. (Page 11, third full paragraph.)
It would have been obvious to substitute Cosgrove ’059’s ramipril for Zhang’s enalapril because both were known to be ACE inhibitors useful in treating Alport syndrome. It is prima facie obvious to substitute art-recognized equivalents for the same purpose. See MPEP 2144.06(II).
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang in view of Marcinkiewicz, Zallocchi, and Cosgrove ’059 as applied to claims 16 and 19 above and further in view of Kagami et al. (2002, Laboratory Investigation 82: 1219-1227; on 4/26/23 IDS).
The teachings of Zhang, Marcinkiewicz, Zallocchi, and Cosgrove ’059 are relied upon as above.
Zhang, Marcinkiewicz, Zallocchi, and Cosgrove ’059 do not teach that the [Symbol font/0x61]1 integrin blocking agent comprises an [Symbol font/0x61]1 integrin neutralizing antibody.
Kagami teaches a function-blocking [Symbol font/0x61]1 integrin antibody. (Abstract.) Kagami teaches that administering the antibody to a model of glomerulonephritis suppressed mesangial-cell proliferation and collagen accumulation, leading to mesangial ECM expansion. (Page 1221; page 1222, column 1.) Kagami concludes that the modulation of [Symbol font/0x61]1b1 integrin expression by activated mesangial cells in nephritic glomeruli may provide a new therapeutic approach for regulating abnormal mesangial remodeling leading to glomerulosclerosis. (Page 1225, column 1.)
It would have been obvious to the person of ordinary skill in the art to substitute Kagami’s function-blocking [Symbol font/0x61]1 integrin antibody for Marcinkiewicz’s [Symbol font/0x61]1b1 integrin-inhibiting obtustatin in the method of Zhang in view of Marcinkiewicz, Zallocchi, and Cosgrove ’059 because both agents inhibit [Symbol font/0x61]1 integrin upon administration to a subject. See MPEP 2143(I)(B) (simple substitution of known elements for each other to obtain predictable results is obvious); MPEP 2144.06 (substitution of art-recognized equivalents for same purpose is prima facie obvious).
Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang in view of Marcinkiewicz, Zallocchi, Cosgrove ’059, and Kagami as applied to claim 20 above and further in view of Gross (2003, Kidney International 63: 438-446; on 4/26/23 IDS).
The teachings of Zhang, Marcinkiewicz, Zallocchi, Cosgrove ’059, and Kagami are relied upon as above.
Zhang, Marcinkiewicz, Zallocchi, Cosgrove ’059, and Kagami do not teach administering ramipril at 10 mg/kg/day.
Gross teaches providing 10 mg/kg/day ramipril to a mouse model of Alport syndrome. (Abstract; page 439, column 2.) Gross teaches that this dosage is well below the toxic range and equivalent to the maximum therapeutic dose of 10 mg per day in humans. (Page 439, column 2.)
It would have been obvious to provide Cosgrove ’059’s ramipril at 10 mg/kg/day because Gross teaches giving this dose to treat a mouse model of Alport syndrome. The person of ordinary skill in the art would have been motivated to provide this dosage because Gross teaches that it corresponds to the maximum therapeutic dose in humans.
Claims 1, 2, 7, 8, 11, 14, 15, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (2016, Pediatric Nephrology 31: 67-72; reference U) taken in view of Cosgrove (US Patent 6,492,325; on 4/26/23 IDS).
Zhang teaches that ACE inhibitors and ARBs are administered to treat Alport syndrome. (Abstract; page 67, column 2.) Regarding claims 7 and 8, Zhang teaches that a patient receives a diagnosis of Alport syndrome proven by at least two methods including kidney biopsy, skin biopsy, and/or mutation analysis. (Page 68, column 1.)
Regarding claim 15, Zhang teaches that the ACE inhibitor may be enalapril. (Page 67, column 2.)
Regarding claim 17, Zhang teaches that the ARB may be losartan. (Page 67, column 2.)
Zhang does not teach coadministering an [Symbol font/0x61]1 integrin blocking agent, for example an [Symbol font/0x61]1 integrin neutralizing antibody that prevents signaling through the [Symbol font/0x61]1b1 integrin receptor (claims 11 and 14).
Cosgrove ’325 teaches administering a [Symbol font/0x61]1[Symbol font/0x62]1 integrin neutralizing antibody to a mouse model of Alport syndrome. (Example 5 at column 32, lines 30-42.) Cosgrove ’325 teaches that the basement membranes in treated animals were “largely regular, having the normal trilaminar appearance,” which is an indicator that “a soluble agent that blocks the integrin [Symbol font/0x61]1[Symbol font/0x62]1 receptor will slow Alport GBM disease progression . . . .” (Column 32, lines 44-51.)
The person of ordinary skill in the art would have found it obvious to add Cosgrove ’325’s neutralizing antibody to Zhang’s ACE inhibitor/ARB treatment regimen because they are both recognized as treatments for Alport syndrome. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose . . . . [T]he idea of combining them flows logically from their having been individually taught in the prior art.” MPEP 2144.06 (quoting In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980)).
Claims 3-6 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (2016, Pediatric Nephrology 31: 67-72) taken in view of Cosgrove (US Patent 6,492,325) as applied to claims 1, 2, 7, 8, 11, 14, 15, and 17, above, and further in view of Zallocchi et al. (2013, American Journal of Pathology 183: 1269-1280; on 4/26/23 IDS).
The teachings of Zhang and Cosgrove ’325 are relied upon as above.
Zhang and Cosgrove ’325 do not address all of the outcomes in claims 3-6.
Regarding claims 3, 5, and 6, Zallocchi teaches that Alport syndrome is characterized by delayed-onset progressive glomerulonephritis mediated by progressive accumulation of laminin 211 in the glomerular basement membrane (GBM), which is caused by [Symbol font/0x61]1b1-integrin-mediated mesangial-cell-process invasion of the glomerular capillary loop. (Page 1269, column 1; page 1270, column 1; page 1278, column 2.) Regarding claim 4, Zallocchi further teaches that Alport syndrome is characterized by glomerular injury due to biomechanical strain. (Page 1270, column 1; page 1278, column 2.) Zallocchi teaches that integrin [Symbol font/0x61]1-null mouse models of Alport syndrome show no mesangial-cell-process invasion and slowed accumulation of laminin 211. (Page 1270, column 1.) Zallocchi teaches that Alport patients have functional GBM for the first several years of life and only develop symptoms later. (Page 1269, column 2.) Zallocchi teaches that Alport syndrome is caused by mutations in type IV collagen genes (COL4A5, COL4A3, and COL4A4). (Page 1269, column 1.)
Zhang and Cosgrove ’325 both teach treating Alport syndrome, and Zallocchi teaches that the outcomes in claims 3-6 would flow from the treatment of Alport syndrome since that treatment would address all of the underlying mechanisms identified by Zallocchi.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang in view of Cosgrove ’325 and Zallocchi as applied to claims 3-6, above, and further in view of Greinwald, Jr. (US 20040166495).
The teachings of Zhang, Cosgrove ’325, and Zallocchi are relied upon as above. In addition, Zallocchi teaches that in Alport-syndrome patients, the GBM is functional for the first few years of life, only deteriorating later. (Page 1269, column 2.)
Zhang, Cosgrove ’325, and Zallocchi do not teach determining that a subject is at risk for developing Alport glomerular disease before the onset of proteinuria prior to administering the [Symbol font/0x61]1 integrin blocking agent and ACE inhibitor and/or ARB.
Greinwald teaches diagnostic assays for predicting an individual’s risk for Alport syndrome based on screening for linked mutations. (Abstract; paragraphs 20, 23.) Regarding claim 9, Greinwald teaches that detecting a risk of hearing loss is beneficial in infants before their hearing loss can begin. (Paragraphs 3-5.)
The person of ordinary skill in the art would have found it obvious to determine that a subject is at risk for developing Alport glomerular disease before administering Cosgrove ’325’s neutralizing antibody and Zhang’s ACE inhibitor and/or ARB. This is so because the skilled artisan would have understood based on Zallocchi that blocking [Symbol font/0x61]1 integrin activation prevents the GBM deterioration characteristic of Alport syndrome. The skilled artisan would have predicted that Greinwald’s risk-assessment method in view of Zhang would identify subjects who would benefit from the treatment regimen combining Cosgrove ’325’s neutralizing antibody and Zhang’s ACE inhibitor and/or ARB.
The skilled artisan would have found it obvious to carry out Greinwald’s risk-assessment method in view of Zhang before proteinuria (or any Alport syndrome symptoms) begin in order to achieve Greinwald’s goal of early intervention. The skilled artisan would have understood based on Zallocchi that GBM is functional in Alport-syndrome patients for the first few years of their lives, so it would have been obvious to screen for Alport-syndrome risk at an early age.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (2016, Pediatric Nephrology 31: 67-72) taken in view of Cosgrove (US Patent 6,492,325) as applied to claims 1, 2, 7, 8, 11, 14, 15, and 17, above, and further in view of Cosgrove (US 20150175695; on 4/26/23 IDS).
The teachings of Zhang and Cosgrove ’325 are relied upon as above.
Zhang and Cosgrove ’325 do not teach delaying and/or treating one or more sensory and/or hearing loss associated with Alport syndrome.
Cosgrove ’695 teaches that the symptoms of Alport syndrome are characterized by abnormalities in the basement membranes of the glomerulus (leading to hematuria, glomerulosclerosis, and end-stage kidney disease (ESRD)), cochlea (causing deafness), and eye (resulting in lenticonus and perimacular flecks). (Paragraph 3.)
The person of ordinary skill in the art would have found it obvious that the combination of Cosgrove ’325’s neutralizing antibody and Zhang’s ACE inhibitors/ARBs would delay and/or treat the sensory and/or hearing losses Cosgrove ’695 teaches are associated with Alport syndrome. This is so because Cosgrove ’695 teaches that Alport-associated deafness, lenticonus, and perimacular flecks are caused by type IV collagen defects in the basement membranes of the cochlea and eye.
Claims 16, 19, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (2016, Pediatric Nephrology 31: 67-72) taken in view of Cosgrove (US Patent 6,492,325) as applied to claims 1, 2, 7, 8, 11, 14, 15, and 17, above, and further in view of Cosgrove (WO 2014/028059; on 4/26/23 IDS).
The teachings of Zhang and Cosgrove ’325 are relied upon as above.
Zhang and Cosgrove ’325 do not teach that the ACE inhibitor is ramipril.
Cosgrove ’059 teaches that Alport syndrome may be treated with the ACE inhibitor ramipril, an agent known in the art. (Page 11, third full paragraph.)
It would have been obvious to substitute Cosgrove ’059’s ramipril for Zhang’s enalapril because both were known to be ACE inhibitors useful in treating Alport syndrome. It is prima facie obvious to substitute art-recognized equivalents for the same purpose. See MPEP 2144.06(II).
Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang in view of Cosgrove ’325 and Cosgrove ’059 as applied to claims 16, 19, and 20 above and further in view of Gross (2003, Kidney International 63: 438-446; on 4/26/23 IDS).
The teachings of Zhang, Cosgrove ’325, and Cosgrove ’059 are relied upon as above.
Zhang, Cosgrove ’325, and Cosgrove ’059 do not teach administering ramipril at 10 mg/kg/day.
Gross teaches providing 10 mg/kg/day ramipril to a mouse model of Alport syndrome. (Abstract; page 439, column 2.) Gross teaches that this dosage is well below the toxic range and equivalent to the maximum therapeutic dose of 10 mg per day in humans. (Page 439, column 2.)
It would have been obvious to provide Cosgrove ’059’s ramipril at 10 mg/kg/day because Gross teaches giving this dose to treat a mouse model of Alport syndrome. The person of ordinary skill in the art would have been motivated to provide this dosage because Gross teaches that it corresponds to the maximum therapeutic dose in humans.
Claims 1-6, 12-17, and 19 are/remain rejected under 35 U.S.C. 103 as being unpatentable over Wilson (US 20180193405) in view of Marcinkiewicz (US 20030186334) and Zallocchi et al. (2013, American Journal of Pathology 183: 1269-1280; on 4/26/23 IDS).
Wilson teaches that ACE inhibitors and ARBs are administered to treat and prevent Alport syndrome. (Paragraphs 240, 280, 285.) In particular, Wilson teaches coadministering ACE inhibitors and ARBs with therapeutic peptides to treat Alport syndrome. (Paragraphs 280, 285.) Wilson teaches that coadministering these agents will have greater than additive effects. (Paragraph 285.)
Regarding claims 15, 16, and 19, Wilson teaches that captopril, alacepril, lisinopril, imidapril, quinapril, temocapril, delapril, benazepril, cilazapril, trandolapril, enalapril, ceronapril, fosinopril, imadapril, mobertpril, perindopril, ramipril, spirapril, and randolapril are ACE inhibitors used to treat Alport syndrome. (Paragraph 240.)
Regarding claim 17, Wilson teaches that losartan, candesartan, valsartan, eprosartan, telmisartan, and irbesartan are ARBs that have been used to treat Alport syndrome. (Paragraph 240.)
Wilson does not teach that the therapeutic peptide is an [Symbol font/0x61]1 integrin blocking agent (claims 1-6), for example an [Symbol font/0x61]1 integrin blocking agent comprising obtustatin or one that prevents signaling through the [Symbol font/0x61]1b1 integrin receptor (claims 12-14). Wilson does not address all of the outcomes in claims 3-6.
Marcinkiewicz teaches that obtustatin is a peptide that is a potent, specific inhibitor of [Symbol font/0x61]1b1 integrin and can be administered as a pharmaceutical. (Abstract; paragraphs 16, 19, 108.)
Regarding claims 1-3, 5, and 6, Zallocchi teaches that Alport syndrome is characterized by delayed-onset progressive glomerulonephritis mediated by progressive accumulation of laminin 211 in the glomerular basement membrane (GBM), which is caused by [Symbol font/0x61]1b1-integrin-mediated mesangial-cell-process invasion of the glomerular capillary loop. (Page 1269, column 1; page 1270, column 1; page 1278, column 2.) Regarding claim 4, Zallocchi further teaches that Alport syndrome is characterized by glomerular injury due to biomechanical strain. (Page 1270, column 1; page 1278, column 2.) Zallocchi teaches that integrin [Symbol font/0x61]1-null mouse models of Alport syndrome show no mesangial-cell-process invasion and slowed accumulation of laminin 211. (Page 1270, column 1.) Zallocchi teaches that Alport patients have functional GBM for the first several years of life and only develop symptoms later. (Page 1269, column 2.) Zallocchi teaches that Alport syndrome is caused by mutations in type IV collagen genes (COL4A5, COL4A3, and COL4A4). (Page 1269, column 1.)
The person of ordinary skill in the art would have found it obvious to substitute Marcinkiewicz’s obtustatin for the therapeutic peptide in Wilson’s composition because Marcinkiewicz teaches that obtustatin inhibits [Symbol font/0x61]1b1 integrin and Zallocchi teaches that increased [Symbol font/0x61]1b1 integrin signaling results in mesangial invasion of glomerular capillaries, thereby initiating Alport syndrome symptoms. Zallocchi teaches the progression to symptomatic Alport syndrome is inhibited by the knockout of integrin [Symbol font/0x61]1. The person of ordinary skill in the art would therefore have understood that inhibiting [Symbol font/0x61]1b1 integrin would have achieved the outcomes in claims 1-6 because Zallocchi teaches that the “key aspect of Alport glomerular disease initiation”—mesangial-cell-process invasion—is blocked when [Symbol font/0x61]1b1 integrin signaling is blocked.
Regarding claims 12-14, Marcinkiewicz teaches that obtustatin is a small peptide that is a potent, specific inhibitor of [Symbol font/0x61]1b1 integrin. (Abstract, e.g.)
Regarding claims 15-17, Wilson teaches that any of the ACE inhibitors and ARBs, respectively, listed in the claims can be used to treat Alport syndrome. (Paragraph 240.) It would therefore have been obvious to select any of Wilson’s enumerated compounds for that purpose. See MPEP 2143(I)(E) (obvious to try finite number of identified, predictable solutions to achieve predictable outcome); MPEP 2144.06 (prima facie obvious to substitute art-recognized equivalents for same purpose).
Claims 7-9 remain rejected under 35 U.S.C. 103 as being unpatentable over Wilson in view of Marcinkiewicz and Zallocchi as applied to claims 1-6, 12-17, and 19 above and further in view of Greinwald, Jr. (US 20040166495).
The teachings of Wilson, Marcinkiewicz, and Zallocchi are relied upon as above. In addition, Wilson teaches that Alport syndrome can be detected by assaying reduction of function, decreased expression level of, and/or deficiency in the COL4A3, COL4A4, and/or COL4A5 genes using diagnostic or prognostic assays known in the art. (Paragraph 247.) Furthermore, Zallocchi teaches that in Alport-syndrome patients, the GBM is functional for the first few years of life, only deteriorating later. (Page 1269, column 2.)
Wilson, Marcinkiewicz, and Zallocchi do not teach determining that a subject is at risk for developing Alport glomerular disease prior to administering the [Symbol font/0x61]1 integrin blocking agent and ACE inhibitor and/or ARB.
Greinwald teaches diagnostic assays for predicting an individual’s risk for Alport syndrome based on screening for linked mutations. (Abstract; paragraphs 20, 23.) Regarding claim 9, Greinwald teaches that detecting a risk of hearing loss is beneficial in infants before their hearing loss can begin. (Paragraphs 3-5.)
The person of ordinary skill in the art would have found it obvious to determine that a subject is at risk for developing Alport glomerular disease before administering Marcinkiewicz’s [Symbol font/0x61]1 integrin blocking agent and Wilson’s ACE inhibitor and/or ARB. This is so because the skilled artisan would have understood based on Zallocchi that blocking [Symbol font/0x61]1 integrin activation prevents the GBM deterioration characteristic of Alport syndrome. The skilled artisan would have predicted that Greinwald’s risk-assessment method in view of Wilson would identify subjects who would benefit from the treatment regimen combining Marcinkiewicz’s [Symbol font/0x61]1 integrin blocking agent and Wilson’s ACE inhibitor and/or ARB.
Regarding claim 9, the skilled artisan would have found it obvious to carry out Greinwald’s risk-assessment method in view of Wilson before proteinuria (or any Alport syndrome symptoms) begin in order to achieve Greinwald’s goal of early intervention. The skilled artisan would have understood based on Zallocchi that GBM is functional in Alport-syndrome patients for the first few years of their lives, so it would have been obvious to screen for Alport-syndrome risk at an early age.
Claim 10 remains rejected under 35 U.S.C. 103 as being unpatentable over Wilson in view of Marcinkiewicz and Zallocchi as applied to claims 1-6, 12-17, and 19 above and further in view of Cosgrove (US 20150175695; on 4/26/23 IDS).
The teachings of Wilson, Marcinkiewicz, and Zallocchi are relied upon as above.
Wilson, Marcinkiewicz, and Zallocchi do not teach delaying and/or treating one or more sensory and/or hearing loss associated with Alport syndrome.
Cosgrove ’695 teaches that the symptoms of Alport syndrome are characterized by abnormalities in the basement membranes of the glomerulus (leading to hematuria, glomerulosclerosis, and end-stage kidney disease (ESRD)), cochlea (causing deafness), and eye (resulting in lenticonus and perimacular flecks). (Paragraph 3.)
The person of ordinary skill in the art would have found it obvious that the combination of Marcinkiewicz’s [Symbol font/0x61]1b1 integrin-inhibiting obtustatin and Wilson’s ACE inhibitors/ARBs would delay and/or treat the sensory and/or hearing losses Wilson teaches are associated with Alport syndrome. This is so because Zallocchi teaches that [Symbol font/0x61]1b1 integrin inhibition restores type IV collagen architecture and Cosgrove ’695 teaches that Alport-associated deafness, lenticonus, and perimacular flecks are caused by type IV collagen defects in the basement membranes of the cochlea and eye.
Claims 11 and 20 are/remain rejected under 35 U.S.C. 103 as being unpatentable over Wilson in view of Marcinkiewicz and Zallocchi as applied to claims 1-6 and 12-17 above and further in view of Kagami et al. (2002, Laboratory Investigation 82: 1219-1227; on 4/26/23 IDS).
The teachings of Wilson, Marcinkiewicz, and Zallocchi are relied upon as above.
Wilson, Marcinkiewicz, and Zallocchi do not teach that the [Symbol font/0x61]1 integrin blocking agent comprises an [Symbol font/0x61]1 integrin neutralizing antibody.
Kagami teaches a function-blocking [Symbol font/0x61]1 integrin antibody. (Abstract.) Kagami teaches that administering the antibody to a model of glomerulonephritis suppressed mesangial-cell proliferation and collagen accumulation, leading to mesangial ECM expansion. (Page 1221; page 1222, column 1.) Kagami concludes that the modulation of [Symbol font/0x61]1b1 integrin expression by activated mesangial cells in nephritic glomeruli may provide a new therapeutic approach for regulating abnormal mesangial remodeling leading to glomerulosclerosis. (Page 1225, column 1.)
It would have been obvious to the person of ordinary skill in the art to substitute Kagami’s function-blocking [Symbol font/0x61]1 integrin antibody for Marcinkiewicz’s [Symbol font/0x61]1b1 integrin-inhibiting obtustatin in the method of Wilson in view of Marcinkiewicz and Zallocchi because both agents inhibit [Symbol font/0x61]1 integrin upon administration to a subject. See MPEP 2143(I)(B) (simple substitution of known elements for each other to obtain predictable results is obvious); MPEP 2144.06 (substitution of art-recognized equivalents for same purpose is prima facie obvious).
Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang in view of Wilson, Marcinkiewicz, Zallocchi, and Kagami as applied to claim 20 above and further in view of Gross (2003, Kidney International 63: 438-446; on 4/26/23 IDS).
The teachings of Wilson, Marcinkiewicz, Zallocchi, and Kagami are relied upon as above.
Wilson, Marcinkiewicz, Zallocchi, and Kagami do not teach administering ramipril at 10 mg/kg/day.
Gross teaches providing 10 mg/kg/day ramipril to a mouse model of Alport syndrome. (Abstract; page 439, column 2.) Gross teaches that this dosage is well below the toxic range and equivalent to the maximum therapeutic dose of 10 mg per day in humans. (Page 439, column 2.)
It would have been obvious to provide Wilson’s ramipril at 10 mg/kg/day because Gross teaches giving this dose to treat a mouse model of Alport syndrome. The person of ordinary skill in the art would have been motivated to provide this dosage because Gross teaches that it corresponds to the maximum therapeutic dose in humans.
Response to Arguments
Regarding the rejections based on Wilson, applicant alleges that the examiner has applied impermissible hindsight and that modifying Wilson in the manner set forth in the rejection would impermissibly change Wilson’s principle of operation. (Reply at 8.) Applicant suggests that the teachings of Wilson about coadministering ACE inhibitors and ARBs along with therapeutic peptides apply only to Wilson’s particular therapeutic peptide and that substituting Marcinkiewicz’s peptide would result in a loss of synergy. (Reply at 8-9.) As stated previously, however, it is not clear why inhibiting the underlying cause of Alport syndrome using Marcinkiewicz’s peptide would change the principle of operation of Wilson’s ACE inhibitors or ARBs. Applicant’s concerns about Wilson’s principle of operation are not relevant to the rejections based on Zhang, who only teaches coadministration of ACE inhibitors and ARBs to treat Alport syndrome.
Applicant alleges that even if a prima facie showing were made, it would be overcome by evidence of unexpected results, specifically a synergistic effect as described in “the inventor disclosure statement,” presumably the Cosgrove declaration. (Reply at 9-10.) The evidence in the specification and the Cosgrove declaration have been fully considered as they relate to the obviousness rejections based on each of Zhang and Wilson, but they are not convincing of error.
As discussed previously, the Cosgrove declaration details experiments using a single unclaimed [Symbol font/0x61]1-integrin-inhibiting antibody and a single ACE inhibitor. “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range.” MPEP 716.02(d). Claim 1 is open to all ACE inhibitors and all angiotensin-receptor blockers in combination with all [Symbol font/0x61]1-integrin-blocking agents. The Cosgrove declaration’s testing of a single such combination does not clearly represent the entire scope of claim 1. This point has not been refuted by applicant in the 4/30/26 remarks. Even if the data shows a greater-than-additive effect for the single tested embodiment, that fact would not demonstrate nonobviousness across the entire scope of the claims.
Beyond the lack of a nexus to the claimed invention, the data in the Cosgrove declaration does not clearly show truly unexpected results. See MPEP 716.02(b). As discussed above, the specification contends that the person of ordinary skill in the art would have expected both [Symbol font/0x61]1-integrin-inhibiting agents and ACE inhibitors/ARBs to be therapeutic for Alport syndrome. (Specification at page 18, lines 14-16 and 31.) Figure 2 of the Cosgrove declaration shows an improvement of ~29 weeks average survival in Mu31/8-ramipril combination-treated mouse models of Alport syndrome compared to ~13 weeks and ~22.5 weeks average survival in such mice treated with Mu31/8 or ramipril alone, respectively. Applicant explains that this data equates to an increase in survival of 18 weeks for the combination-treated models as opposed to 2 weeks and 12 weeks for the individual-agent-treated models. (Reply at 10-11.) Applicant’s allegation appears to be that 18-week survival is truly unexpected relative to 14-week survival (2 weeks + 12 weeks). Applicant does not explain, however, why the person of ordinary skill in the art would have found that improvement truly unexpected and unobvious given the known ability of each agent alone to treat Alport syndrome. “Evidence pertaining to secondary considerations must be taken into account whenever it has been properly presented; however, it does not necessarily control the obviousness conclusion.” MPEP 2145 (quoting Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1372 (Fed. Cir. 2007) (when the record established a strong case of obviousness, allegedly unexpectedly superior results were ultimately insufficient to overcome obviousness conclusion)).
Applicant alleges that claims 7-11 are nonobvious because the base rejections are improper. (Reply at 11-12.) The base rejections have been maintained for the reasons given above, so the dependent claims are/remain rejected as well.
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.
US Patent 9,719,981
Claims 1-6, 10, 12-17, and 19 are/remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 4-11 of U.S. Patent No. 9,719,981 in view of Wilson (US 20180193405), Marcinkiewicz (US 20030186334) and Zallocchi (2013, American Journal of Pathology 183: 1269-1280; on 4/26/23 IDS).
The ’981 patent claims a method for inhibiting Alport pathogenesis in a subject by administering an antibody that inhibits endothelin-1. (Claim 1.) Regarding examined claims 2, 3, and 5, the ’981 patent claims such methods in which glomerular disease progression is inhibited (claim 4), glomerulonephritis is treated (claim 5), and deposition of laminin 211 in the GBM is inhibited (claim 6). Regarding examined claims 6 and 10, the ’981 patent claims that mesangial cell process invasion of the glomerular capillary loop is inhibited (claim 7), and one or more sensory and/or hearing losses associated with Alport disease is treated or prevented (claim 8). Regarding examined claims 7-9, the ’981 patent claims a method further comprising a step of first determining that the subject is at risk for developing Alport glomerular disease by various means, wherein the determination is made before the onset of proteinuria in the subject. (Claims 9-11).
The ’981 patent does not claim a method for inhibiting Alport pathogenesis in a subject by administering both an [Symbol font/0x61]1 integrin inhibitor and an ACE inhibitor and/or ARB to the subject.
Wilson teaches that ACE inhibitors and ARBs are administered to treat and prevent Alport syndrome. (Paragraphs 240, 280, 285.) In particular, Wilson teaches coadministering ACE inhibitors and ARBs with therapeutic peptides to treat Alport syndrome. (Paragraphs 280, 285.) Wilson teaches that coadministering these agents will have greater than additive effects. (Paragraph 285.)
Regarding claims 15, 16, and 19, Wilson teaches that captopril, alacepril, lisinopril, imidapril, quinapril, temocapril, delapril, benazepril, cilazapril, trandolapril, enalapril, ceronapril, fosinopril, imadapril, mobertpril, perindopril, ramipril, spirapril, and randolapril are ACE inhibitors used to treat Alport syndrome. (Paragraph 240.)
Regarding claim 17, Wilson teaches that losartan, candesartan, valsartan, eprosartan, telmisartan, and irbesartan are ARBs that have been used to treat Alport syndrome. (Paragraph 240.)
Marcinkiewicz teaches that obtustatin is a peptide that is a potent, specific inhibitor of [Symbol font/0x61]1b1 integrin and can be administered as a pharmaceutical. (Abstract; paragraphs 16, 19, 108.)
Regarding examined claims 1-3, 5, and 6, Zallocchi teaches that Alport syndrome is characterized by delayed-onset progressive glomerulonephritis mediated by progressive accumulation of laminin 211 in the glomerular basement membrane (GBM), which is caused by [Symbol font/0x61]1b1-integrin-mediated mesangial-cell-process invasion of the glomerular capillary loop. (Page 1269, column 1; page 1270, column 1; page 1278, column 2.) Regarding examined claim 4, Zallocchi further teaches that Alport syndrome is characterized by glomerular injury due to biomechanical strain. (Page 1270, column 1; page 1278, column 2.) Zallocchi teaches that integrin [Symbol font/0x61]1-null mouse models of Alport syndrome show no mesangial-cell-process invasion and slowed accumulation of laminin 211. (Page 1270, column 1.) Zallocchi teaches that Alport patients have functional GBM for the first several years of life and only develop symptoms later. (Page 1269, column 2.) Zallocchi teaches that Alport syndrome is caused by mutations in type IV collagen genes (COL4A5, COL4A3, and COL4A4). (Page 1269, column 1.)
The person of ordinary skill in the art would have found it obvious to add Wilson’s ACE inhibitors and ARBs to the treatment method of the ’981 patent because Wilson teaches that ACE inhibitors and ARBs are routinely used to treat Alport syndrome. See MPEP 2143(I)(A) (combining prior-art methods according to known methods to yield predictable results is obvious); MPEP 2144.06(I) (combining known equivalents is prima facie obvious).
The person of ordinary skill in the art would have found it obvious to substitute Marcinkiewicz’s obtustatin for the ’981 patent’s anti-endothelin-1 antibody because obtustatin is a peptide that is a potent, specific inhibitor of [Symbol font/0x61]1b1 integrin and Zallocchi teaches that the cause of Alport syndrome is [Symbol font/0x61]1b1-integrin-mediated mesangial-cell-process invasion of the glomerular capillary loop. The person of ordinary skill in the art would have understood that making the substitution would treat or prevent Alport syndrome by blocking its initiating event.
Regarding claims 15-17, Wilson teaches that any of the ACE inhibitors and ARBs, respectively, listed in the claims can be used to treat Alport syndrome. (Paragraph 240.) It would therefore have been obvious to select any of Wilson’s enumerated compounds for that purpose. See MPEP 2143(I)(E) (obvious to try finite number of identified, predictable solutions to achieve predictable outcome); MPEP 2144.06 (prima facie obvious to substitute art-recognized equivalents for same purpose).
Claims 7-9 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 4-11 of U.S. Patent No. 9,719,981 in view of Wilson, Marcinkiewicz, and Zallocchi as applied to claims 1-6, 10, 12-17, and 19 above and further in view of Greinwald, Jr. (US 20040166495).
The claims of the ’981 patent and the teachings of Wilson, Marcinkiewicz, and Zallocchi are relied upon as above. In addition, Wilson teaches that Alport syndrome can be detected by assaying reduction of function, decreased expression level of, and/or deficiency in the COL4A3, COL4A4, and/or COL4A5 genes using diagnostic or prognostic assays known in the art. (Paragraph 247.) Furthermore, Zallocchi teaches that in Alport-syndrome patients, the GBM is functional for the first few years of life, only deteriorating later. (Page 1269, column 2.)
The ’981 patent does not claim, and Wilson, Marcinkiewicz, and Zallocchi do not teach, determining that a subject is at risk for developing Alport glomerular disease prior to administering the [Symbol font/0x61]1 integrin blocking agent and ACE inhibitor and/or ARB.
Greinwald teaches diagnostic assays for predicting an individual’s risk for Alport syndrome based on screening for linked mutations. (Abstract; paragraphs 20, 23.) Regarding claim 9, Greinwald teaches that detecting a risk of hearing loss is beneficial in infants before their hearing loss can begin. (Paragraphs 3-5.)
The person of ordinary skill in the art would have found it obvious to determine that a subject is at risk for developing Alport glomerular disease before administering Marcinkiewicz’s [Symbol font/0x61]1 integrin blocking agent and Wilson’s ACE inhibitor and/or ARB. This is so because the skilled artisan would have understood based on Zallocchi that blocking [Symbol font/0x61]1 integrin activation prevents the GBM deterioration characteristic of Alport syndrome. The skilled artisan would have predicted that Greinwald’s risk-assessment method in view of Wilson would identify subjects who would benefit from the treatment regimen combining Marcinkiewicz’s [Symbol font/0x61]1 integrin blocking agent and Wilson’s ACE inhibitor and/or ARB.
Regarding claim 9, the skilled artisan would have found it obvious to carry out Greinwald’s risk-assessment method in view of Wilson before proteinuria (or any Alport syndrome symptoms) begin in order to achieve Greinwald’s goal of early intervention. The skilled artisan would have understood based on Zallocchi that GBM is functional in Alport-syndrome patients for the first few years of their lives, so it would have been obvious to screen for Alport-syndrome risk at an early age.
Claims 11 and 20 are/remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 4-11 of U.S. Patent No. 9,719,981 in view of Wilson, Marcinkiewicz, and Zallocchi as applied to claims 1-6, 10, 12-17, and 19 above and further in view of Kagami et al. (2002, Laboratory Investigation 82: 1219-1227; on 4/26/23 IDS).
The claims of the ’981 patent and the teachings of Wilson, Marcinkiewicz, and Zallocchi are relied upon as above.
The ’981 patent does not claim, and Wilson, Marcinkiewicz, and Zallocchi do not teach, that the [Symbol font/0x61]1 integrin blocking agent comprises an [Symbol font/0x61]1 integrin neutralizing antibody.
Kagami teaches a function-blocking [Symbol font/0x61]1 integrin antibody. (Abstract.) Kagami teaches that administering the antibody to a model of glomerulonephritis suppressed mesangial-cell proliferation and collagen accumulation, leading to mesangial ECM expansion. (Page 1221; page 1222, column 1.) Kagami concludes that the modulation of [Symbol font/0x61]1b1 integrin expression by activated mesangial cells in nephritic glomeruli may provide a new therapeutic approach for regulating abnormal mesangial remodeling leading to glomerulosclerosis. (Page 1225, column 1.)
It would have been obvious to the person of ordinary skill in the art to substitute Kagami’s function-blocking [Symbol font/0x61]1 integrin antibody for Marcinkiewicz’s [Symbol font/0x61]1b1 integrin-inhibiting obtustatin in the method of the ’981 patent in view of Wilson, Marcinkiewicz, and Zallocchi because both agents inhibit [Symbol font/0x61]1 integrin upon administration to a subject. See MPEP 2143(I)(B) (simple substitution of known elements for each other to obtain predictable results is obvious); MPEP 2144.06 (substitution of art-recognized equivalents for same purpose is prima facie obvious).
Claim 21 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 4-11 of U.S. Patent No. 9,719,981 in view of Wilson, Marcinkiewicz, Zallocchi, and Kagami as applied to claims 11 and 20 above and further in view of Gross (2003, Kidney International 63: 438-446; on 4/26/23 IDS).
The claims of the ’981 patent and the teachings of Wilson, Marcinkiewicz, Zallocchi, and Kagami are relied upon as above.
The ’981 patent does not claim, and Wilson, Marcinkiewicz, Zallocchi, and Kagami do not teach administering ramipril at 10 mg/kg/day.
Gross teaches providing 10 mg/kg/day ramipril to a mouse model of Alport syndrome. (Abstract; page 439, column 2.) Gross teaches that this dosage is well below the toxic range and equivalent to the maximum therapeutic dose of 10 mg per day in humans. (Page 439, column 2.)
It would have been obvious to provide Wilson’s ramipril at 10 mg/kg/day because Gross teaches giving this dose to treat a mouse model of Alport syndrome. The person of ordinary skill in the art would have been motivated to provide this dosage because Gross teaches that it corresponds to the maximum therapeutic dose in humans.
US Patent 6,492,325
Claims 1-6, 10, 12, 14-17, and 19 are/remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 8 and 9 of U.S. Patent No. 6,492,325 in view of Wilson (US 20180193405) and Zallocchi (2013, American Journal of Pathology 183: 1269-1280; on 4/26/23 IDS).
The ’325 patent claims a method for delaying the onset of and/or slowing the progression of Alport disease in a patient by administering an effective amount of an [Symbol font/0x61]1b1 integrin inhibitor, for example a peptide.
The ’325 patent does not claim achieving the outcomes in claims 1-6 by administering both an [Symbol font/0x61]1 integrin inhibitor and an ACE inhibitor and/or ARB to the subject.
Wilson teaches that ACE inhibitors and ARBs are administered to treat and prevent Alport syndrome. (Paragraphs 240, 280, 285.) In particular, Wilson teaches coadministering ACE inhibitors and ARBs with therapeutic peptides to treat Alport syndrome. (Paragraphs 280, 285.) Wilson teaches that coadministering these agents will have greater than additive effects. (Paragraph 285.)
Regarding claims 15 and 16, Wilson teaches that captopril, alacepril, lisinopril, imidapril, quinapril, temocapril, delapril, benazepril, cilazapril, trandolapril, enalapril, ceronapril, fosinopril, imadapril, mobertpril, perindopril, ramipril, spirapril, and randolapril are ACE inhibitors used to treat Alport syndrome. (Paragraph 240.)
Regarding claim 17, Wilson teaches that losartan, candesartan, valsartan, eprosartan, telmisartan, and irbesartan are ARBs that have been used to treat Alport syndrome. (Paragraph 240.)
Regarding examined claims 1-3, 5, and 6, Zallocchi teaches that Alport syndrome is characterized by delayed-onset progressive glomerulonephritis mediated by progressive accumulation of laminin 211 in the glomerular basement membrane (GBM), which is caused by [Symbol font/0x61]1b1-integrin-mediated mesangial-cell-process invasion of the glomerular capillary loop. (Page 1269, column 1; page 1270, column 1; page 1278, column 2.) Regarding examined claim 4, Zallocchi further teaches that Alport syndrome is characterized by glomerular injury due to biomechanical strain. (Page 1270, column 1; page 1278, column 2.) Zallocchi teaches that integrin [Symbol font/0x61]1-null mouse models of Alport syndrome show no mesangial-cell-process invasion and slowed accumulation of laminin 211. (Page 1270, column 1.) Zallocchi teaches that Alport patients have functional GBM for the first several years of life and only develop symptoms later. (Page 1269, column 2.) Zallocchi teaches that Alport syndrome is caused by mutations in type IV collagen genes (COL4A5, COL4A3, and COL4A4). (Page 1269, column 1.)
The person of ordinary skill in the art would have found it obvious to add Wilson’s ACE inhibitors and ARBs to the treatment method of the ’325 patent because Wilson teaches that ACE inhibitors and ARBs are routinely used to treat Alport syndrome. See MPEP 2143(I)(A) (combining prior-art methods according to known methods to yield predictable results is obvious); MPEP 2144.06(I) (combining known equivalents is prima facie obvious).
The person of ordinary skill in the art would have reasonably expected success in achieving the outcomes set forth in claims 1-6 because Zallocchi teaches that glomerular disease progression, glomerulonephritis, biomechanical strain, laminin 211 deposition in the GBM, and mesangial cell process invasion of the glomerular capillary loop are all phenomena caused in Alport syndrome patients by overactivity of [Symbol font/0x61]1 integrin. The skilled artisan would have found it obvious that inhibiting [Symbol font/0x61]1 integrin would accordingly result in the outcomes listed in claims 1-6.
Regarding claims 15-17, Wilson teaches that any of the ACE inhibitors and ARBs, respectively, listed in the claims can be used to treat Alport syndrome. (Paragraph 240.) It would therefore have been obvious to select any of Wilson’s enumerated compounds for that purpose. See MPEP 2143(I)(E) (obvious to try finite number of identified, predictable solutions to achieve predictable outcome); MPEP 2144.06 (prima facie obvious to substitute art-recognized equivalents for same purpose).
Claims 7-9 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 8 and 9 of U.S. Patent No. 6,492,325 in view of Wilson and Zallocchi as applied to claims 1-6, 10, 12, 14-17, and 19 above and further in view of Greinwald, Jr. (US 20040166495).
The claims of the ’325 patent and the teachings of Wilson and Zallocchi are relied upon as above. In addition, Wilson teaches that Alport syndrome can be detected by assaying reduction of function, decreased expression level of, and/or deficiency in the COL4A3, COL4A4, and/or COL4A5 genes using diagnostic or prognostic assays known in the art. (Paragraph 247.) Furthermore, Zallocchi teaches that in Alport-syndrome patients, the GBM is functional for the first few years of life, only deteriorating later. (Page 1269, column 2.)
The ’325 patent does not claim, and Wilson and Zallocchi do not teach, determining that a subject is at risk for developing Alport glomerular disease prior to administering the [Symbol font/0x61]1 integrin blocking agent and ACE inhibitor and/or ARB.
Greinwald teaches diagnostic assays for predicting an individual’s risk for Alport syndrome based on screening for linked mutations. (Abstract; paragraphs 20, 23.) Regarding claim 9, Greinwald teaches that detecting a risk of hearing loss is beneficial in infants before their hearing loss can begin. (Paragraphs 3-5.)
The person of ordinary skill in the art would have found it obvious to determine that a subject is at risk for developing Alport glomerular disease before administering the ’325 patent’s [Symbol font/0x61]1 integrin inhibitor and Wilson’s ACE inhibitor and/or ARB. This is so because the skilled artisan would have understood based on Zallocchi that blocking [Symbol font/0x61]1 integrin activation prevents the GBM deterioration characteristic of Alport syndrome. The skilled artisan would have predicted that Greinwald’s risk-assessment method in view of Wilson would identify subjects who would benefit from the treatment regimen combining the ’325 patent’s [Symbol font/0x61]1 integrin inhibitor and Wilson’s ACE inhibitor and/or ARB.
Regarding claim 9, the skilled artisan would have found it obvious to carry out Greinwald’s risk-assessment method in view of Wilson before proteinuria (or any Alport syndrome symptoms) begin in order to achieve Greinwald’s goal of early intervention. The skilled artisan would have understood based on Zallocchi that GBM is functional in Alport-syndrome patients for the first few years of their lives, so it would have been obvious to screen for Alport-syndrome risk at an early age.
Claims 11 and 20 are/remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 8 and 9 of U.S. Patent No. 6,492,325 in view of Wilson and Zallocchi as applied to claims 1-6, 10, 12, 14-17, and 19 above and further in view of Kagami et al. (2002, Laboratory Investigation 82: 1219-1227; on 4/26/23 IDS).
The claims of the ’325 patent and the teachings of Wilson and Zallocchi are relied upon as above.
The ’325 patent does not claim, and Wilson and Zallocchi do not teach, that the [Symbol font/0x61]1 integrin blocking agent comprises an [Symbol font/0x61]1 integrin neutralizing antibody.
Kagami teaches a function-blocking [Symbol font/0x61]1 integrin antibody. (Abstract.) Kagami teaches that administering the antibody to a model of glomerulonephritis suppressed mesangial-cell proliferation and collagen accumulation, leading to mesangial ECM expansion. (Page 1221; page 1222, column 1.) Kagami concludes that the modulation of [Symbol font/0x61]1b1 integrin expression by activated mesangial cells in nephritic glomeruli may provide a new therapeutic approach for regulating abnormal mesangial remodeling leading to glomerulosclerosis. (Page 1225, column 1.)
It would have been obvious to the person of ordinary skill in the art to substitute Kagami’s function-blocking [Symbol font/0x61]1 integrin antibody for the ’325 patent’s [Symbol font/0x61]1b1 integrin-inhibiting obtustatin in the method of the ’981 patent in view of Wilson, Marcinkiewicz, and Zallocchi because both agents inhibit [Symbol font/0x61]1 integrin upon administration to a subject. See MPEP 2143(I)(B) (simple substitution of known elements for each other to obtain predictable results is obvious); MPEP 2144.06 (substitution of art-recognized equivalents for same purpose is prima facie obvious).
Claim 13 remains rejected on the ground of nonstatutory double patenting as being unpatentable over claims 8 and 9 of U.S. Patent No. 6,492,325 in view of Wilson and Zallocchi as applied to claims 1-6, 10, 12, 14-17, and 19 above and further in view of Marcinkiewicz (US 20030186334).
Marcinkiewicz teaches that obtustatin is a peptide that is a potent, specific inhibitor of [Symbol font/0x61]1b1 integrin and can be administered as a pharmaceutical. (Abstract; paragraphs 16, 19, 108.)
The person of ordinary skill in the art would have found it obvious to substitute Marcinkiewicz’s obtustatin for the ’325 patent’s [Symbol font/0x61]1b1 integrin-inhibiting peptide because obtustatin is a peptide that is a potent, specific inhibitor of [Symbol font/0x61]1b1 integrin. The person of ordinary skill in the art would have understood that making the substitution would treat or prevent Alport syndrome by blocking its initiating event. See MPEP 2144.06 (substituting known equivalents for same purpose is prima facie obvious).
Claim 21 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 8 and 9 of U.S. Patent No. 6,492,325 in view of Wilson, Marcinkiewicz, Zallocchi, and Kagami as applied to claims 11 and 20 above and further in view of Gross (2003, Kidney International 63: 438-446; on 4/26/23 IDS).
The claims of the ’325 patent and the teachings of Wilson, Marcinkiewicz, Zallocchi, and Kagami are relied upon as above.
The ’325 patent does not claim, and Wilson, Marcinkiewicz, Zallocchi, and Kagami do not teach, administering ramipril at 10 mg/kg/day.
Gross teaches providing 10 mg/kg/day ramipril to a mouse model of Alport syndrome. (Abstract; page 439, column 2.) Gross teaches that this dosage is well below the toxic range and equivalent to the maximum therapeutic dose of 10 mg per day in humans. (Page 439, column 2.)
It would have been obvious to provide Wilson’s ramipril at 10 mg/kg/day because Gross teaches giving this dose to treat a mouse model of Alport syndrome. The person of ordinary skill in the art would have been motivated to provide this dosage because Gross teaches that it corresponds to the maximum therapeutic dose in humans.
Response to Arguments
Regarding the rejection over the ’981 patent, applicant alleges that coadministering an [Symbol font/0x61]1 integrin blocking agent and an ACE inhibitor/ARB instead of the ’981 patent’s antibody “would be a complete change of the underlying mechanism of action that is fundamental to the claimed ’981 method.” (Reply at 13.) It is not clear why this should be the case. The ’981 patent claims that as a part of its method, mesangial cell process invasion of the glomerular capillary loop is inhibited (claim 7). Zallocchi teaches that Alport syndrome was known to be caused by [Symbol font/0x61]1b1-integrin-mediated mesangial-cell-process invasion of the glomerular capillary loop. (Page 1269, column 1; page 1270, column 1; page 1278, column 2.) The person of ordinary skill in the art would have therefore understood that administration of the ’981 patent’s endothelin-1 antibody impacts the same underlying mechanism as Marcinkiewicz’s obtustatin, namely mesangial-cell-process invasion of the glomerular capillary loop.
Regarding the rejection over the ’325 patent, applicant argues that “the ’325 claims do not claim administration of an [Symbol font/0x61]1 integrin blocking agent, specifically . . . .” (Reply at 14.) This statement is not supported by evidence. Claim 8 of the ’325 patent administers “an effective amount of an [Symbol font/0x61]1[Symbol font/0x62]1 integrin receptor inhibitor.” An inhibitor of [Symbol font/0x61]1[Symbol font/0x62]1 integrin is necessarily an inhibitor of [Symbol font/0x61]1 integrin, and applicant provides no explanation for why the person of ordinary skill in the art would not consider an “inhibitor” to be a “blocking agent.” Applicant also contends that the ’325 patent does not claim the administration of an ACE inhibitor or ARB. (Reply at 14.) This aspect of the invention is taught by Wilson.
Regarding both double-patenting rejections, applicant incorporates the arguments set forth against the rejections under 35 U.S.C. 103 “and submits that those arguments are relevant to the double-patenting rejections as well.” The examiner agrees that they are relevant. Those arguments have been fully addressed above in the discussion of obviousness.
Conclusion
No claims are allowed. No claims are free of the art.
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/Lora E Barnhart Driscoll/Primary Examiner, Art Unit 3991
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