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 .
Drawings
The drawings are objected to because they contain color. Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2). The objection to the drawings will not be held in abeyance.
A renewed petition to include color drawings was supplied in this application on 10/21/25. A decision on that petition will be mailed in a separate communication.
Status of Claims
Applicant’s 1/27/26 claim listing amends claim 18. No other claims were amended, canceled, or added. Claims 1-18 are pending and under examination.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 18 remains rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Independent claim 1 is a method of treating Alport syndrome in a subject comprising administering an [Symbol font/0x61]1 integrin blocking agent plus an ACE inhibitor and/or an ARB to the subject; claim 18 requires that the administration of an [Symbol font/0x61]1 integrin blocking agent plus an ACE inhibitor “is synergistic in protecting renal function in Alport syndrome.” Applicant has not demonstrated possession of such synergy as a result of administering the claimed agents.
“Synergy” in disease treatment is understood in the pharmaceutical art to be an effect beyond additive when multiple agents are administered to a subject. See, e.g., Scott, US 20040203043, at paragraph 7 (synergy is a “property of a combination to be more potent and/or selective than expected based on the individual components”). Eliaz (US 20120171228) teaches, “What is frequently desired, but rarely observed, is a synergistic combination of two agents administered against a common target or disease condition. By definition, such synergy is unpredictable.” (Paragraph 10.) Feider (US 20170086461) concurs, writing that “synergy has been found to be an unpredictable phenomenon. Often like compounds display varying synergistic profiles when combined with a particular active. It may be that no synergy is evidenced or it may be that synergy exists but over a different synergistic range. Because of this observation, it is difficult, if not impossible, to draw conclusions regarding the synergistic profile of one compound based upon the synergistic profile of a like compound.” (Paragraph 2.) Even after the invention’s effective filing date, synergy remained unpredictable; Li (US 20240335407) teaches that “even two different drugs with the same pharmacodynamic effect are applied in combination, the efficacy of the combined application is very complicated and unpredictable, and may result in the phenomenon of synergy, addition and even antagonism of drugs.” (Paragraph 8.) In short, in the absence of experimental evidence, the skilled artisan would not have inferred the presence of synergy in any given coadministration.
MPEP 2163(II)(A)(3)(a)(i) instructs, “Patents and printed publications in the art should be relied upon to determine whether an art is mature and what the level of knowledge and skill is in the art.” A review of the contemporaneous knowledge in the art, for example that discussed above, reveals that the art of predicting synergy is not mature. “[F]or inventions in emerging and unpredictable technologies, or for inventions characterized by factors not reasonably predictable which are known to one of ordinary skill in the art, more evidence is required to show possession.” MPEP 2163(II)(A)(3)(a)(i). Such is the case here.
Given the unpredictability of synergy in two coadministered agents, the specification does not demonstrate synergy in coadministration of an [Symbol font/0x61]1 integrin blocking agent together with an ACE inhibitor, as claim 18 requires. The relevant working example, Example 1, does not coadminister these two agents. Instead, it teaches administering ramipril (an ACE inhibitor) to genetically modified mice in which the integrin [Symbol font/0x61]1 gene has been knocked out. (Page 18, lines 7-9.) In these [Symbol font/0x61]1-integrin-null mice (“DKO” or “Alport mice”), applicant observed an improved lifespan upon daily administration of ramipril. (Page 18, lines 10-14.) The specification contains no examples, however, in which an [Symbol font/0x61]1 integrin blocking agent is coadministered with an ACE inhibitor, so it does not represent evidence of synergy as claim 18 recites it. The fact that [Symbol font/0x61]1-integrin-inhibiting antibodies were known (specification at page 17, line 37, through page 18, line 9) does not compel a conclusion that coadministering those antibodies an ACE inhibitor would generate synergy. The skilled artisan would not have reasonably concluded that applicant possessed the subject matter of claim 18 before the effective filing date.
Response to Arguments
Applicant supplies a declaration under 37 CFR 1.132 by inventor Cosgrove in support of adequate written description. (Reply at 6-7.) The Cosgrove declaration reviews Example 1 in the specification and contends that “the same technical effect would be observed for DKO mice lacking [Symbol font/0x61]1 integrin and mice treated with an [Symbol font/0x61]1 integrin inhibitor.” (Cosgrove declaration ¶ 11.) This statement is unsubstantiated by citation to prior-art references and therefore represents the declarant’s opinion about the state of the art. Opinion evidence is entitled to consideration and some weight so long as the opinion is not on the ultimate legal conclusion at issue. See M.P.E.P. § 716.01(c), part III. In assessing the probative value of an expert opinion, the examiner must consider (1) the nature of the matter sought to be established, (2) the strength of any opposing evidence, (3) the interest of the expert in the outcome of the case, and (4) the presence or absence of factual support for the expert’s opinion. Ashland Oil, Inc. v. Delta Resins & Refractories, Inc., 776 F.2d 281, 227 USPQ 657 (Fed. Cir. 1985).
In this case, the Cosgrove declaration seeks to establish a factual matter, namely the understanding of skilled artisans as to the equivalence of a complete [Symbol font/0x61]1 integrin knockout and the administration of an agent that inhibits [Symbol font/0x61]1 integrin to an unspecified degree in the context of a prediction of synergy. The rejection under section 112(a) cites several pieces of prior art post-filing art as evidence that achieving synergy was unpredictable before the effective filing date and remains so; the Cosgrove declaration provides no evidence to contradict those factual findings. Finally, declarant Cosgrove has a clear interest in the outcome of the case since he is an inventor. On balance, paragraph 11 of the Cosgrove declaration is insufficient to overcome the rejection of record because it is an opinion unsupported by evidence, supplied by an inventor on this application.
As applicant acknowledges, the Cosgrove declaration also provides post-filing data about an alleged synergistic effect between a particular [Symbol font/0x61]1-integrin-blocking agent (antibody Mu31/8) and a particular ACE inhibitor (ramipril) in a mouse model of Alport disease. (Reply at 6, Cosgrove declaration ¶ 12 and Figures.) This portion of the Cosgrove declaration is not clearly relevant, however, to what the skilled artisan would have concluded based on the original disclosure that applicant possessed as of the claims’ effective filing date. “If the examiner concludes that the claimed subject matter is not supported [described] in an application as filed, this would result in a rejection of the claim on the ground of a lack of written description under 35 U.S.C. 112(a) . . . .” MPEP 2163.01. Applicant has identified no basis in law or in agency policy for allowing post-filing evidence to supplement the as-filed disclosure in order to bring it into compliance with § 112(a).
Beyond the inability of post-filing evidence to augment an original disclosure for purposes of § 112(a), the Cosgrove declaration is not commensurate in scope with claim 18. The evidence in the Cosgrove declaration is confined to a discussion of Example 1 in the specification—which does not coadminister two agents—and a discussion of experiments using a single unclaimed [Symbol font/0x61]1-integrin-blocking agent (antibody Mu31/8) and a single ACE inhibitor (ramipril). (Cosgrove declaration, ¶¶ 11-12.) Claim 18 is open to all [Symbol font/0x61]1-integrin-blocking agents and all ACE inhibitors. The Cosgrove declaration’s evidence does not share a nexus with the invention as claim 18 sets it forth and therefore cannot establish patentability of that claim.
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 1-6 and 12-17 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 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.)
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 and 12-17 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 and 12-17 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 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 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 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 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).
Response to Arguments
Applicant alleges that Wilson’s teachings are insufficient to render the claims prima facie obvious. (Reply at 9.) This point is not in dispute; Wilson was not, however, applied alone under section 103. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). See MPEP 2145(IV).
Applicant contends that substituting Marcinkiewicz’s [Symbol font/0x61]1-integrin-inhibiting peptide for Wilson’s therapeutic peptide would impermissibly change the principle of operation of Wilson’s method. (Reply at 9.) Wilson, however, is relied upon for the administration of ACE inhibitors and ARBs to treat Alport syndrome. Zallocchi teaches that skilled artisans understood Alport syndrome to be caused by [Symbol font/0x61]1-integrin-mediated basement-membrane pathology, and that the progression to symptomatic Alport syndrome is inhibited by the knockout of integrin [Symbol font/0x61]1. Marcinkiewicz establishes that obtustatin is a small peptide that is a potent, specific inhibitor of [Symbol font/0x61]1b1 integrin. It is not clear why inhibiting the underlying cause of Alport syndrome would change the principle of operation of Wilson’s ACE inhibitors or ARBs. Simple substitution of one known element for another would have been obvious when the substituted components were known in the art and the results of substituting them would have been predictable. See MPEP 2143(I)(B), e.g. Example 1 (finding it obvious to substitute an evaporative distillation step for an aqueous extraction step because both would separate caffeine from oil).
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 of record, but they are not convincing of error for several reasons.
First, again, the relevant working example in the specification does not coadminister an [Symbol font/0x61]1-integrin-blocking agent and an ACE inhibitor. It investigates the effects of ramipril, one particular ACE inhibitor, in DKO mice that are null for [Symbol font/0x61]1 integrin. Neither the specification nor the Cosgrove declaration provides evidence that the person of ordinary skill in the art would have understood that any [Symbol font/0x61]1-integrin-blocking agent would reasonably mimic the effects of a genetic knockout of [Symbol font/0x61]1 integrin.
Beyond that point, applicant has not explained why the evidence in the specification demonstrates synergy. As discussed in the § 112(a) rejection, synergy is a greater-than-expected effect. (Scott, US 20040203043, at paragraph 7.) Example 1 shows improved survival in a ramipril-treated DKO mouse relative to an untreated DKO mouse or ramipril alone—an average of ~26.75 weeks compared to ~16 weeks and ~21.5 weeks, respectively. (Figure 2, survival probability = 0.50.) There is no evidence in the specification or the Cosgrove declaration, however, that the person of ordinary skill in the art would not have expected this improvement in what applicant characterizes as a combination therapy. Applicant bears the burden of explaining all proffered data, and evidence relied upon for secondary considerations should establish “that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance.” See MPEP 716.02(b) (emphases added). A greater-than-additive effect may be relevant to obviousness, but even a showing of a greater-than-additive effect is not necessarily sufficient to overcome a prima facie rejection. See MPEP 716.02(a)(I). The specification actually contends that due to a paper published in 2000, the skilled artisan would have expected attenuated pathology and an increased lifespan when [Symbol font/0x61]1 integrin is deleted. (Page 18, lines 14-16.) It also states that ACE inhibitors like ramipril are the “standard of care” in Alport syndrome. (Page 18, line 31.) Given these statements, it is not clear why the person of ordinary skill in the art would not have expected an improved result for combination therapy using two modalities that are each known to give the same endpoint in Alport syndrome. See MPEP 2144.06(I) (quoting In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980)).
The data described in paragraph 12 of the Cosgrove declaration has also been fully considered, but it is not convincing of error in the § 103 rejections. 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.
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. It does not explain by evidence, however, why the person of ordinary skill in the art would have found that improvement surprising given the known ability of each agent alone to treat Alport syndrome.
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 and 12-17 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 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.)
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, and 12-17 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.
Claim 11 remains 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, and 12-17 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).
US Patent 6,492,325
Claims 1-6, 10, 12, and 14-17 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, and 14-17 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.
Claim 11 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, and 14-17 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, and 14-17 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).
Response to Arguments
In response to the rejections for nonstatutory double patenting, applicant supplies arguments similar to those submitted in reply to the rejections under § 103. (Reply at 13, 14 (change in principle of operation of reference-patent claims)). These arguments are unconvincing of error for the same reasons set forth above. Given the teachings of Wilson, Marcinkiewicz, and Zallocchi about the treatment of Alport syndrome with ACE inhibitors and ARBs and about the [Symbol font/0x61]1-integrin-involved pathology of Alport syndrome, the claimed invention would have been an obvious variant of both the ’981 patent and the ’325 patent when taken in view of those references.
Conclusion
No claims are allowed.
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/Lora E Barnhart Driscoll/ Primary Examiner, Art Unit 3991