RESPONSE TO APPLICANT’S AMENDMENT
1. Applicant's amendment, filed 11/17/2025, is acknowledged.
2. Claims 1-17, 19, 48-49 are pending.
3. In view of Applicant amendment to claims 1, 5, 12 and 6, 13, to recite “undergone renal replacement therapy”, “end-stage renal disease” and “hemodialysis”, respectively. The new rejections of Claims 1, 5-6 are necessitated by Applicant’s Amendment.
4. Claims 4, 11, 48-49 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions.
5. Claims 1-3, 5, 7-10, 12-13 14-17 and 19 are under examination as they read on a method of treating neointimal hyperplasia with an inhibitor of F11R/JAM-1, and the species of arterio-venous graft as the blood vessel abnormality, and end-stage renal disease as the condition and SEQ ID NO: 3 as the peptide.
6. The Salifu declaration, filed 11/17/2025, under 37 CF §1.130 is sufficient to overcome the Babinska et al (15th Annual American Society of Diagnostic and Interventional Nephrology (Atlanta, Georgia) February 15-17, 2019). The declaration states that the relied-upon disclosures in Babinska were made “by the inventor” to satisfy §102(b)(1)(A). The declaration states that the subject matter of the Babinska et al, which was published less than one year from the filing date of the instant application, was previously disclosed by the inventors. The Declaration is sufficient to disqualify Babinska et al reference as prior art. Further, the declaration established that the inventors were the sole inventors of the relied-upon disclosure in the Babinska et al reference.
7. In view of the claims amendment to recited the peptides of SEQ ID NOs: 2-17, the previous Written Description rejection is here by withdrawn.
8. The following new grounds of rejection are necessitated by the amendment submitted 11/17/2025.
9. Claims 1-3, 5, 7-10, 12-13 14-17 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Zernecke et al (Translational Sciences, 2006, 26(2):e10-e13-IDS-2), in view of Kokubo (J Am Soc Nephrol 20: 1236 –1245, 2009) or Lee et al (Advances in Chronic Kidney Disease, 22(6):431-437, 2015) and US 20170202918 and Babinska et al (Peptide Science, 102(4), 2014-9, IDS-9).
Zernecke et al show that the genetic deletion of JAM-A in apolipoprotein E– deficient (apoE-/-) mice significantly reduced neointimal hyperplasia after wire injury (abnormal) of carotid arteries without altering medial area (abstract). Genetic deletion of JAM-A significantly decreased the neointimal area. Zernecke et al concluded that data indicate that JAM-A plays a crucial role in neointimal lesion formation and infiltration after arterial injury in an atherosclerotic context, which can be ascribed to a direct contribution to monocyte recruitment and deposition of platelet RANTES on activated or recovering endothelium and may be targeted to limit lesion development after injury.
Kokubo teaches that arteriovenous (AV) access failure resulting from venous neointimal hyperplasia is a major cause of morbidity in patients with ESRD. Kokubo teaches that when they treated animals with bone morphogenic protein-7, which promotes VSMC differentiation, before creation of the arteriovenous (AV) anastomosis, the effect of Chronic kidney disease (CKD) on the development of neointimal hyperplasia was eliminated. CKD accelerates development of neointimal hyperplasia at the anastomotic site of an AV fistula, and administration of bone morphogenic protein-7 neutralizes this effect (abstract).
Lee et al teaches that more than 70% of patients with ESRD use hemodialysis as their primary form of kidney replacement therapy. To deliver successful, consistent, and sustainable dialysis therapy, a functional and durable vascular access is required. Thus, the vascular access is the lifeline for the hemodialysis patient. The 2 most preferred types of permanent vascular access are the arteriovenous fistula (AVF) and arteriovenous graft (AVG). However, vascular access dysfunction, which negatively affects patient morbidity and mortality, remains a significant problem in both AVF and AVG. Venous stenosis is the most common angiographic lesion seen in AVF and AVG dysfunction (Fig 1). AVF maturation failure, resulting from both early neointimal hyperplasia development and poor vascular remodeling, is the most common problem seen in AVF dysfunction (Fig 1). In AVGs, recurrent stenosis secondary to aggressive neointimal hyperplasia development is the primary cause of vascular access failure. At present, there is a poor understanding of the biologic mechanisms that lead to AVF maturation failure and AVG stenosis. Consequently, there are few if any effective therapies to date to effectively treat vascular access dysfunction in AVFs and AVGs (abstract).
The reference teachings differ from the claimed invention in the recitation that the subject has chronic kidney disease or ESRD and has undergone renal replacement therapy and F11R/JAM-A inhibitor of SEQ ID NOs: 3 and in claim 1, the abnormality is an arteriovenous fistula / graft in claims 2 and 9 and wherein the RRT is hemodialysis in claim 6, pharmaceutically acceptable excipient in claim 14, parentally administering in claim 15, intravenous injection in claim 16, repeating administration of the inhibitor in claim 17 and PEG tag in claim 19.
However, the `918 publication teaches that knockout mice lacking GDF-15 are relatively protected against the development of pulmonary arterial hypertension [0015], [0128]. Furhter, the `918 publication demonstrated that antagonism of GDF-15 using TGFBRII-Fc, a TGF -beta1/3, GDF-15 ligand trap, improves pulmonary arterial hypertension (PAH) in two animal models [0040]. The `918 publication teaches that the GDF-15 inhibitor comprises polyethylene glycol (PEG) [0050].
Babinska et al teach the development of new antiatherosclerotic and antithrombotic drugs utilizing F11 receptor (F11R/JAM-A) peptides, Peptide 1 (SVTVHSSEPEVRIPENNPVKLSC, SEQ ID NO: 12) and Peptide 4 (KSVTREDTGTYTC) that inhibit homophilic interactions between surface-located F11R molecules. The two lead F11R peptides were modified with D-Arg and D-lys at selective sites, for attaining higher stability to proteolysis in vivo. Babinska et al teach the inhibitory effects of the F11R peptides - SSEPEV-dR-IPENNPV(1D, SEQ ID NO: 12) and (dK)-SVT(dR)-EDTYTC (4D, SEQ ID NO: 3) (see abstract and page 323, 2nd ¶). The F11R peptide analogs, peptides 1D and 4D, containing D-arg and D-lys at selective positions, with enhanced resistance to proteolysis by trypsin and thrombin, were synthesized and examined for their effects on platelet function (age 328, under Results). These results have allowed us to select and modify the lead peptide which we currently use in-vivo, in studies of the inhibition of atherosclerotic-plaque formation in an animal model of atherosclerosis. The results presented a therapeutic agent for the prevention and regression of atherosclerotic plaque formation here, together with our initial positive results in vivo, clearly demonstrate that peptide 4D should be tested NOW in human patients as a therapeutic agent for the prevention and regression of atherosclerotic plaque formation (see page 332, bridging ¶).
Given the teachings of the `918 publication that knockout mice lacking GDF-15 are relatively protected against the development of pulmonary arterial hypertension. Further, the `918 publication demonstrated that antagonism of GDF-15 using TGFBRII-Fc, a TGF -beta1/3, GDF-15 ligand trap, improves pulmonary arterial hypertension (PAH) in two animal models. Further given the teachings of Zernecke et al that genetic deletion of JAM-A significantly decreased the neointimal area, those of skill in the art would to antagonize the F11R with the F11R inhibitory peptides taught by Babinska et al to treat neointimal hyperplasia taught by Zernecke et al in a subject has CKD or ESRD and has undergone RRT such as hemodialysis. Those skilled in that would have been motivated to do so because transgenic animals having made containing specific genetic defects are useful in characterizing the effect of such protection on the organism as a whole, and developing pharmacological treatments for protecting the disease as taught by the `918 publication.
Claims 15-17 are included because a person having ordinary skill in the art would have found it obvious to determine the optimum route of administering the peptides 1D and 4D that treat neointimal hyperplasia of result-effective variables known in the art. It is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272, 276, 205 USPQ 215,219 (CCPA 1980).
Claim 19 is included because `918 publication teaches that the GDF-15 inhibitor comprises polyethylene glycol (PEG) [0050], it would have been obvious to pegylate the F11R/JAM-A peptide taught by Babinska et al to improve their stability, solubility and circulation time.
Thos of skill in the art would have had reason to treat neointimal hyperplasia in arteriovenous fistulas stenosis during or after renal failure taught by Kokubo and Lee et al with F11R Peptides 1D and 4D taught by Babinska in view of Zernecke to prevent venous stenosis in AVG caused by neointimal hyperplasia.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Applicant’s arguments, filed 11/17/2025, have been fully considered, but have not been found convincing.
Applicant argues even if relevant to the claims at all, this disclosure does not in any way suggest to a skilled person that there would be any likelihood of successfully treating neointimal hyperplasia in a subject with chronic kidney disease or end stage renal disease that has undergone renal replacement therapy by administering a F11R/JAM-A inhibitor. Nothing in Zernecke 2006, or any other cited reference, would indicate effectiveness of such treatment in this patient population, as claimed and supported in examples disclosed in the application.
This is not found persuasive because Applicant’s arguments that there is no suggestion to combine the references, the examiner recognizes that obviousness can only be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine 5 USPQ2d 1596 (Fed. Cir 1988) and In re Jones 21 USPQ2d 1941 (Fed. Cir. 1992). In this case, the teachings of Zernecke et al pretraining to the genetic deletion of JAM-A in mice significantly reduced neointimal hyperplasia and the teachings of the `918 publication pertaining to GDF-15 knockout mice protected against the development of pulmonary arterial hypertension, wherein the antagonism of GDF-15 using TGFBRII-Fc indicating success in pulmonary arterial hypertension (PAH) in the face of having to solve a similar problem would have led one of ordinary skill in the art at the time the invention was made to combine the references to solve a similar problem in the art. The strongest rationale for combining reference is a recognition, expressly or implicitly in the prior art or drawn from a convincing line of reasoning based on established scientific principles or legal precedent that some advantage or expected beneficial result would have been produced by their combination In re Sernaker 17 USPQ 1, 5-6 (Fed. Cir. 1983) see MPEP 2144. Furthermore, in KSR Int'l Co. v. Teleflex Inc., 550 U.S. m, 2007 WL 1237837, at "13 (2007) it was stated that "if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond his or her skill"
Thos of skill in the art would have had reason to treat neointimal hyperplasia in arteriovenous fistulas stenosis during or after renal failure taught by Kokubo and Lee et al with F11R Peptides 1D and 4D taught by Babinska in view of Zernecke to prevent venous stenosis in AVG caused by neointimal hyperplasia.
10. No claim is allowed.
11. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
112. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MAHER M HADDAD whose telephone number is (571)272-0845. The examiner can normally be reached on Monday-Friday from7:00AM to 4:30PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu, can be reached at telephone number 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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December 22, 2025
/MAHER M HADDAD/ Primary Examiner, Art Unit 1644