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 .
Applicant’s remarks, filed 10/17/2025, are acknowledged and entered into the record. Applicants added new claim 15 in the remarks of 10/17/2025.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 10/17/2025 has been entered.
Election/Restrictions
Applicant’s election without traverse of the species, pulmonary fibrosis, in the reply filed on 7/8/2024 is acknowledged. Applicant canceled claims 2, 3, 5 and 9-10 in the response submitted 7/8/2024.
Status of Claims
Claims 1, 4, 6-8 and 11-15 are pending and being examined on the merits.
Claim Rejections – Maintained, Amended
The following rejection has been amended to include newly added claim 15.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 4, 6-8 and 11-15 are rejected under 35 U.S.C. 103 as being unpatentable over Porter et al., (from IDS; US20150086483; published 3/26/2015) over Martinez et al., (from IDS; US 20130287795; published 10/31/2013) and Lagares et al., (from IDS; Nat Med., 23(12); Epub 10/23/2017).
Porter et al. teaches methods and medicaments useful for treating idiopathic pulmonary fibrosis comprising administering an anti-CTFG antibody (abstract). Porter teaches a method for selecting a subject with idiopathic pulmonary fibrosis comprising comparing a radiographic scan of the subject’s lungs before treatment and after treatment, and selecting a subject for continued treatment based on treatment-mediated reduction or stabilization of at least one pulmonary radiographic parameter (pg. 19, claim 25). Porter teaches the radiographic scan consists of a high resolution computerized tomography (HRCT) scan or chest x-ray (pg. 19, claim 26). Porter teaches that subjects diagnosed with idiopathic pulmonary fibrosis have the presence of one or more characteristics including bibasilar inspiratory crackles, digital clubbing and pulmonary hypertension (pg. 11, para. 0122). Porter further teaches a method for selecting a subject with idiopathic pulmonary fibrosis for continued treatment based on treatment-mediated reduction or stabilization in quantitative interstitial lung disease (pg. 19, claim 34). Thus, Porter teaches methods of treating pulmonary fibrosis in an individual, selected by HCRT scans with identifiable characteristics, or including interstitial lung disease, comprising administering an anti-CTFG antibody. However, Porter does not teach that the antibody is an anti-ephrin-B2 antibody.
Martinez et al. teaches novel antibodies against ephrin-B2 and their use as medicament for inhibiting angiogenesis in the treatment of diseases (abstract). Specifically, Martinez teaches two anti-Ephrin-B2 antibodies, B11 and 2B1. Antibody B11 specifically recognizes and binds to ephrin-B2 so that it inhibits its binding to the Eph B4 receptors (pg. 2, para. 0013, 0015); antibody 2B1 has a lower affinity for ephrin B2 compared to B11 (pg. 3, para. 0027), and does not compete with the Eph B4 receptor, but also reduces angiogenesis (pg. 2, para. 0014). Martinez teaches the expression and selection of antibody species from Clones B11 and 2B1 (pg. 6, paras. 0068-0073; figs. 1-3). Martinez teaches the antibodies are preferably the human antibody isotype IgG1, IgG2, IgG3 or IgG4; human, humanized or affinity matured; and can be monoclonal antibodies (pg. 2, paras. 0020-0022). Martinez teaches that the antibody may be used for detection of (pg. 4, paras. 0044-0045), or as a medicament for the therapeutic treatment of (pg. 5, paras. 0051-0052), a pathological condition associated with angiogenesis, including non-neoplastic diseases such as lung inflammation and scleroderma (i.e. systemic sclerosis; pg. 4, para. 0045; pg. 5, para. 0052). Martinez demonstrates that the antibodies B11 and 2B1 are effective treatments for reducing angiogenesis in vivo (pg. 10, example 3, para. 0117). Thus, Martinez teaches the antibody clones B11 and 2B1 for generation of humanized antibodies against ephrin-B2 for treatment of pathological conditions associated with angiogenesis. However, Martinez does not specifically teach the anti-ephrin-B2 antibodies for treatment of pulmonary fibrosis.
Lagares et al. teaches ephrin-B2 shedding promotes myofibroblast activation and organ fibrosis (title, abstract). Lagares teaches that fibrosis results in the distortion of tissue architecture and organ failure in a variety of human diseases including pulmonary fibrosis and scleroderma (pg. 2, introduction, para. 1); and that fibrosis results from excessive recruitment and activation of myofibroblasts. Lagares teaches that ephrin-B2 is upregulated in lung fibroblasts from individuals with idiopathic pulmonary fibrosis or scleroderma-associated interstitial lung disease (pg. 2, para. 2); and that ephrin-B2 contributes to angiogenesis and is implicated in the vascular contributions to the development of fibrosis in human disease (pg. 3, top paragraph), via its activation of EphB3/EphB4 receptor signaling (abstract). Lagares utilized a mouse model of pulmonary fibrosis (pg. 13, para. 2), and demonstrated that upstream inhibition of ephrin-B2 signaling, via inhibition of ADAM10-mediated shedding of soluble ephrin-B2 with the ADAM10 inhibitor GI254023X, resulted in inhibition of lung fibrosis and significantly increased survival curves in pulmonary fibrotic mice (pg. 27, fig. 5). Lagares concludes that ephrin-B2 is a potent mediator of tissue fibrosis (pg. 10, discussion, para. 1), playing a central role in the pathogenesis of fibrotic diseases; and identifies inhibition of sEphrin-B2 activation of its receptors, EphB3/EphB4, as potential therapeutic targets (pg. 12; para. 3; pg. 28, fig. 6L). Thus, the teachings of Lagares provide motivation for inhibition of ephrin-B2 ligand : EphB3/EphB4 receptor signaling as therapeutic strategy for treatment of idiopathic pulmonary fibrosis and/or scleroderma associated interstitial lung disease.
It would have been obvious to one of skill in the art to modify the methods for treating idiopathic pulmonary fibrosis, as taught by Porter et al., by substituting the anti-ephrin-B2 antibody of Martinez in place of the anti-CTFG antibody. One would have been motivated to do so given the suggestion by Lagares et al., that inhibition of ephrin-B2 activation of Eph3/Eph4 receptors is an effective therapeutic strategy in treating pulmonary fibrosis. There would have been a reasonable expectation for success given the knowledge that the anti-ephrin-B2 antibodies, B11 and 2B1, specifically recognize ephrin-B2 and inhibit its binding to Eph4 receptors; and that the anti-ephrin-B2 antibodies effectively inhibited ephrin-B2-mediated angiogenesis in vivo, as demonstrated Martinez et al. Thus, the invention as a whole was prima facie obvious to one of skill in the art at the time the invention was made.
Regarding claims 1 and 14, the modified method of the combination of Porter, Martinez and Lagares, as described above, makes obvious the method of treating pulmonary fibrosis comprising identifying a subject with pulmonary fibrosis and administering an effective amount of an anti-ephrin-B2 antibody. Porter teaches the method is for treatment of idiopathic pulmonary fibrosis (re. claim 14).
Regarding claims 4 and 6, Porter teaches an effective amount of an antibody refers to an amount that is sufficient to produce a reversal in pathologic rate of decline in one or more pulmonary function parameters, including the normalization of one or more pulmonary function parameters (pg. 5, para. 0050); thus encompassing improved lung function. Porter teaches that the method requires a treatment-mediated reduction or stabilization of at least one pulmonary radiographic parameter, and that the HRCT scans detect subpleural, basal predominance of fibrosis; reticular abnormality and the presence of honeycombing, upper or mid-lung predominance of fibrosis (pg. 4, para. 0046). Further, Porter teaches that an effective amount is also one that reduces, stabilizes or reverses histopathologic features such as degree of myofibroblast infiltration, rate of collagen deposition and formation of fibroblastic foci (pg. 6, para. 0075). Regarding claim 6, Porter teaches the methods of the invention are also appropriate for the treatment of subjects having bibasilar inspiratory crackles as this is a characteristic known in the art to be indicative of the presence of idiopathic pulmonary fibrosis (pg. 11, para. 0122).
Regarding claims 7 and 8, the modified method of the combination of Porter, Martinez and Lagares is described above. It is known in the art that pulmonary fibrosis develops in (subsets of) patients with scleroderma (i.e. systemic sclerosis). Lagares teaches that ephrin-B2 is upregulated in lung fibroblasts from individuals with idiopathic pulmonary fibrosis or scleroderma-associated interstitial lung disease (pg. 2, para. 2). Martinez teaches that the anti-ephrin-B2 antibodies may be used in methods of detection (pg. 4, paras. 0044-0045) and methods of treatment (pg. 5, paras. 0051-0052) for scleroderma (i.e. systemic sclerosis). Porter teaches that subjects with idiopathic pulmonary fibrosis have the presence of one or more characteristics including digital clubbing and pulmonary hypertension (pg. 11, para. 0122). Porter further teaches a method for selecting a subject with idiopathic pulmonary fibrosis for continued treatment based on treatment-mediated reduction or stabilization in quantitative interstitial lung disease (pg. 19, claim 34); thus the patients have idiopathic pulmonary fibrosis and interstitial lung disease. Thus, the modified method of Porter, Martinez and Lagares makes obvious the method of claim 1 wherein the subject has systemic sclerosis (re. claim 7) and interstitial lung disease (re. claim 8).
Regarding claims 11-13, Martinez teaches the anti-ephrin-B2 antibodies are derived from clone B11 (re. claim 11) or 2B1 (re. claim 12); and that the antibody may be humanized (re. claim 13).
Regarding new claim 15, Porter teaches providing novel methods for reducing, stabilizing or reversing the progression and severity of IPF and for preventing or treating one or more symptoms of IPF (pg. 1, para. 0007; pg. 19, para. 0189), and thus the combination of Porter, Martinez and Lagares makes obvious instant claim 15.
Response to Arguments
Applicant's arguments filed 10/17/2025 have been fully considered but they are not persuasive.
Applicants contend that the cited references to not teach all of the elements of the presently claimed method because the Lagares reference fails to teach that blocking soluble ephrin-B2 ectodomain treats established; rather, the Lagares reference teaches that inhibitionof ADAM10 can prevent the initiation of pulmonary fibrosis (remarks, pg. 5, para. 1). Applicants continue by citing the Lagares Declaration that supports that inhibition of ADAM10 was expected to inhibit the activation step of fibroblasts and thereby prevent events leading to fibrosis, but the data do not demonstrate that myofibroblasts, once activated, can be reverted to a quiescent phenotype by ADAM10 inhibition (remarks, pgs. 5-6; Lagares Declaration, item 7). Applicants state that it was the applicant’s work, described in the instant specifications, that showed for the first time that anti-ephrinB2 antibodies can treat pulmonary fibrosis; whereby in bleomycin-challenged mice, treated with the antibody at day 14, the treatment reverses already-established lung fibrosis, including decreased measures of α-SMA, which is a marker of differentiation from fibroblast to pathogenic myofibroblasts (remarks, pg. 6, para. 2; Lagares Declaration, item 8). Applicants cite that it is Dr. Lagares’ opinion that treatment of already established pulmonary fibrosis is categorically different from prevention of pulmonary fibrosis, and that the Lagares reference teaches a prophylactic method; whereas the claimed method deactivates chronically activated fibroblasts and allows regeneration of alveolar progenitor cells in established disease. Specifically, that antibody blockade of ephrin-B2 signaling in established disease is expected to act via (a) blocking ephrin-B2 signaling that keeps scar-forming fibroblasts chronically activated, and (b) removing ephrin-B2 restraints on repair, permitting alveolar progenitor cells to repopulate damaged lung, and enable regeneration (remarks, pg. 6, paras. 3-4; Lagares Declaration, item 9). Applicants conclude that the Lagares reference fails to teach or suggest a method for treating pulmonary fibrosis in a subject (remarks, pg. 7, para. 1).
In response to applicant’s assertion that the Lagares reference teaches ADAM10 inhibition of cleavage of the ephrinB2 ectodomain as a prophylactic for pulmonary fibrosis, the examiner contends that the Lagares reference teaches the pathway for inducing pulmonary fibrosis is attributable, in part, to soluble ephrinB2 binding to its receptors Eph3/Eph4. ADAM10 is a protease that cleaves the ectodomain of ephrinB2 resulting in soluble ephrinB2, which is pathogenic. Thus, ADAM10 cleavage is upstream of soluble ephrinB2 signaling. The examiner also cited that the Lagares reference teaches an alternative strategy, which is coating beads with an anti-ephrinB2 antibody to act as a “sink”, binding soluble ephrinB2, and thereby inhibiting its binding to Eph3/Eph4 receptors. Thus, the Lagares reference teaches an ephrinB2 antibody, which is substitutable for ADAM10, as both are means of inhibiting soluble ephrinB2 binding its receptors, which is the pathology underlying pulmonary fibrosis. ADAM10 prevents the generation of soluble ephrinB2, while the anti-ephrinB2 antibody prevents its binding to receptors; two alternative means to prevent soluble ephrinB2 binding to its cellular receptors. Lagares teaches the concept that idiopathic pulmonary fibrosis is attributable to the excess recruitment of fibroblasts to sites of tissue injury, and/or their excessive activation to an effector myofibroblast phenotype (Lagares, pg. 2, Introduction, para. 1). Specifically regarding the use of an anti-ephrinB2 antibody, Lagares teaches “our results suggest that sEphrin-B2 oligomers are present in BAL following lung injury and are biologically active in terms of being able to mediate pro-fibrotic functions of fibroblasts;” and that “consistent with this hypothesis, depletion of sEphrin-B2 in BAL from bleomycin-challenged mice with magnetic beads coated with the N-terminus-specific anti-ephrin-B2 mAb markedly though not completely reduced the fibroblast chemotaxis that was induced by these BAL samples,” (Lagares et al., pg. 5 last paragraph – pg. 6, first paragraph). Thus, Lagares teaches the benefits of an anti-ephrinB2 antibody is the sequestration of soluble ephrinB2 away from its receptors and thus prevents the chemotaxis of pathological myofibroblasts. Porter et al. teaches administering antibodies for the treatment of pulmonary fibrosis, and Martinez et al. teaches the specific anti-ephrinB2 antibodies of the instant claims bind to soluble ephrinB2 and prevent their binding to Eph3/Eph4 receptors. Thus, it is obvious to a skilled artisan to use the antibodies of Martinez, in the methods of Porter, with motivation provided by Lagares. The examiner has previously iterated that the Lagares reference teaches more than ADAM10 inhibition, that ADAM10 inhibition versus anti-ephrinB2 inhibition, via an anti-ephrinB2 antibody, are equivalent strategies for the purpose of inhibiting pathological soluble ephrinB2 signaling in pulmonary fibrosis, and that the examiner is relying on the use of an anti-ephrinB2 antibody in Lagares et al., and not an ADAM10 inhibitor, and therefore the teachings of ADAM10 inhibition are irrelevant to the rejection; see the office action of 4/18/2025, response to arguments section.
Having established that the Lagares reference teaches the inhibition of soluble ephrinB2 signaling, via an anti-ephrinB2 antibody, as a means of inhibiting the pathology of pulmonary fibrosis, the examiner next will address the argument that treatment of already established pulmonary fibrosis is categorically different from prevention of pulmonary fibrosis. First, the nature of the system is that fibroblasts naturally work to “repair and regenerate” lung tissue. While the pathogenic myofibroblasts provide an excessive action that leads to scarring and fibrosis, the default mode of the fibroblasts is to repair and regenerate; thus, blocking the pathogenic myofibroblast activity will a) reduce the progression of pulmonary fibrosis and b) support the natural repair and regeneration of lung tissue/function by non-pathogenic fibroblasts. Lagares et al. teaches that fibrosis results from “dysregulated wound repair processes,” and that “the pathological matrix protein accumulation is attributable to the excess recruitment of fibroblasts to sites of tissue injury, and/or their excessive activation to an effector myofibroblast phenotype,” (Lagares, pg. 2, Introduction, para. 1). The instant specifications teach “at the time of diagnosis, lung fibrosis is by definition established but more importantly progressive,” and that “anti-ephrin-B2 antibodies can be used to treat progressive lung fibrosis, including early and late disease,” (specs., pg. 1, lines 24-26). Further, that “activation of scar-forming myofibroblasts is a critical step in the progressive scarring that underlies the development and progression of pulmonary fibrosis,” (pg. 5, lines 30-31). Regarding the definition of “treat”, the specifications describe “a treatment can result in a reduction in fibrosis and a return or approach to normal function of the organ,” (pg. 7, lines 6-7); thus highlighting that reducing the pathology naturally results in a return to normal function (i.e., reversal). Regarding an “effective amount”, the specifications distinguish a “prophylactically effective amount” as preventing “onset” of the disease, versus an amount sufficient to “retard, delay or reduce the risk of progression of the disease,” (specs., pg. 7, lines 21-24). Thus, contrary to a prophylaxis, a treatment encompasses a “reduction of progression of the disease,” whereby natural repair and regenerative processes may be upregulated. Porter et al. also teaches that “alveolar cell injury and activation initiate a dysregulated, exaggerated fibrotic healing process characterized by myofibroblast proliferation,” (Porter, pg. 1, para. 0005). Porter also teaches the present invention provides agents for reducing, stabilizing or reversing the progression and severity for preventing or treating” (Porter, pg. 1, para. 0007), and that the method for “treating” idiopathic pulmonary fibrosis includes reducing the pathologic rate of decline of a pulmonary function parameter by at least 5% (pg. 1, para. 0008). Thus, Porter also supports that a method of reducing the pathology of pulmonary fibrosis naturally results in a restoration of the fibrotic healing process and an improvement in lung function, consistent with a “treatment”, and not just a prophylactic; and is also consistent with the statements of Dr. Lagares whereby blockade of ephrinB2 in established disease in expected to act to (a) block ephrinB2 signaling that keeps scar-forming fibroblasts chronically activated, and (b) remove the restraints on repair, permitting alveolar progenitor cells to repopulate the damaged lung (Lagares Declaration, item 9).
In support of the alleged unexpected results of “reversing” the activated phenotype of myofibroblasts, applicants highlight the experiments of Figures 7A-7C and 8A-8C (Lagares Declaration, item 8). Figures 7-8 shows a decreased level of α-SMA (a biomarker of activated myofibroblasts) after treatment, compared to a group with no treatment. Figures 7-8 utilize the experimental protocol depicted in Figure 6; whereby both groups received bleomycin for 14 days, and the therapeutic group received anti-ephrinB2 antibody treatment for days 15-21, whereas the control group did not receive treatment for days 15-21. As the data are showing a comparison between a treatment group and a control group, the data do not support the assertion of “reversal” of fibrosis; rather, the data support that treatment reduced the progression of fibrosis compared to no-treatment. In order for data to suggest a reversal, the proper comparison would show that the α-SMA at day 14, of the treatment group, was higher than it was at day 21, following 7 days of treatment, of the treatment group. This would suggest that treatment lowered, or reversed, the already higher α-SMA levels. Instead, Figures 7-8 support that treatment slowed the “progression” of fibrosis compared to non-treated groups. Thus, Figures 7-8 do not show unexpected results, rather they support that “treatment” encompasses a decrease in progression of the fibrosis, via inhibiting the underlying pathology, and resulting in naturally improved lung function. Whether the anti-ephrinB2 antibody therapy is a “prophylactic” or a “treatment” is only dependent on whether the patient has, or has not, already been diagnosed with pulmonary fibrosis before the treatment is administered. It is not dependent on the mechanisms of action of the anti-ephrinB2 antibody therapy, and, in the case of pulmonary fibrosis being a chronically progressing disease that restrains the natural repair and regenerative wound healing processes in the lung, it is not categorically different (or patentably distinct) whether the antibody is administered prophylactically or as a treatment for already established pulmonary fibrosis. It is working in the same way in either situation, to decrease soluble ephrinB2 signaling and thus decrease progression of the disease, and therefore it would be obvious for the skilled artisan to use it as a prophylactic or as a treatment.
As Porter et al. teaches the antibody therapy may be used as a prophylactic or a treatment for pulmonary fibrosis, such that it reduces, stabilizes or reverses the progression and severity of pulmonary fibrosis, it would be obvious for one of skill in the art to utilize an anti-ephrinB2 antibody for inhibiting the myofibroblast-mediated pathology of pulmonary fibrosis, as taught by Lagares et al., utilizing the anti-ephrinB2 antibodies taught by Martinez et al., in the method for treating pulmonary fibrosis as taught by Porter et al. Therefore, the applicant’s remarks are not persuasive and the rejection is maintained.
Conclusion
No claims are allowed.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAMES R. MELCHIOR whose telephone number is (703)756-4761. The examiner can normally be reached M-F 8:00-5:00 CST.
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/JAMES RYLAND MELCHIOR/Examiner, Art Unit 1644
/DANIEL E KOLKER/Supervisory Patent Examiner, Art Unit 1644