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 .
Status of Claims
Claims 1 and 3-13 are pending as of the response and amendments filed on 12/18/25. Claims 2 and 14 have been canceled.
The 103 rejection of claims 1, 5-7, and 9-12 as being unpatentable over McCormack is withdrawn in view of the amendments.
Claims 3-4, 8, and 14 were previously rejected as being unpatentable over McCormack in view of Lederer. The rejection over claim 14 is rendered moot as this claim has been canceled. Applicants’ reasons for traversal over the other claims are addressed below.
Applicants have argued McCormack fails to demonstrate the efficacy of any composition for treating any disease in an experimental model recognized in the art, let alone a recognized idiopathic pulmonary fibrosis model. Applicants have argued the disclosures in McCormack are speculative with quinacrine and IPF merely cited in laundry lists of hypothetical A-SMase inhibitors and chronic lower respiratory diseases to be treated. Applicants have stated McCormack only exemplifies an in vitro assay for A-SMase activity. Applicants have further stated some of the A-SMase inhibitors listed in McCormack are known to potentiate or exacerbate pulmonary fibrosis, referring to Anzic et. al. J Breast Cancer 23(5): 449-459 (Oct. 2020). Applicants have reproduced Table 1 from Anzic as evidence that tamoxifen, listed in McCormack as a A-SMase inhibitor, increases the risk of pulmonary fibrosis, a finding that they have argued was repeated across numerous independent studies.
Applicants’ arguments are not persuasive. The statute under 35 USC 103 doesn’t require demonstration of efficacy in order to establish a prima facie case of obviousness. Regarding Applicants’ argument quinacrine and IPF are merely cited in laundry lists, it is noted that McCormack is focused on the treatment of respiratory diseases by administering an NO-donor in combination with an A-SMase inhibitor, with IPF included within a list of exemplary respiratory diseases for treatment (abstract; p. 1, lines 5-15; p. 4, lines 28-31). Notably, IPF is recited in a preferred list among a total of 5 respiratory diseases to be treated (p. 41, lines 23-24). While McCormack does include quinacrine among other A-SMase inhibitors, the list of such agents is clear and defined, not an endless laundry list (p. 5, line 26-p. 6, line 5; p. 59, claim 4; p. 60, claim 7). Additionally, a prior art referenced can be relied upon for all that it teaches or suggests, not just examples; see MPEP 2123. Regarding Anzic, it is noted that this reference suggests tamoxifen in combination with radiation may be associated with increased incidence of PF in the few studies. See p. 453 of Anzic, next to last para, where it is stated “TAM alone, without concomitant RT, had no effect on the incidence of PF”. As noted in McCormack, radiation exposure is a known risk factor for the development of PF. Anzic notes that the referenced studies “have many limitations”, including being older studies, using older radiation techniques, and including a small number of patients (p. 456, last 2 lines-p. 457, top para); additionally, Anzic concludes “Importantly, the incidence of clinically evident PF after RT is very low” (p. 457). Notably, Anzic suggests nothing about quinacrine and IPF.
Applicants have further stated without acquiescing to the merits of the previous rejection and solely to expedite prosecution, claim 1 has been amended to recite “a method for treating or preventing PDGF-BB signaling-induced-, FGF signaling-induced-, or bleomycin-induced-idiopathic pulmonary fibrosis (IPF) in a subject in need thereof”, thereby rendering the rejection moot. Applicants have further argued McCormack merely hypothesizes the use of quinacrine to treat lower respiratory diseases induced by hyperactive A-SMase, therefore the skilled artisan would recognize the IPF disease state of McCormack is induced by stimuli and pathways that are non-overlapping and entirely distinct from those recited by the instant claims. Applicants have argued McCormack fails to teach or suggest what, if any amount of quinacrine would be effective to treat or prevent PDGF-BB signaling-induced-, FGF signaling-induced-, or bleomycin-induced- IPF. Applicants have maintained McCormack doesn’t suggest a composition that inhibits A-SMase can be reasonably equated to successfully treat or prevent PDGF-BB signaling-induced-, FGF signaling-induced-, or bleomycin-induced- IPF. Applicants have further argued Lederer and Sengupta fail to teach or suggest any methods of treating or preventing PDGF-BB signaling-induced-, FGF signaling-induced-, or bleomycin-induced- (IPF).
Applicants’ arguments are not persuasive. While it is acknowledged McCormack doesn’t explicitly teach treating IPF induced by PDGF-BB, FGF, or bleomycin, McCormack does teach treating pulmonary fibrosis caused by different factors, including due to inhalation of gases, chemicals, fumes, vapors, or radiation (p. 41, lines 11-14). Additionally, the teachings of Lederer were relied upon for this limitation, as Lederer teaches factors leading to IPF include TGF-β (p. 1813, right col., top para). Regarding Applicants’ argument McCormack fails to teach or suggest what, if any amount of quinacrine would be effective to treat or prevent PDGF-BB signaling-induced-, FGF signaling-induced-, or bleomycin-induced- IPF, 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). Furthermore, it is noted Applicants’ claims recite “a therapeutically effective amount” without reciting a specific dose or concentration range that meets this limitation, and that this phrase is very broadly defined in Applicants’ specification (p. 6, para [0025]). As such, the 103 rejections over McCormack in view of Lederer, and over Sengupta are maintained. These rejections are modified below to account for the amended claims.
Claims 1 and 3-13 were examined and are rejected.
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.
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.
Claim(s) 1 and 3-12 is/are rejected under 35 U.S.C. 103 as being unpatentable over McCormack et. al., WO 2010035047 A1, in view of Lederer et. al., The New England Journal of Med., vol. 378, pp. 1811-1823, publ. 2018.
McCormack teaches pharmaceutical compositions comprising an A-SMase inhibitor and a NO-donor for treating or preventing respiratory disorders such as chronic cough, cystic fibrosis, COPD, idiopathic pulmonary fibrosis (IPF), and emphysema (title & abstract; p. 1, lines 5-15; p. 5, lines 8-11). McCormack teaches A-SMase as acid sphinogomyelinase (p. 5, lines 13-19). McCormack further includes quinacrine along the list of A-SMase inhibitors (p. 5, line 26-p. 6, line 5, with emphasis on p. 5, line 30; p. 59, claim 4; p. 60, claim 7). McCormack teaches the pharmaceutical compositions to further include one or more pharmaceutically acceptable excipients (p. 28, lines 7-13), wherein the compositions can be administered by a variety of delivery routes including orally, parenterally, or via the airway, with inhalation delivery being preferred (p. 30, lines 17-21; p. 31, lines 29-30). McCormack teaches an embodiment wherein the composition is provided via an aerosol device, in the form of particles, wherein the particles have a mass median aerodynamic diameter of less than 10 µm (p. 31, line 32-p. 32, line 15). Particularly, McCormack teaches the A-SMase inhibitor and/or NO-donor as present in the form of particles with a mass median aerodynamic diameter between .001-500 µm (p. 37, line 30-p. 38, line 8); this overlaps with nanoparticle diameter size. McCormack further teaches the particles containing the active agent can be coated with a lubricant, glidant, or carrier material (p. 33, line 28-p. 34, line 8); this limitation meets the A-SMase inhibitor, such as quinacrine, being encapsulated in nanoparticles, as recited by instant claim 12. In another embodiment, McCormack teaches treatment of a respiratory disorder, including IPF, by administering a therapeutically effective amount of a A-SMase inhibitor, without the presence of the NO-donor (p. 41, line 26-p. 42, line 14; p. 42, lines 23-27). Treatment of a human patient is taught (p. 45, lines 21-25). McCormack teaches treating of chronic pulmonary fibrosis caused by inhalation of chemicals, gases, fumes, vapors, or radiation exposure (p. 41, lines 11-14). Therefore, it would have been prima facie obvious that IPF is a chronic disease, and to have administered the composition daily for an extended time period, e.g., a week or more as recited by instant claim 11.
As McCormack teaches administering an A-SMase inhibitor in combination with an NO-donor, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claims to have administered the A-SMase inhibitor, quinacrine, separately, sequentially, or simultaneously with the NO-donor to the subject in need of treatment for IPF, as recited by instant claim 7.
Regarding the limitations of claims 9 and 10, McCormack teaches treatment of the same patient population as claimed, a subject with IPF, by administering a therapeutically effective amount of an A-SMase inhibitor, with quinacrine included as an A-SMase inhibitor. It would have been prima facie obvious that by administering the same agent as claimed to the same patient population, the same therapeutic effects would have been achieved as recited by claims 9 and 10.
McCormack doesn’t explicitly teach or suggest wherein the additional therapeutic agent is pirfenidone or nintedanib, or wherein the IPF is induced by TGF-β signaling.
Lederer teaches IPF as the most common idiopathic interstitial pneumonia, occurring primarily in older adults and having a high mortality rate (p. 1811, 1st para). Lederer teaches symptoms of interstitial pneumonia, including IPF to include unexplained exertional dyspnea, chronic dry cough, clubbing, and bilateral Velcro-like crackling lung sounds (p. 1811, 3rd para; p. 1813, Table 1). Lederer teaches active TGF-β signaling as a process in the pathogenesis of IPF (p. 1814, see Fig. 2A). Lederer teaches pharmacological management of IPF involves administration of the tyrosine kinase inhibitor, nintedanib, which slows FVC decline by 50%; and pirfenidone, which acts via inhibition of TGF-β production and downstream signaling (p. 1818, Table 3).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claims to have treated a subject having IPF induced by TGF-β signaling and symptoms of shortness of breath, dry cough, and clubbing by administering the A-SMase inhibitor, quinacrine; and to have further administered an additional agent such as nintedanib and/or pirfenidone, in consideration of the combined teachings of McCormack and Lederer. McCormack teaches treatment of respiratory disorders such as IPF comprising administering a therapeutically effective amount of an A-SMase inhibitor such as quinacrine, while Lederer teaches IPF symptoms to include shortness of breath, dry cough, and clubbing. Lederer further teaches TGF-β signaling is involved in the pathogenesis of IPF, and that management of this condition involves treatment with nintedanib and pirfenidone, wherein pirfenidone acts to inhibit TGF-β production and downstream signaling. One of ordinary skill in the art would have been motivated to have administered quinacrine in combination with nintedanib and/or pirfenidone, as each of these agents are taught to have utility for the treatment of IPF, and have had a reasonable expectation of success.
Regarding claim 4, “wherein EMT…”, it is noted that claim 3 recites EMT as a symptom of IPF in the alternative only, and claim 4 doesn’t explicitly require the subject with IPF to have EMT.
Claim(s) 13 is/are rejected under 35 U.S.C. 103 as being unpatentable over McCormack et. al., WO 2010035047 A1 in view of Lederer, The New England Journal of Med., vol. 378, pp. 1811-1823, publ. 2018, as applied to claims 1 and 3-12, in view of Sengupta et. al., WO 2006099445 A2, publ. 9/21/2006.
The teachings of McCormack and Lederer as discussed above are incorporated herein. However, McCormack and Lederer don’t explicitly teach or suggest wherein the nanoparticles are PLGA hybrid nanoparticles.
Sengupta et. al. teaches nanocell compositions, wherein the nanocells comprise a nanocore surrounded by a lipid matrix, for the treatment of tumors, asthma, Grave’s disease, cystic fibrosis, and pulmonary fibrosis (title & abstract; para [007]). Sengupta teaches an embodiment wherein the nuclear nanocore has a diameter between about 60-600 nm (para [0010]), and wherein the nanocells deliver therapeutic agents efficiently directly to a desired biological site (para [0017]). Treatment of IPF is taught in an embodiment, wherein the nanocell contains an antifibrotic agent and optionally a second therapeutic agent (para [0029]); in another embodiment, Sengupta teaches the nanocell is administered via inhalation for the treatment of IPF (para [0030]). Sengupta further teaches the nanocore to comprise a biodegradable polymer such as PLGA (para [0023]), and another embodiment wherein the therapeutic agent is encapsulated within PLGA (para [00146]). Sengupta further teaches conjugates of biodegradable polymers, such as PLGA, can be used to prepare the nanocore (para [0064]); therefore, one of ordinary skill in the art would have readily envisioned a nanocore comprised of a PLGA hybrid. Sengupta teaches the nanocells result in improved efficacy (para [0038]).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claims to have treated IPF induced by TGF-β signaling in a subject comprising administering a therapeutically effective amount of quinacrine, wherein the quinacrine is administered encapsulated in nanoparticles, wherein the nanoparticles are PLGA hybrid nanoparticles, in consideration of the combined teachings of McCormack, Lederer and Sengupta. McCormack teaches treatment of respiratory disorders such as IPF comprising administering a therapeutically effective amount of an A-SMase inhibitor such as quinacrine, while Sengupta teaches a nanocell composition for the efficient delivery of a therapeutic agent directly to a target site. Sengupta further teaches an embodiment wherein the nanocell composition is delivered for the treatment of IPF, and wherein the nanocell composition contains an antifibrotic agent. Sengupta additionally teaches an embodiment wherein the therapeutic agent is encapsulated by a degradable polymer such as PLGA. Therefore, one of ordinary skill in the art would have been motivated to have practiced the method taught by McCormack by administering quinacrine in a nanocell composition, encapsulated by a biodegradable polymer such as PLGA or a hybrid thereof, for the advantages taught by Sengupta, e.g., efficient and direct delivery of the antifibrotic to the target site.
THIS ACTION IS MADE FINAL. 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.
Correspondence
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SARAH . PIHONAK
Primary Examiner
Art Unit 1627
/SARAH PIHONAK/Primary Examiner, Art Unit 1627