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 .
Priority
This application filed on 10/25/2023, is a national phase application under 35 U.S.C. § 371 of International Application No. PCT/KR2022/006231, filed on 05/02/2022, which claims priority to Korean Application No. KR10-2021-0062252, filed 05/13/2021.
Information Disclosure Statement
The information disclosure statement (IDS) filed on 10/25/2023, 01/02/2024, 08/08/2024, 02/20/2025, 05/21/2025, 12/03/2025 and 02/12/2026, complies with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, it has been placed in the application file and the information therein has been considered as to the merits, except where noted.
DETAILED ACTION
Applicant’s amendment and arguments filed on 05/11/2026 have been received and have been fully considered. Claims 12, 14-15 and 21 were amended, and claim 13 was cancelled.
Claims 12 and 14-22 are pending.
Withdrawn claim Objection
Objection to claim 21 for reciting “the second component” instead of “the first component”, is withdrawn in view of Applicant amendment filed on 05/11/2026 that amended claim 21 by deleting “second” and added “first”.
Withdrawn Claim Rejections - 35 USC § 112 (a) (Scope of Enablement)
Rejection of claims 12-22 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification does not reasonably provide enablement for preventing any of the diseases or disorders recited in claims 12-14 or treating Scleroderma, Keloid, Hypertrophic scar, etc., is withdrawn in view of Applicant amendment filed on 05/11/2026 that cancelled claim 13 and amended claim 12 with “a method for treating fibrosis interstitial lung disease (ILD1)”.
Withdrawn Double Patenting
Provisional double patenting rejection over copending Application No. 18/577,071 (US PG BUB 2024/0307365A1) and provisional double patenting rejection over copending Application No. 18/288,296 (US PG BUB 2024/0216363A1), are withdrawn because Applicant filed Terminal Disclaimer on 05/11/2026. The Terminal Disclaimer reviewed and approved on 05/17/2026.
Terminal Disclaimer
The terminal disclaimer filed on 11 May 2026 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of any patent granted on Application Number 18/577,071 and 18/288,296 has been reviewed and is accepted. The Terminal Disclaimer has been recorded.
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 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 12 and 14-22 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of B. Lee at al. (US PG PUB 2019/0359617A1, 11/28/2019, “Lee” cited in the IDS dated 08/08/2024), and Kim SH, et al. (Biomolecules. 2020 Dec 1;10(12):1625, “Kim” cited in the IDS dated 02/20/2025) in view of T. King et al. (New England Journal of Medicine 2014, vol. 370, 22, pp 2083-2092, “King” cited in the PTO-892), L. Richeldi et al. (New England Journal of Medicine, 2014, vol. 370, IS 22, pp 2071-2082, “Richeldi” cited in the PTO-892), and Flaherty KR, et al. (Eur. Respir. J. 2018; 52: 1800230, “Flaherty” cited in the IDS dated 08/08/2024).
Lee teaches prolyl-tRNA synthetase inhibitors of Formula I for treating fibrosis. [pg. 1, [0007], [0008]]. Lee teaches compound Ex. 40 as species of Formula I (claimed compound Formula 1) [pg. 20, [0423]]:
PNG
media_image1.png
200
722
media_image1.png
Greyscale
Lee teaches biological assays on inhibition of prolyl-tRNA synthetase by compound of Formula I, [pg. 63, [1013]-[1015]], wherein compound Ex. 40 is one of the few species that demonstrate high inhibitory activity of IC50 100-500 nM [Table 1].
Lee teaches that the prolyl-tRNA synthetase inhibitors e.g., compound Ex. 40, use as antifibrosis agent alone or in combination with existing targeted agents. [pg. 1, [0005].
Kim teaches Prolyl-tRNA Synthetase inhibitor, DWN-12088 (claimed compound, Formula 1) for the treatment of idiopathic pulmonary fibrosis (IPF):
PNG
media_image2.png
72
166
media_image2.png
Greyscale
Kim teaches that in IPF patient-derived primary lung fibroblasts, treatment with DWN-12088 reduced the synthesis of collagen and α-smooth muscle actin (α-SMA) under transforming growth factor-β (TGF-β) induction. Kim teaches that, in the mouse model of bleomycin-induced pulmonary fibrosis, oral administration of DWN-12088 for 2 weeks significantly reduced cardiac fibrosis and the collagen amount in lung tissues and bronchoalveolar lavage fluid. Kim teaches that DWN-12088 provided considerable repair of lung function in this mouse model. Kim teaches that DWN-12088 was designated as drug for IPF by FDA in 2019. Kim teaches administration of DWN-12088 to human subjects, wherein some cohorts received single dose of 100 mg, 200 mg, 500 mg, or 800 mg of DWN-12088, and other cohorts received multiple doses of 25 mg, 75 mg, 150 mg, or 300 mg of DWN-12088. [pg. 16].
Lee and Kim do not teach the combination of DWN-12088 with Formula 2 (pirfenidone) or Formula 3 (nintedanib). However, King, Richeldi, and Flaherty provide skilled artisan with the motivation to combined DWN-12088 with pirfenidone or nintedanib to treat IPF.
King teaches the effeteness of pirfenidone in treating idiopathic pulmonary fibrosis. King teaches that administration of 2403 mg of pirfenidone to patients with idiopathic pulmonary fibrosis reduced disease progression, as reflected by lung function, exercise tolerance, and improved progression-free survival. [Abstract].
Richeldi teaches the efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. [Title]. Richeldi teaches that “administration of 150 mg of nintedanib twice daily associated with a reduced decline in FVC, fewer acute exacerbations, and the preservation of health-related quality of life.” [pg. 2071, col. 1, 2nd para.]. Richeldi teaches that nintedanib slowing of disease progression in patients with idiopathic pulmonary fibrosis [pg. 2079, col. 2, 2nd para.].
Flaherty teaches combination of nintedanib and pirfenidone for the treatment of idiopathic pulmonary fibrosis. Flaherty teaches that 1602–2403 mg/day pirfenidone and 200–300 mg/day nintedanib administered to patients with idiopathic pulmonary fibrosis. Flaherty teaches that “although pirfenidone and nintedanib have both demonstrated efficacy in reducing rates of disease progression compared with placebo, the disease is neither stopped nor reversed and patients continue to experience lung function decline while on treatment”, which promote combination of pirfenidone and nintedanib. Flaherty teaches that the differing putative mechanisms of action of pirfenidone and nintedanib provide a physiological rationale for combining these two agents in an attempt to further reduce lung function decline in patients with IPF. [pg. 2, 1st 2nd para.]. Flaherty teaches that the benefits of combining therapies with different mechanisms of action have been demonstrated in a variety of chronic diseases, including chronic obstructive pulmonary disease, asthma and pulmonary arterial hypertension (PAH). Evidence from long-term studies in PAH has demonstrated that combination treatments have the potential to significantly delay disease progression, and the treatment strategy for PAH is shifting towards use of first-line combination therapy. Results of the current study suggest that combination treatment with pirfenidone and nintedanib could provide a viable future option for patients with IPF. [pg. 8, 3rd para.].
In view of the foregoing discussion, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of instantly claimed invention to combined DWN-12088 taught by Lee and Kim with other IPF agent such as pirfenidone or nintedanib in view of the teachings of King, Richeldi and Flaherty. One of ordinary skill in the art would have been motivated to use DWN-12088 (the claimed Formula 1) in treating IPF with reasonable expectation of success because: Lee teaches DWN-12088 is a potent prolyl-tRNA synthetase inhibitor used for the treatment of fibrosis alone or in combination with existing targeted agents; Kim teaches that treatment of IPF patient with DWN-12088 reduces the synthesis of collagen and α-smooth muscle actin, significantly reduced cardiac fibrosis and the collagen amount in lung tissues, and provided considerable repair of lung function. One of ordinary skill in the art would have been motivated to combine the effective IPF drug DWN-12088 with IPF agents pirfenidone or nintedanib with reasonable expectation of success because both IPF agents, pirfenidone or nintedanib reduced disease progression, reduced lung-function decline and improved progression-free survival as taught by King and Richeldi; and it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Therefore, its prima facie obvious to combine DWN-12088 with pirfenidone or nintedanib to treat the very same IPF. Moreover, Flaherty teaches that combination therapy for treating IPF have the potential to significantly delay disease progression because the disease is neither stopped nor reversed and patients continue to experience lung function decline while on treatment monotherapy of pirfenidone or nintedanib “although both monotherapy (pirfenidone and nintedanib) have demonstrated efficacy in reducing rates of disease progression compared with placebo”; and Flaherty teaches that the differing putative mechanisms of action of IPF agents provide a physiological rationale for combining two agents in an attempt to further reduce lung function decline in patients with IPF. Therefore, Flaherty provide motivation to treat IPF with combination therapy rather than monotherapy, which would motivate skilled artisan to combine DWN-12088 with pirfenidone or nintedanib for the treatment of IPF.
With regard to new amendment to claim 12 of “a weight ratio of the first component and the second component is 1:0.5 to 1:30”, Kim teaches that the dose of DWN-12088 administered to human subjects is 500 mg/day, [pg. 16], and King’s dose of pirfenidone is 2403 mg/day. The combination of DWN-12088 and pirfenidone would have a weight ratio of DWN-12088: pirfenidone of about 1:4.8 (500 mg: 2403 mg = 4.8).
Therefore, the combination of Lee, Kim, King, Richeldi and Flaherty teach each and every limitation of claims 12 and 15-16.
Claim 14 is met because the cited reference teaches a method of treating idiopathic pulmonary fibrosis (IPF).
Claims 17 and 20 are met because Kim teaches that the dose of DWN-12088 administered to human subjects is 100 mg/day, [pg. 16], and Richeldi’s dose of nintedanib is 150 mg [Abstract]. The combination of DWN-12088 and nintedanib would have a weight ratio of DWN-12088: nintedanib of about 1: 1.5 (100 mg: 500 mg = 1.5).
Claim 18 is met because Kim teaches that the dose of DWN-12088 administered to human subjects is 100 mg/day, [pg. 16].
Claim 19 is met because Kim teaches that the dose of DWN-12088 administered to human subjects is 100 mg/day, [pg. 16], and Flaherty’s dose of nintedanib is 200 mg/day [Abstract]. The combination of DWN-12088 and nintedanib would have a weight ratio of DWN-12088: nintedanib of about 1: 1.5 (100 mg: 500 mg = 1.5).
Claim 21 is met because Kim teaches that DWN-12088 administered to human subjects twice a day, every 12 hours. [pg. 16], and Richeldi teaches that nintedanib is administered twice a day [Abstract].
Claim 22 is met because Kim teaches that DWN-12088 administered to human subjects twice a day, and King teaches that pirfenidone is administered with food in three equally divided doses [pg. 2084, col. 2, 2nd para.].
Response to Argument
Applicant argues:
According to the present specification, the presently-claimed subject matter is characterized not merely by the co-administration of two components, but by the use of: (i) the compound represented by Chemical Formula 1, and (ii) pirfenidone or nintedanib, in a specific weight ratio, wherein such combination exhibits a remarkable and unexpected synergistic effect. Examples 1 to 3 of the present specification clearly demonstrate that co-administration of the first component and the second component produces a remarkable synergistic effect, as compared with administration of each component alone. The action considers that the combination of DWN12088 with pirfenidone or nintedanib would have been obvious in view of D3 King), D4 (Richeldi), and D5 (Flaherty). Specifically, D3 discloses the therapeutic effect of pirfenidone for IPF, while D4 discloses the therapeutic effect of nintedanib for IPF. In addition, D5 suggests the possibility of combination therapy using pirfenidone and nintedanib. However, D5 is limited to the combination between pirfenidone and nintedanib and does not provide any teaching or suggestion regarding combination therapy with DWN12088, which is a PRS inhibitor. Accordingly, D3 and D4 merely disclose general technical background relating to combination therapy, and even when considering D5, it appears difficult to sufficiently establish a motivation to combine with DWN12088 as claimed in the present application. Furthermore, according to the Examples of the present specification, the synergistic effect resulting from the combination of DWN12088 with pirfenidone (or nintedanib) at specific content ratios appears to be clearly demonstrated. In particular, the Examples consistently show a remarkable synergistic effect of the combination therapy as compared with monotherapy, and the reported numerical ranges do not appear to represent merely additive effects. In particular, the remarkable synergistic effect demonstrated in the present disclosure would have been unpredictable.
Examiner response:
Applicant’s arguments have been fully considered but they are not persuasive for the following reasons. It appears that Applicant is attempting to show unexpected results. As provided in MPEP 716 (b), the evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992). "[A]ppellants have the burden of explaining the data in any declaration they proffer as evidence of non-obviousness." Ex parte Ishizaka, 24 USPQ2d 1621, 1624 (Bd. Pat. App. & Inter. 1992). Applicant asserted that the claimed combination exhibits unexpected synergistic effect. In Experimental Example 2, the first component at 10 mg and the second component at 60 mg and 200 mg were administered to animals individually or in combination ((10mg/kg + 60mg/kg) and (10mg/kg +200 mg/kg)) and then the peripheral capillary oxygen saturation, SpO2 was measured to determine the anti-fibrotic efficacy, see instant specification page 11, Table 4. The lung function evaluation was determined by SpO2 measuring device, and the results were shown in Table 5:
PNG
media_image3.png
244
636
media_image3.png
Greyscale
As shown in Table 5 above, the average value of SpO2 for vehicle is 76.1. The first component alone improves the average value by 3.1, the second component alone improves the value by 3.8, and the combination of first component at 10mg/kg and second component at 60mg/kg improves the value by 6.2. Thus, the combination shows only 2.4 improvement of the average value over 60mg/kg of the second component alone. Moreover, the combination shows only 0.5 improvement over the 200mg/kg of the second component alone. Thus, the combination of the first and second component does not produce statistical and practical significance, and the claimed synergistic effect appears to be not significant. Note that the first component, the second component, or the combination does not reach a clinically significant value (SpO2 of 95-100). It also noted that the dosage of 200 mg/kg of the second component (60mg/kg vs. 200mg/kg) appear to have more effect on the average value. The Table also shows that the administration protocol (e.g., PID) have positive effect on the value. The independent claim 12 does not require specific dosage amount. Thus, this asserted unexpected results is not commensurate in scope with the scope of claim 12. As provided in MPEP 716 (d), “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." Similarly, Table 6 summaries the result of total collagen content in the lung, which as described above, the effect is a function of the amount administered (200mg/kg PID and 60mg/kg NIN). Note that the specification does not recite any synergistic effect or provide a combination index for the claimed combination. Applicant does not explain how 0.5 improvement in the SpO2 average value considered “remarkably unexpected synergistic”. "[A]ppellants have the burden of explaining the asserted unexpected synergistic effect. Thus, the claimed ratio is not fully reflected by the provided data. Note that, the second component is either Formula 2 or Formula 3 (two different compounds with different biologically, pharmacologically and kinetic properties), yet the instant specification in the Examples does not specify which one of the two has been tested, and the 60 mg/kg or 200mg/kg represent which compound. In view of the above, the asserted unexpected results are insufficient to overcome the outstanding rejection because the presented results are statistically, practically and clinically insignificant, and do not commensurate with the scope of the claim. Thus, it still stands that claims 12 and 14-22 are obvious over Lee, Kim, King, Richeldi, and Flaherty.
Conclusion
Claims 12 and 14-22 are rejected. No claim is allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MANAHIL MIRGHANI ALI ABDALHAMEED whose telephone number is (571)272-1242. The examiner can normally be reached M-F 7:30 am - 5:00 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James H Alstrum-Acevedo can be reached on 571-272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/M.M.A./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/
Supervisory Patent Examiner, Art Unit 1622
1 Examiner conducted search to determine the enablement of ILD and the connection between prolyl-tRNA synthetase inhibition and treatment of ILD, and considered that one of skill in the art could practice this subject matter, upon the filing date of the instant application, without undue experimentation. MPEP § 2164.02; In re Brana, 51 F.3d 1560, 1566, 34 USPQ2d 1486, 1441 (Fed. Cir. 1995). A. Shibata et al. PLoS ONE (2017). 12(10): e0186587, “Shibata” cited in the PTO-892 dated 02/13/2026.
Prosecution Insights