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, and 12/03/2025, 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
The preliminary amendment that cancelled claims 1-11, and added claims 12-22 is acknowledged. Claims 12-22 are pending.
Claim objections
Claim 21 is objected to for the following informalities:
Claim 21 recites “The method according to claim 12, wherein: the second component and the second component are each administered twice a day or three times a day.” Claim 12 recites method of preventing or treating fibrosis …, comprising a first component (Formula 1), and a second component (Formula 2 or Formula 3). The underlined “second component” appears to be referring to “the first component”. Correction that replaces the underlined “second component” with “first component” is required to overcome this objection.
Appropriate correction is required.
In view of compact prosecution, and for the purpose of applying prior art, claim 21 is interpreted as: The method according to claim 12, wherein: the first component and the second component are each administered twice a day or three times a day
Claim Rejections - 35 USC § 112 (a) (Scope of Enablement)
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.
Claims 12-22 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating idiopathic pulmonary fibrosis (IPF)1, does not reasonably provide enablement for treating the other diseases or disorders recited in claims 12-14 e.g., Scleroderma, Keloid, Hypertrophic scar, etc., or preventing any of the diseases or disorders recited in claims 12-14. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The claims are failing to comply with the enablement requirement because the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Under MPEP 2164, in order to satisfy the enablement requirement, a disclosure must enable a person skilled in the art to practice the claimed invention without undue experimentation. The so-called “Wands factors” provide a standard for determining whether a disclosure satisfies the enablement requirement or whether, on the other hand, any experimentation is necessary for the practice of the invention is “undue”. In re Wands, 858 f.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). The Wands factors are:
(1) The breadth of the claims
(2) The nature of the invention
(3) The state of the prior art
(4) The level of one of ordinary skill
(5) The level of predictability in the art
(6) The amount of direction provided by the inventor
(7) The existence of working examples
(8) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
MPEP. § 2164.01(a); In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
The breadth of the claims:
The presently claimed invention is directed to A method for preventing or treating fibrosis in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising compound of formula 1 and any one of formula 2 or 3, wherein: the fibrosis is Interstitial lung disease (ILD), Scleroderma, Keloid, Hypertrophic scar, Non-alcoholic Fatty Liver Disease, Primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), diabetic retinopathy, Age-related Macular Degeneration (AMD), hypertrophic cardiomyopathy, myocardial infarction, Muscular Dystrophy, Diabetic kidney disease, focal segmental glomerulosclerosis (FSGS), or Inflammatory bowel disease (IBD), wherein the Interstitial lung disease (ILD) is idiopathic pulmonary fibrosis (IPF), systemic sclerosis associated interstitial lung disease (SSc-ILD), or chronic fibrosing interstitial lung diseases with a progressive phenotype (PF-ILD). The claims are directed to a combination of small molecule compounds inhibiting Aminoacyl tRNA synthetases, i.e., Prolyl-tRNA synthetase. Park and Adachi described the complex nature of Aminoacyl tRNA synthetases and highly flexible binding site of Prolyl-tRNA synthetase. Park (S. Park, et al. Proc. Natl. Acad. Sci. U.S.A, 2008. 105 (32) 11043-11049, cited in the PTO-892, “Park”), Aminoacyl tRNA synthetases (AARSs) are essential for protein synthesis and cell viability because Aminoacyl tRNA synthetases catalyze the ligation of amino acids to their cognate tRNAs. Park teaches that functional versatility of Aminoacyl tRNA synthetases resulted from their ability to interact with diverse molecules and small chemicals such as amino acids. [pg. 11043, col. 1]. Park teaches that AARSs are tightly bound together in a large multi-synthetase complex, with at least nine synthetases and three synthetase-associated proteins are bound together, and it is not known whether other synthetases are more loosely bound with the complex. The complex-forming AARSs are involved in the regulation of transcription, translation, and various signaling pathways, which endow them with functional diversity through the interactions with various cellular partners, and the expanded functions of tRNA synthetases are not simply correlated with their being tightly associated with the complex. [pg. 11043, col. 2]. Park teaches that “considering the functional versatility of these enzymes, their expanded functions and expression may be pathologically associated with various human diseases.” [pg. 11043, col. 3]. However, Park teaches that the connections of AARSs with various human diseases make them attractive as targets for the development of therapeutics but have not yet been linked to a specific disease. [pg. 11047, col. 3]. Adachi (R. Adachi et al. Biochemical and Biophysical Research Communications, 2017, Volume 488, Issue 2, pages 393-399, “Adachi” cited in the PTO-892) teaches that “although a few Prolyl-tRNA synthetase (PRS) inhibitors have been derivatized from natural sources or substrate mimetics, small-molecule human PRS inhibitors have not been reported [Abstract]. Adachi teaches that “the absence of a robust and high-throughput assay system for PRS has hindered the development of small-molecule inhibitors.” [pg. 394, col. 1]. Adachi teaches that steady-state biochemical analysis on the inhibitory mode revealed PRS distinctive characteristics of inhibition with proline un-competition and ATP competition. [Abstract]. Adachi also teaches that PRS ATP-binding site nature is highly flexible. Moreover, Adachi teaches that the different molecular mode of actions of inhibitors could influence their intracellular actions depending on the cellular environment. [pg. 397, col. 2].
The nature of the invention:
The present claims describe a use of combination of compound of Formula 1 and one of Formula 2 or 3 in the method for preventing or treating fibrosis, wherein the fibrosis is Interstitial lung disease (ILD), Scleroderma, Keloid, Hypertrophic scar, Non-alcoholic Fatty Liver Disease, Primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), diabetic retinopathy, Age-related Macular Degeneration (AMD), hypertrophic cardiomyopathy, myocardial infarction, Muscular Dystrophy, Diabetic kidney disease, focal segmental glomerulosclerosis (FSGS), or Inflammatory bowel disease (IBD), wherein the Interstitial lung disease (ILD) is idiopathic pulmonary fibrosis (IPF), systemic sclerosis associated interstitial lung disease (SSc-ILD), or chronic fibrosing interstitial lung diseases with a progressive phenotype (PF-ILD). That is; in order to be enabled to practice the present invention, the skilled artisan would have to accept that by administering the combination of Formula 1 and Formula 2 or 3 that such therapeutic objectives (preventing and treating the claimed conditions above) could actually be achieved. However, in light of the fact that the specification fails to provide the skilled artisan with any direction or guidance as to how the prevention and treatment of the breadth of the diseases and conditions in general could be achieved, or how the administration of the claimed combination will treat and prevent these diseases and conditions, the present specification is viewed as lacking an enabling disclosure of the entire scope of the claimed invention.
The state of the Prior Art:
The instant claims are directed to the use of combination of compound of Formula 1 and one of Formula 2 or 3 in the method for preventing or treating fibrosis, wherein the fibrosis is Interstitial lung disease (ILD), Scleroderma, Keloid, Hypertrophic scar, Non-alcoholic Fatty Liver Disease, Primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), diabetic retinopathy, Age-related Macular Degeneration (AMD), hypertrophic cardiomyopathy, myocardial infarction, Muscular Dystrophy, Diabetic kidney disease, focal segmental glomerulosclerosis (FSGS), or Inflammatory bowel disease (IBD), wherein the Interstitial lung disease (ILD) is idiopathic pulmonary fibrosis (IPF), systemic sclerosis associated interstitial lung disease (SSc-ILD), or chronic fibrosing interstitial lung diseases with a progressive phenotype (PF-ILD). Li (M. Li et al. Exp Ther Med. 2016 Dec;12(6):3633-3641, “Li” cited in the PTO-892) teaches the genes that are associated with fibroblasts and keratinocytes during keloid scar progression and development. [Abstract]. Li teaches that “there are a variety of clinical treatment methods for keloids, however, clinical data reveal that the therapeutic effects are poor due to easy recurrence and high morbidity. Li teaches that the pathogenesis of keloid scar formation is complicated, particularly the key roles of fibroblasts and keratinocytes in this type of disease. Li teaches that “Keloid-derived keratinocytes were shown to perform a promoting role on fibroblast growth and proliferation, and there is increasing evidence that many key molecules play crucial roles during keloid scar development through fibroblasts and keratinocytes from a molecular perspective. For instance, downregulation of the inhibitors SMAD6 and SMAD7 was found in keloid scar tissue, and overexpression of bone morphogenetic protein (BMP) contributed to fibroblast cell proliferation and collagen synthesis during cholesteatoma progression. Li further teaches that although many researchers have focused on the pathogenesis of fibroblasts and keratinocytes in keloid scar development and progression, the molecular mechanism remains incompletely elucidated. [pg. 3633, col. 2]. Floreani (A. Floreani et al. Digestive and Liver Disease 53 (2021) 1531–1538, “Floreani” cited in the PTO-892) teaches that “Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease, whose hallmarks are inflammation, fibrosis and destruction of intra and extrahepatic bile ducts which can lead to cirrhosis.” Floreani teaches that “despite significant efforts, to date there is no medical treatment able to prolong the time of liver transplantation, which still represents the only effective therapeutic option in late-stage disease.” [pg. 1531, col. 1]. Floreani teaches that mechanism underlying the negative clinical outcomes in patients receiving UDCA at high dose has not been elucidated. [pg. 1531, col. 2]. Floreani teaches that “several types of agents targeting bile composition, immunomodulation, fibrosis or the gut microbiome have been conducted in PSC patients so far, and the ideal treatment scheme for PSC is probably a combination of different drugs targeting different pathogenic mechanisms. No data are available on robust endpoints, such as amelioration of endoscopic changes or transplant-free survival. Indeed, the absence of valid surrogate outcomes and the lack of good prognostic models can affect the clinical trial investigations on new experimental drugs.” [pg. 1536, col. 1]. Stahl (A. Stahl, Dtsch Arztebl Int. 2020 Jul 20;117(29-30):513-520, “Stahl” cited in the PTO-892) teaches the challenges in the treatment of Age-related macular degeneration (AMD) early and intermediate stages. Stahl only described supplementation and diet balancing with no success in treating the condition, and no protective effect of laser treatment was found. Stahl teaches that there is no effective treatment yet available for the atrophic late form of AMD, and all of the clinical trials carried out to date have yielded negative results. [pg. 516, col. 1-2]. Shibata (A. Shibata et al. PLoS ONE (2017). 12(10): e0186587, “Shibata” cited in the PTO-892) teaches that the pathogenesis of scleroderma remains unknown, and various fibrotic phenotypes containing collagen type I proteins production are associated with scleroderma. Shibata teaches that While various cytokines and growth factors are considered to contribute to skin fibroblast activation in scleroderma, transforming growth factor-β (TGF-β) plays an important role in the fibrotic reaction of scleroderma pathology. However, until now, no drug has been approved as an anti-fibrotic capable of preventing progression or recovery from existing fibrosis. [pg. 1-2]. Shibata suggests treatment for scleroderma by inhibiting prolyl-tRNA synthetase (PRS), however, Shibata teaches that not all PRS inhibitor are capable of treating scleroderma and determining the binding site of the PRS inhibitor play essential role in the effectiveness of the inhibitor. [pg. 2, and whole document]. Shibata teaches that further research is required for the detailed mechanism of the relationship between PRS inhibition and anti-fibrotic effect. [pg. 14, 1st para.]. In view of the prior art teachings above, treatment (let alone prevention) of the diseases and conditions recited in the claims is clearly not enabling by instant specification. Accordingly, there is substantive “reason for one skilled in the art to question the objective truth of the statement of utility or its scope” (In re Langer, 183 USPQ 288, 297).
The skill of those in the art:
The skill of those in the art is expected to be high, requiring advanced training in chemistry, medicine, or pharmacology.
The level of predictability in the art:
The multitude of intricate, interacting biological processes within the human body presents a significant level of unpredictability in drug development, Wang, introduction (Z. Wang, et al. Drug Discovery Today, Volume 19, Issue 2, 2014, Pages 145-150, ISSN 1359-6446). The instant claims are directed to the use of combination of compound of Formula 1 and one of Formula 2 or 3 in the method for preventing or treating fibrosis, wherein the fibrosis is listed on claims 13-14. However, the complicated interaction of different molecular pathways involved in the claimed diseases and condition, challenges associate with development of small-molecule inhibitors, and the highly flexible nature of prolyl-tRNA synthetase binding site as described by Park, Adachi, Li, Floreani, Stahl, and Shibata above increases the difficulty of targeted therapy. As discussed above, it appears that there is no drug or approved method of treatment of the claimed diseases and conditions and the pathologies and mechanism of action of the claimed diseases have not yet elucidated, e.g., Scleroderma, Keloid, Primary sclerosing cholangitis and Age-related Macular Degeneration. Thus, the mechanism and the degree of complexity of the claimed diseases and disorders is unknown and therefore, treatment (and prevention) to such diseases and conditions is unpredictable. The invention is directed toward medicine and is therefore physiological in nature. It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved,” and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). With this in mind the level of predictability in the art is sufficiently low. The level of unpredictability in the art renders the scope of instant claims to be not enabled.
The amount of direction provided and Working examples:
The instant claims are directed to the use of combination of compound of Formula 1 and one of Formula 2 or 3 in the method for preventing or treating fibrosis, wherein the fibrosis is Interstitial lung disease (ILD), Scleroderma, Keloid, Hypertrophic scar, Non-alcoholic Fatty Liver Disease, Primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), diabetic retinopathy, Age-related Macular Degeneration (AMD), hypertrophic cardiomyopathy, myocardial infarction, Muscular Dystrophy, Diabetic kidney disease, focal segmental glomerulosclerosis (FSGS), or Inflammatory bowel disease (IBD), wherein the Interstitial lung disease (ILD) is idiopathic pulmonary fibrosis (IPF), systemic sclerosis associated interstitial lung disease (SSc-ILD), or chronic fibrosing interstitial lung diseases with a progressive phenotype (PF-ILD). Neither the instant specification nor the art of record teaches one of skill in the art how administering the combination of compounds of Formula 1 and Formula 2 or 3 will treat all the diseases and conditions listed above. Moreover, as discussed above, the art of record teaches that there are still many challenges for developing Prolyl-tRNA synthetase targeted therapy, and a lot of basic and clinical research are still needed to achieve targeting the Prolyl-tRNA synthetase in the treatment of fibrosis diseases. The instant specification provides in vitro and in vivo studies of the claimed combination for treating idiopathic pulmonary fibrosis (IPF) only, and there is no direction or working examples targeting the diseases and conditions recited in claims 13 and 14. IPF pathology and mechanism is distinct from the recited diseases as described by the cited prior art above. The specification does not include exemplary embodiments directed toward the use of the claimed compounds in treating or preventing the breadth of the claimed diseases and disorders. Neither the art of record nor the specification provides guidance with respect to the connection between inhibiting Prolyl-tRNA synthetase and treating the diseases or disorders recited in claims 13 and 14 e.g., Scleroderma, Keloid, Primary sclerosing cholangitis and Age-related Macular Degeneration, etc., or preventing any of the claimed diseases or conditions. Thus, the specification is very narrow compared to the claim breadth.
The quantity of experimentation needed:
In the current case, claims 12-22 are properly rejected under 35 U.S.C. § 112, first paragraph, for lack of enablement because upon balancing the above-discussed factors, the specification at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the invention. In the instant case, the specification discloses treatment of IPF with the claimed combination. But neither the specification nor the art of record discloses to one of skill in the art how to treat, and prevent the diseases and conditions recited in the claims. Therefore, it is considered that at the relevant time for one of skill in the art to practice treatment of the diseases as claimed without undue experimentation. The main factors contributing to the instant rejection is: the breadth of diseases and disorders sought to be treated in view of their mechanistic and symptomatic coupled with the lack of guidance in the specification and the art of record; the art of record teaches significant unpredictability in the treatment or prevention of the claimed conditions; and The specification does not supplement the art of record with the additional guidance needed to enable the full claim scope. Rather, the specification provides only treatment of one fibrosis condition, IPF. These factors are balanced with contradictory evidence and the unpredictability in treating, and preventing the claimed diseases and conditions to establish a prima facie case that the experimentation required by one of skill in the art to practice the full claim scope is undue.
In view of the foregoing, the amount of experimentation needed to enable the full scope of claims 12-22 is undue in view of Applicant’s disclosure and rejection under 35 U.S.C. § 112, first paragraph, is appropriate.
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 12-22 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 use 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.
Therefore, the combination of Lee, Kim, King, Richeldi and Flaherty teach each and every limitation of claim 12.
Claims 13 and 14 are met because the cited reference teaches a method of treating idiopathic pulmonary fibrosis (IPF).
Claims 15-16 are met because 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).
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.].
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.
Double Patenting Rejection over copending Application No. 18/577,071
Claims 12-14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of copending Application No. 18/577,071 (US PG BUB 2024/0307365A1). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Instant claims 12-22 recite “a method for preventing or treating fibrosis in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising: Chemical Formula 1, or a pharmaceutically acceptable salt thereof, and Chemical Formula 2, or Chemical Formula 3 and a pharmaceutically acceptable salt thereof, administered in combination with the same preparation or different preparations:
[Formula 1]
PNG
media_image3.png
72
166
media_image3.png
Greyscale
[Formula 2]
PNG
media_image4.png
155
149
media_image4.png
Greyscale
[Formula 3]
PNG
media_image5.png
319
421
media_image5.png
Greyscale
wherein: the fibrosis is Interstitial lung disease (ILD), Scleroderma, Keloid, Hypertrophic scar, Non-alcoholic Fatty Liver Disease, Primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), diabetic retinopathy, Age-related Macular Degeneration (AMD), hypertrophic cardiomyopathy, myocardial infarction, Muscular Dystrophy, Diabetic kidney disease, focal segmental glomerulosclerosis (FSGS), or Inflammatory bowel disease (IBD), wherein: the Interstitial lung disease (ILD) is IPF, SSc-ILD, or PF-ILD, wherein: a weight ratio of the first component and the second component is 1:0.5 to 1:30, wherein: the first component is contained in an amount of 100 mg to 150 mg, and Chemical Formula 2, in an amount of 200 mg to 800 mg, or Chemical Formula 3, 100 mg to 150 mg, administered twice a day or three times a day.”
Co-pending Application No. 18/577,071 recites in claims 1-6 “a pharmaceutical composition for preventing or treating systemic fibrosis, comprising a compound represented by the following Chemical Formula 1, or a pharmaceutically acceptable salt thereof:
PNG
media_image3.png
72
166
media_image3.png
Greyscale
[Chemical Formula 1], wherein: the systemic fibrosis is systemic sclerosis-associated interstitial lung disease (SSc- ILD), wherein, the pharmaceutical composition further comprises other active ingredient used for the prevention or treatment of systemic fibrosis, wherein, the other active ingredient used for the prevention or treatment of systemic fibrosis is Nintedanib or Tocilizumab.”
Co-pending Application No. 18/577,071 independent claims 1 combining with dependent claim 6 meet the limitations of instant claim 12. Note that Pirfenidone is represented in instant claims by chemical formula 2, and Nintedanib is represented by chemical formula 3, see the above 103 Rejection.
Claims 13 and 14 are met because co-pending Application No. 18/577,071 recites that the systemic fibrosis is systemic sclerosis-associated interstitial lung disease (SSc- ILD).
Claims 15-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims of copending Application No. 18/577,071 (US PG BUB 20240307365A1) as applied above to claims 12-14, in view of Kim SH, et al. Biomolecules. 2020 Dec 1;10(12):1625, “Kim” cited in the IDS dated 02/20/2025), 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). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The disclosure of co-pending Application No. 18/577,071 is set forth above and incorporated herein by reference. The co-pending Application No. 18/577,071 does not recite the amounts and the weight ratios of Formula 1 and Nintedanib, or the administration protocol.
The disclosure set forth above in the 103 Rejection over the same Kim, King, Richeldi and Flaherty reference (page 13-15) is herein incorporated by reference.
Claims 15-22 are rejected by the combination of co-pending Application No. 18/577,071 and Kim, King, Richeldi and Flaherty for the same rationale discussed above, page 16-17.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Double Patenting Rejection over copending Application No. 18/288,296
Claims 12-14, and 18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 7-12 of copending Application No. 18/288,296 (US PG BUB 2024/0216363A1). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Instant claims 12-22 recite: a method for preventing or treating fibrosis in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising Chemical Formula 1, or a pharmaceutically acceptable salt thereof, and Chemical Formula 2, or Chemical Formula 3 and a pharmaceutically acceptable salt thereof, administered in combination with the same preparation or different preparations:
[Formula 1]
PNG
media_image3.png
72
166
media_image3.png
Greyscale
[Formula 2]
PNG
media_image4.png
155
149
media_image4.png
Greyscale
[Formula 3]
PNG
media_image5.png
319
421
media_image5.png
Greyscale
wherein: the fibrosis is Interstitial lung disease (ILD), Scleroderma, Keloid, Hypertrophic scar, Non-alcoholic Fatty Liver Disease, Primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), diabetic retinopathy, Age-related Macular Degeneration (AMD), hypertrophic cardiomyopathy, myocardial infarction, Muscular Dystrophy, Diabetic kidney disease, focal segmental glomerulosclerosis (FSGS), or Inflammatory bowel disease (IBD), wherein: the Interstitial lung disease (ILD) is IPF, SSc-ILD, or PF-ILD, wherein: a weight ratio of the first component and the second component is 1:0.5 to 1:30, wherein: the first component is contained in an amount of 100 mg to 150 mg, and Chemical Formula 2, in an amount of 200 mg to 800 mg, or Chemical Formula 3, 100 mg to 150 mg, administered twice a day or three times a day.
Co-pending Application No. 18/288,296 recites in claims 7-12 “A method for preventing or treating fibrosis in a subject in need thereof, comprising administering to the subject 100 mg to 150 mg of a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof twice a day (BID): [Chemical Formula 1]
PNG
media_image3.png
72
166
media_image3.png
Greyscale
, wherein the fibrosis is Interstitial lung disease (ILD), Scleroderma, etc., wherein the ILD is idiopathic pulmonary fibrosis (IPF), systemic sclerosis associated interstitial lung disease (SSc-ILD), or chronic fibrosing interstitial lung diseases with a progressive phenotype (PF-ILD), wherein the pharmaceutical composition further comprises other active component used for the prevention or treatment of fibrosis, wherein the other active component used for the prevention or treatment of fibrosis is Pirfenidone or Nintedanib.
Co-pending Application No. 18/288,296 independent claims 7 combining with dependent claim 12 meet the limitations of instant claim 12. Note that Pirfenidone is represented in instant claims by chemical formula 2, and Nintedanib is represented by chemical formula 3, see the above 103 Rejection.
Claims 13 and 14 are met because co-pending Application No. 18/288,296 recites that the fibrosis is IPF, SSc-ILD, etc. Claim 18 is met because co-pending Application No. 18/288,296 recites is claim 7 the amount of formula 1 administered is 100-150 mg.
Claims 15-17, and 19-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 7-12 of co-pending Application No. 18/288,296 (US PG BUB 2024/0307365A1) as applied above to claims 12-14, and 18, in view of Kim SH, et al. Biomolecules. 2020 Dec 1;10(12):1625, “Kim” cited in the IDS dated 02/20/2025), 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). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The disclosure of co-pending Application No. 18/288,296 is set forth above and incorporated herein by reference. The co-pending Application No. 18/288,296 does not recite the amounts and the weight ratios of Formula 1 and Nintedanib, or the administration protocol.
The disclosures set forth above in the 103 Rejection over the same Kim, King, Richeldi and Flaherty references (page 13-15) are herein incorporated by reference.
Claims 15-17, and 19-22 are rejected by the co-pending Application No. 18/288,296 and the teachings of Kim, King, Richeldi and Flaherty for the same rationale discussed above, page 16-17.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Claims 12-22 are rejected. No claim is allowed.
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 Searches were conducted to determine art-known connection between inhibition of prolyl-tRNA synthetase and idiopathic pulmonary fibrosis (IPF). Upon balancing and art-known connection between prolyl-tRNA synthetase inhibition and IPF mechanism with the predictability in the art and guidance in the specification (demonstrating the connection between the claimed combination and inhibition of prolyl-tRNA synthetase), it is 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).See the cited prior art in the 103 Rejection below.