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 .
DETAILED ACTION
1. Claims 5-10 are pending in the current application.
2. This application is a 371 of PCT/KR2022/007778 05/31/2022; FOREIGN APPLICATIONS: KOREA, REPUBLIC OF 10-2021-0071130 06/01/2021.
Claim Rejections - 35 USC § 112
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.
3. Claims 5-10 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 pulmonary fibrosis, does not reasonably provide enablement for preventing or administering a “prophylactically effective dose”. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and the invention commensurate in scope with these claims. Pulmonary fibrosis is an end state of a number of conditions, (fibrosing alveolitis, Hamman-Rich syndrome, acute interstitial pneumonia, CPOD, silicosis, etc.). Idiopathic pulmonary fibrosis is fibrosis of unknown cause, and is more difficult to treat Sharma “Idiopathic Pulmonary Fibrosis : Newer Concepts and Management Strategies” Indian J Chest Dis Allied Sci 2003; 45 : 31-49, “There is little evidence that any treatment prolongs survival or improves quality of life in patients with IPF.” “Idiopathic pulmonary fibrosis (IPF) is a fatal age-associated disease that is characterized by progressive and irreversible scarring of the lung. The pathogenesis of IPF is not completely understood and current therapies are limited to those that reduce the rate of functional decline in patients with mild-to-moderate disease….IPF is a complex, age-related, epithelial-driven fibrotic lung disorder. The disease is progressive and lethal, usually within a few years of diagnosis, and limited therapeutic options exist. Only recently have two drugs that slow the progression of the disease been formally registered.” Mora Nat Rev Drug Discov. 2017 October 30; 16(11): 810. For some of the conditions the only means of prevention is never having the insult to start (smoke, silica, radiation, etc.). None of these conditions are preventable by drugs. For the case of idiopathic pulmonary fibrosis since the cause is not known and the condition would be not suspected without symptoms it is unclear how a patient for prevention would be identified unless the approach were to add the compound to the water supply.
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.
4. Claim(s) 5-7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ryu “Discovery of 2-((R)-4-(2-Fluoro-4-(methylsulfonyl)phenyl)-2-methylpiperazin-1-yl)-N- ((1R,2s,3S,5S,7S)-5-hydroxyadamantan-2-yl)pyrimidine-4-carboxamide (SKI2852): A Highly Potent, Selective, and Orally Bioavailable Inhibitor of 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1).” Journal of Medicinal Chemistry, 2016, 59(22), 10176-10189 in view of Park “Anti-inflammatory effect of a selective 11.beta.-hydroxysteroid dehydrogenase type 1 inhibitor via the stimulation of heme oxygenase-1 in LPS-activated mice and J774.1 murine macrophages.” Journal of Pharmacological Sciences (Amsterdam, Netherlands), 2016, 131(4), 241-250 and Jaffar “Inhibition of NF-κB by ACT001 reduces fibroblast activity in idiopathic pulmonary fibrosis” Biomedicine & Pharmacotherapy 138 (2021) 111471 Available online 15 March 2021. The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determining the scope and contents of the prior art
Ryu teaches the claimed compound 18a (SKI2852), a potent, selective, and orally bioavailable inhibitor of 11β-hydroxysteroid dehydrogenase type 1 (abstract). Starting with previous lead compound 9 and making various modifications, “The PD activity of 18a was even superior to the picolinamide lead compound 9, despite having a lower cLogP value (cLogP = 1.98) than that of 9. Moreover, the pyrimidine-4-carboxamide compound 18a neither inhibited five major CYP isozymes nor activated PXR, a nuclear receptor that upregulates genes involved in drug metabolism (e.g., CYP3A4),34 suggesting that 18a has a low potential for CYP mediated drug−drug interactions (Table 3).” [page 10180 col. 2] “On the basis of its favorable in vitro, pharmacokinetic, pharmacodynamic, and toxicologic profiles, compound 18a (SKI2852)39 was selected as our final candidate.” [page 10182, col. 2], According to Ryu “11β-HSD1 is a key enzyme that acts as an NADPH-dependent reductase and converts inactive glucocorticoids (cortisone in humans and 11-dehydrocorticosterone in rodents) into the receptor-active glucocorticoids (cortisol in humans and corticosterone in rodents). This enzyme is highly expressed in metabolically active tissues, including the liver and adipose tissue, and regulates tissue specific glucocorticoid levels.8−11” [Page 10176, col. 2]
Park investigated the anti-inflammatory effects of “(KR-66344), a selective 11b-HSD1 inhibitor, in lipopolysaccharide (LPS)-activated C57BL/6J mice and macrophages. LPS increased 11b-HSD1 activity and expression in macrophages, which was inhibited by KR-66344. In addition, KR-66344 increased survival rate in LPS treated C57BL/6J mice. HO-1 mRNA expression level was increased by KR-66344, and this effect was reversed by the HO competitive inhibitor, ZnPP, in macrophages. Moreover, ZnPP reversed the suppression of ROS formation and cell death induced by KR-66344. ZnPP also suppressed animal survival rate in LPS plus KR-66344 treated C57BL/6J mice. In the spleen of LPS-treated mice, KR-66344 prevented cell death via suppression of inflammation, followed by inhibition of ROS, iNOS and COX-2 expression. Furthermore, LPS increased NFkB-p65 and MAPK phosphorylation, and these effects were abolished by pretreatment with KR-66344.” (abstract). As discussed on page 243 “3.8. Effects of KR-66344 on LPS-mediated signaling pathways LPS treatment markedly increased NFkB-p65 and MAPK phosphorylation, and this effect was abolished by treatment with KR-66344 (Fig. 7B). However, the protective effect of KR-66344 was significantly reversed by ZnPP. Using the same in vitro model, in macrophages, treatment with 50 ng/ml LPS increased NFkB-p65 and MAPK phosphorylation when assessed after 120 min (data not shown). This effect was abolished by co incubation with KR-66344 in a concentration-dependent manner (Supplementary Fig. 5B)” [page 248]
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According to Jaffar, “Nuclear factor kappa-B (NF-κB) is a key transcription factor mediator of IL-6 [6] and IL-8 [7] and has been suggested as a potential therapeutic target for inhibition in IPF (Idiopathic Pulmonary Fibrosis) [8,9]. NF-κB promotes the transcription of pro-inflammatory cytokines such as transforming growth factor (TGF)-β1 [10]. TGF-β1 is a well-known cytokine that drives fibrotic disease progression [11–13] including fibroblast-to-myofibroblast transition (FMT) [14,15], whereby myofibroblasts are differentiated from fibroblasts by expression of the contractile protein α-smooth muscle actin (-SMA). Fibroblasts become dysregulated in IPF [16] and NF-κB itself has been shown to mediate FMT in lung fibroblasts [17]. Elevated NF-κB has been implicated in the accumulation of fibroblasts in the lung tissue of patients with IPF [18], which results in the exaggerated deposition of extracellular matrix (ECM) [19].” [page 111471 col. 1-2] “[T]he aim of this study was to investigate the efficacy of ACT001, an NF-ĸB inhibitor, on primary fibroblasts derived from patients with and without IPF….. ACT001 inhibited fibroblast activity in a concentration-dependent manner in both groups of fibroblasts. ACT001 inhibited IL-6 but not IL-8 production in unstimulated fibroblasts. ACT001 is a water-soluble compound with a stable half-life in plasma, thus making it an attractive candidate for further investigation as a therapeutic in IPF. This study adds to the growing body of literature that demonstrates anti-fibrotic activity of NF-ĸB inhibition in the context of IPF.” [abstract]
Ascertaining the differences between the prior art and the claims at issue
Ryu mentions using the claimed compound, 18a (SKI2852), 11β-hydroxysteroid dehydrogenase type 1 inhibitor, to treat metabolic syndrome which has symptoms of obesity, glucose intolerance, insulin resistance, dyslipidemia, hypertension, and inflammatory or prothrombotic states which progresses to type 2 diabetes with associated complication of “cardiovascular disease, diabetic retinopathy, renal failure, nerve damage, and ischemic stroke” [col. 1 . Ryu does not mention pulmonary fibrosis per se.
Resolving the level of ordinary skill in the pertinent art and considering objective evidence present in the application indicating obviousness or nonobviousness
NF-κB is a critical pro-inflammatory transcription factor that drives the progression of pulmonary fibrosis by promoting chronic inflammation. NF-κB signaling is observed in fibrotic lung, making it a key therapeutic target to reduce fibrosis and tissue remodeling. “Fibroblasts become dysregulated in IPF [16] and NF-κB itself has been shown to mediate FMT in lung fibroblasts [17]. Elevated NF-κB has been implicated in the accumulation of fibroblasts in the lung tissue of patients with IPF [18], which results in the exaggerated deposition of extracellular matrix (ECM)” [Jaffar]. 11b-HSD1 inhibitors are known anti-inflammatory agents. The effects of (KR-66344), a selective 11b-HSD1 inhibitor were known to proceed by inhibition of NFkB. Since the claimed compound was also a known 11b-HSD1 inhibitor there is a reasonable expectation of success in reducing NFKB in the pulmonary fibrosis patient providing an anti-inflammatory effect and treatment thereof.
Regarding claim 6, radiation-induced fibrosis of the lungs involves damage to DNA. This DNA damage causes apoptosis in the lung epithelium and subsequent destruction of endothelial cells leading to loss of vascular integrity. Apoptotic death triggers recruitment of the immune effector cells such as neutrophils, macrophages, leukocytes and lymphocytes into the damaged lungs, causing acute phase pneumonitis. Inflammation of the lungs activates NF-κB, which is the major regulator of inflammatory response and has been associated with the production of many inflammatory cytokines and chemokines such as IL-1β, IL-6 and TNF α. Reducing NF-κB via the inhibition of 11b-HSD1 would be expected to treat the irradiated fibrotic patient.
5. Claim(s) 5, 7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Oh “A potent and selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor, SKI2852, ameliorates metabolic syndrome in diabetic mice models.” European Journal of Pharmacology, 2015, 768, 139-148 (cited on the IDS) in view of Kolahian “Diabetic lung disease: fact or fiction?” Rev Endocr Metab Disord (2019) 20:303–319. The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determining the scope and contents of the prior art
Oh teaches the claimed compound (SKI2852), a potent, selective, and orally bioavailable inhibitor of 11β-hydroxysteroid dehydrogenase type 1 for treating type 2 diabetes. “In particular, SKI2852 is a promising novel candidate for anti-metabolic syndrome and anti-diabetes drug. In the present study, we evaluated SKI2852 for 11βHSD1 inhibition potency, for metabolic efficacy in several metabolic disease mice models, and for enhancement of hepatic and whole body insulin sensitivities [page 140 col. 1]….. All together, these results strongly indicate that selective and potent inhibition of 11βHSD1 by SKI2852may efficiently improve many aspects of metabolic parameters in type 2 diabetes and metabolic syndrome [page 146 4. Discussion]….In conclusion, our present study indicates that selective and potent inhibition of 11βHSD1 by SKI2852 may sufficiently improve many aspects of metabolic parameters in type2 diabetes and metabolic diseases, and strongly support that SKI2852 may have a great potential as a better candidate drug than currently available 11βHSD1 inhibitors for the treatment of diabetes and metabolic diseases.” [conclusion]
According to Kolahian on page 310 col. 2 under 11 DM and pulmonary fibrosis:
A first Japanese case-control study showed that DM increases the risk for developing pulmonary fibrosis [231]. A case-control study from the United Kingdom found an association between IPF and DM, the strongest association being with insulin use [225]. Another Mexican case-control study showed that T2DM is the most important independent risk factor associated with pulmonary fibrosis [232]. Furthermore, it has been shown that T1DM is also an independent risk factor for pulmonary fibrosis [233]. Two Korean case-control studies demonstrated the association of DM with IPF [234, 235]. A higher prevalence of hypertension, cardiovascular disease, and other malignancies, excluding lung cancer, has been shown in IPF patients with DM than in IPF patients without DM [235]. A Danish cohort study showed that DM is the third most frequently observed comorbidity of pulmonary fibrosis after cardiovascular disease and arterial hypertension [236]. This study suggested for the first time that DM significantly increases mortality in IPF patients [236]. Advanced glycation end product -modified protein accumulation has been shown in lung macrophages in remodeling lesions of pulmonary fibrosis, suggesting that chemical modification by AGE might be involved in DM-induced pulmonary fibrosis [237]. Taking all these findings together, it may be concluded that DM is one of the main comorbidities in patients with IPF (Fig. 4). The recognition and management of comorbidities in IPF may limit disease progression and increase survival in these patients.
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Ascertaining the differences between the prior art and the claims at issue
Oh teaches using the claimed compound, (SKI2852), an 11β-hydroxysteroid dehydrogenase type 1 inhibitor, to treat type 2 diabetes. Oh does not mention pulmonary fibrosis per se.
Resolving the level of ordinary skill in the pertinent art and considering objective evidence present in the application indicating obviousness or nonobviousness
Since as explained by Kolahian, “taking all these findings together, it may be concluded that DM is one of the main comorbidities in patients with IPF”, treating diabetes as shown by Oh would inherently treat a subpopulation of patients with IPF. One would be motivated to treat this subpopulation of diabetic patients since as explained by Kolahian, “The recognition and management of comorbidities in IPF may limit disease progression and increase survival in these patients.”
6. Claim(s) 8-10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ryu in view of Park and Jaffar as applied to claims 5-7 above, and further in view of Lamb “Nintedanib: A Review in Fibrotic Interstitial Lung Diseases” Adis Drug Evaluation 2021, Volume 81, pages 575–586, Published: 25 March 2021. As discussed above it is obvious to administer the claimed compound to the pulmonary fibrosis patients based upon Ryu in view of Park and Jaffar. Lamb teaches that nintedanib is also useful for treating idiopathic pulmonary fibrosis1. Claims 8-10 are drawn to combining nintedanib with SKI2852. Combining two things known for the same purpose, treating pulmonary fibrosis, in a single composition is obvious. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (MPEP § 2144.06). Therefore it would be obvious to combine nintedanib with SKI2852 for the same treatment.
7. Claim(s) 8, 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Oh in view of Kolahian as applied to claims 5, 7 above, and further in view of Lamb “Nintedanib: A Review in Fibrotic Interstitial Lung Diseases” Adis Drug Evaluation 2021, Volume 81, pages 575–586, Published: 25 March 2021. As discussed above it is obvious to administer the claimed compound to the pulmonary fibrosis patients based upon Oh in view of Kolahian. Lamb teaches that nintedanib is also useful for treating idiopathic pulmonary fibrosis. Claims 8-10 are drawn to combining nintedanib with SKI2852. Combining two things known for the same purpose, treating pulmonary fibrosis, in a single composition is obvious. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (MPEP § 2144.06). Therefore it would be obvious to combine nintedanib with SKI2852 for the same treatment.
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 claims at issue 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); and 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 a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form 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 http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
8. Claims 5-7 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. US 9,096,5712 in view of Park and Jaffar. Although the claims at issue are not identical, they are not patentably distinct from each other because the elected species is a compound in claim 3 col. 162 lines 62-64. Claim 6 is drawn to a composition useful for treating diabetes. The specification discloses that the compound is an 11b-HSD1 inhibitor. As discussed above, the secondary reference discloses that 11b-HSD1 inhibitors are known anti-inflammatory agents. The effects of (KR-66344), a selective 11b-HSD1 inhibitor were known to proceed by inhibition of NFkB. NF-κB is a critical pro-inflammatory transcription factor that drives the progression of pulmonary fibrosis by promoting chronic inflammation. NF-κB signaling is observed in fibrotic lung, making it a key therapeutic target to reduce fibrosis and tissue remodeling. “Fibroblasts become dysregulated in IPF [16] and NF-κB itself has been shown to mediate FMT in lung fibroblasts [17]. Elevated NF-κB has been implicated in the accumulation of fibroblasts in the lung tissue of patients with IPF [18], which results in the exaggerated deposition of extracellular matrix (ECM)” [Jaffar]. Since the patented compound was also a known 11b-HSD1 inhibitor there is a reasonable expectation of success in reducing NFKB in the pulmonary fibrosis patient providing an anti-inflammatory effect and treatment thereof and the instant claims are no more than an obvious variant of that already patented.
9. Claims 5, 7 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. US 9,096,571 in view of Kolahian. Although the claims at issue are not identical, they are not patentably distinct from each other because the elected species is a compound in claim 3 col. 162 lines 62-64. Claim 6 is drawn to a composition useful for treating diabetes. The specification discloses that the compound is an 11b-HSD1 inhibitor useful for treating diabetes. Since as explained by Kolahian, “taking all these findings together, it may be concluded that DM is one of the main comorbidities in patients with IPF”, treating diabetes as shown by the ‘571 patent claims would inherently treat a subpopulation of patients with IPF. One would be motivated to treat this subpopulation of diabetic patients since as explained by Kolahian, “The recognition and management of comorbidities in IPF may limit disease progression and increase survival in these patients.”
10. Claim(s) 8, 10 is/are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. US 9,096,571 in view of Kolahian as applied to claims 5-7 above, and further in view of Lamb. As discussed above it is obvious to administer the claimed compound to the pulmonary fibrosis patients based upon the prior patent claims in view of Kolahian. Lamb teaches that nintedanib is also useful for treating idiopathic pulmonary fibrosis. Claims 8-10 are drawn to combining nintedanib with SKI2852. Combining two things known for the same purpose, treating pulmonary fibrosis, in a single composition is obvious. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (MPEP § 2144.06). Therefore it would be obvious to combine nintedanib with the patented compound for the same treatment.
11. Claim(s) 8-10 is/are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. US 9,096,571 in view of in view of Park and Jaffar as applied to claims 5-7 above, and further in view of Lamb. As discussed above it is obvious to administer the claimed compound to the pulmonary fibrosis patients based upon the prior patent claims in view of in view of Park and Jaffar. Lamb teaches that nintedanib is also useful for treating idiopathic pulmonary fibrosis. Claims 8-10 are drawn to combining nintedanib with SKI2852. Combining two things known for the same purpose, treating pulmonary fibrosis, in a single composition is obvious. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (MPEP § 2144.06). Therefore it would be obvious to combine nintedanib with the patented compound for the same treatment.
Additional3 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.
12. Claim(s) 5-7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ryu U.S. 9,096,571 in view of Park and Jaffar. Ryu U.S. ‘571 on Col 123-124 teaches the compound in the claimed method:
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According to the col. 1 line 55 ff. “Therefore, the effective and selective inhibitors of 11B
HSD1 enzymes inhibit the conversion of glucocorticoids into the active type to Suppress the action of glucocorticoids in the tissue, and as a result, they can be used as therapeutic agents for metabolic syndromes caused by glucocorticoids, such as non-insulin dependent type 2 diabetes, obesity, hyperlipidemia, hypertension, glucose tolerance, and the like.
For this reason, the present inventors searched compounds having effective and selective inhibitory activity for 11B HSD1 enzymes for the purpose of regulating or treating metabolic syndromes such as obesity, diabetes, etc.” “A pharmaceutical composition for treating and/or preventing metabolic syndromes, diabetes, especially non-insulin dependent diabetes, prediabetes, insulin tolerance, low glucose tolerance, hyperglycemia, obesity and weight - related disorders, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, lipid disorders such as low HDL levels or high LDL levels, glaucoma, osteoporosis, cognitive disorders, glucocorticoid- mediated effects on neuron functions, such as anxiety or depression, neurodegenerative diseases, immune disorders such as tuberculosis, leprosy or psoriasis, hypertension, atherosclerosis and complications thereof, vessel restenosis, cardiovascular disease, pancreatitis, retinitis, neuropathy, or nephropathy, the pharmaceutical composition comprising the amide compound or the pharmaceutically acceptable salt, solvate, hydrate, prodrug, racemate, or stereoisomer thereof according to any one of claims 1 to 3, and a pharmaceutically acceptable carrier” [col. 9 lines 43 ff] Also at col. 11 lines 15 ff. Park and Jaffar have the teaching as summarized above.
Ascertaining the differences between the prior art and the claims at issue
Ryu mentions using the claimed compound, a 11β-hydroxysteroid dehydrogenase type 1 inhibitor, to treat metabolic syndromes, diabetes, especially non-insulin dependent diabetes, prediabetes, insulin tolerance, low glucose tolerance, hyperglycemia, obesity and weight - related disorders, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, lipid disorders such as low HDL levels or high LDL levels, glaucoma, osteoporosis, cognitive disorders, glucocorticoid- mediated effects on neuron functions, such as anxiety or depression, neurodegenerative diseases, immune disorders such as tuberculosis, leprosy or psoriasis, hypertension, atherosclerosis and complications thereof, vessel restenosis, cardiovascular disease, pancreatitis, retinitis, neuropathy, or nephropathy. Ryu does not mention pulmonary fibrosis per se.
Resolving the level of ordinary skill in the pertinent art and considering objective evidence present in the application indicating obviousness or nonobviousness
NF-κB is a critical pro-inflammatory transcription factor that drives the progression of pulmonary fibrosis by promoting chronic inflammation. NF-κB signaling is observed in fibrotic lung, making it a key therapeutic target to reduce fibrosis and tissue remodeling. “Fibroblasts become dysregulated in IPF [16] and NF-κB itself has been shown to mediate FMT in lung fibroblasts [17]. Elevated NF-κB has been implicated in the accumulation of fibroblasts in the lung tissue of patients with IPF [18], which results in the exaggerated deposition of extracellular matrix (ECM)” [Jaffar]. 11b-HSD1 inhibitors are known anti-inflammatory agents. The effects of (KR-66344), a selective 11b-HSD1 inhibitor were known to proceed by inhibition of NFkB. Since the claimed compound was also a known 11b-HSD1 inhibitor there is a reasonable expectation of success in reducing NFKB in the pulmonary fibrosis patient providing an anti-inflammatory effect and treatment thereof.
13. Claim(s) 5, 7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ryu U.S. 9,096,571 in view of Kolahian. Ryu U.S. ‘571 on Col 123-124 teaches the compound in the claimed method as discussed above in the rejection over Ryu U.S. 9,096,571 in view of Park and Jaffar. Kolahian on page 310 col. 2 under 11 DM and pulmonary fibrosis as quoted above.
Ascertaining the differences between the prior art and the claims at issue
Ryu mentions using the claimed compound, a 11β-hydroxysteroid dehydrogenase type 1 inhibitor, to treat metabolic syndromes, diabetes, especially non-insulin dependent diabetes, prediabetes, insulin tolerance, low glucose tolerance, hyperglycemia, obesity and weight - related disorders, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, lipid disorders such as low HDL levels or high LDL levels, glaucoma, osteoporosis, cognitive disorders, glucocorticoid- mediated effects on neuron functions, such as anxiety or depression, neurodegenerative diseases, immune disorders such as tuberculosis, leprosy or psoriasis, hypertension, atherosclerosis and complications thereof, vessel restenosis, cardiovascular disease, pancreatitis, retinitis, neuropathy, or nephropathy. Ryu does not mention pulmonary fibrosis per se.
Resolving the level of ordinary skill in the pertinent art and considering objective evidence present in the application indicating obviousness or nonobviousness
Since as explained by Kolahian, “taking all these findings together, it may be concluded that DM is one of the main comorbidities in patients with IPF”, treating diabetes as shown by Oh would inherently treat a subpopulation of patients with IPF. One would be motivated to treat this subpopulation of diabetic patients since as explained by Kolahian, “The recognition and management of comorbidities in IPF may limit disease progression and increase survival in these patients.”
14. Claim(s) 8-10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ryu U.S. 9,096,571 in view of Park and Jaffar as applied to claims 5-7 above, and further in view of Lamb. As discussed above it is obvious to administer the claimed compound to the pulmonary fibrosis patients based upon Ryu in view of Park and Jaffar. Lamb teaches that nintedanib is also useful for treating idiopathic pulmonary fibrosis. Claims 8-10 are drawn to combining nintedanib with SKI2852. Combining two things known for the same purpose, treating pulmonary fibrosis, in a single composition is obvious. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (MPEP § 2144.06). Therefore it would be obvious to combine nintedanib with SKI2852 for the same treatment.
15. Claim(s) 8, 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ryu U.S. 9,096,571 in view of Kolahian as applied to claims 5-7 above, and further in view of Lamb. As discussed above it is obvious to administer the claimed compound to the pulmonary fibrosis patients based upon Ryu U.S. 9,096,571 in view of Kolahian. Lamb teaches that nintedanib is also useful for treating idiopathic pulmonary fibrosis. Claims 8-10 are drawn to combining nintedanib with SKI2852. Combining two things known for the same purpose, treating pulmonary fibrosis, in a single composition is obvious. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (MPEP § 2144.06). Therefore it would be obvious to combine nintedanib with SKI2852 for the same treatment.
Conclusion
16. Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID K O'DELL whose telephone number is (571)272-9071. The examiner can normally be reached on Monday - Friday 9:30 - 7:00 PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached on 571-270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DAVID K O'DELL/Primary Examiner, Art Unit 1621
1 “Nintedanib continues to represent an important therapeutic option in patients with IPF and is the first drug to be approved for use in patients with other chronic fibrosing ILDs with a progressive phenotype or SSc-ILD..” (Lamb abstract).
2 Jae Sun Kim is a common inventor in the instant case and the ‘571 patent. The ‘571 patent is assigned to SK CHEMICALS CO.,LTD., Suwon (KR).
3 After completing the search and writing the 103 rejections over Ryu in view of Park and Jaffar and Oh in view of Kolahian and those rejections further in view of Lamb the double patenting search revealed US 9,096,571 which required the double patenting rejection above. Office policy requires an additional 103 rejection over the US 9,096,571 since it has been published and is itself also prior art. It is substantively no different than the previous rejections and is performative since any action or amendment that would overcome the rejections over Ryu in view of Park and Jaffar and also Oh in view of Kolahian would also overcome a 103 over US 9,096,571 in combination with the same references, Park and Jaffar and Kolahian.