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
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 06/10/2026 has been entered.
The Amendment filed 06/10/2026, amended claims 1-2, 111, cancelled claims 3, 8-14, 19, 24, 41-42, 71, 113-121, and added claims 122-143.
Claims 1-2, 111, and 122-143 are pending.
Priority
This application claims the following priority:
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Election/Restrictions
Applicant elected Group I, the method of treatment, and
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as the species of the compound of Formula (IA), in the reply filed on 08/04/2025.
In the course of the search, the election of species of compounds of Formula (IA) was broadened to include compounds B4 and B5.
Claims 1-2, 111, and 122-143 are examined on the merits herein.
REJECTIONS WITHDRAWN
The status for each rejection and/or objection in the previous Office Action is set out below.
Claim Objections
Applicant’s deletion of claim 115 is sufficient to overcome this objection.
35 U.S.C. § 112(a)
Applicant’s amendments to independent claims 1-2 and 111, that limits the compounds to A18, B4 and B5, are sufficient to overcome this rejection.
REJECTIONS—MAINTAINED, MODIFIED, & NEW
Applicant’s amendments to independent claims 1, 2, and 111, and addition of claims 122-143, have resulted in the below new and modified rejections. US 9,604,924 to Fung continues to be relied upon as the primary reference, PGPub US2019/0275032 to Stowasser, Patani, and Perry continue to be relied upon as secondary references.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 111, 123-126, 128-131, 133-140, and 143 are rejected under 35 U.S.C. 103 as being unpatentable over US 9,604,924 to Fung (published 2017, IDS of 06/25/2024) in view of US 2019/0275032 to Stowasser (published 2019, PTO-892 of 03/10/2026).
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Fung teaches a method of treating or ameliorating fibrosis comprising administering to a subject in need thereof, a compound of
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(Col. 83, claim 1, See also Cols. 83-84, 86 claims 2-21, 23), such as
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and
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(Cols. 85-86, claim 22), which are instant compounds B5 and B4, respectively.
Fung specifically teaches lung fibrosis as a type of fibrosis that its compounds treat, and teaches its compounds as inhibiting α-smooth muscle actin in normal human lung fibroblasts (Col. 48, lines 41-47; Figs. 1-2; Col. 4, line65-Col. 5, line 4)).
Regarding fibrosis, Fung teaches that excessive and persistent activation of cells characterizes both cancer and fibrotic diseases, wherein fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process, which can be benign or pathological. The term fibrosis is often used to indicate a pathological state of excess deposition of connective tissue, which can lead to loss of function and organ failure. During wound healing, myofibroblasts, including α-smooth muscle actin, are important contributors to tissue repair. TGF-ß is the principle growth factor responsible for differentiation to the myofibroblast activated phenotype. During normal tissue repair, myofibroblasts are activated in a controlled and transient manner. Excessive and persistent activation of myofibroblasts play a key role in both fibrotic disease and cancer. In fibrotic disease, large numbers of myofibroblasts accumulate and are responsible for the uncontrolled production of extracellular matrix which leads to loss of function and organ failure. Therefore, drugs, such as those taught by Fung, which inhibit the transition of fibroblasts to myofibroblasts, treat fibrotic diseases (Col. 1, lines l-45).
Regarding claims 1, 2, and 111, while Fung teaches a method of treating fibrotic lung disease by administering a compound of Formula (IA), it differs from that of instant claims 1 and 111, in that it does not teach additionally administering the antifibrotic agent nintedanib or pirfenidone.
Stowasser teaches a method for treating pulmonary fibrosis, such as idiopathic pulmonary fibrosis (IPF) by administering nintedanib, pirfenidone, or pharmaceutically acceptable salts thereof (abstract; pg. 5, claims 1 and 4; [0024]-[0025]).
Stowasser teaches that in mouse IPF models, nintedanib exerts anti-inflammatory effects as shown by significant reductions in lymphocyte and neutrophil counts in the bronchoalveolar lavage fluid, reductions in inflammatory cytokines, and reduction in inflammation and granuloma formation in histological analysis of lung tissue. IPF mouse models also reveal nintedanib associated antifibrotic effects as shown by significant reductions in total lung collagen and by reduced fibrosis identified in histological analyses ([0009], [0014]-[0016]).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to add the nintedanib or pirfenidone of Stowasser to the method of Fung, to arrive at instant claims 1, 2, and 111. One of ordinary skill in the art would have been motivated to make such an addition, with a reasonable expectation of success, because:
-Fung teaches adding one or more additional active agents to its compositions (Col. 4, lines 5-16;
-Fung and Stowasser are both directed toward methods of treating lung fibrosis,
-Fung teaches fibrosis as the formation of excess fibrous connective tissue, and Fung teaches its compounds as treating fibrosis by inhibiting the transition of fibroblasts to myofibroblasts, which accumulate and are responsible for the uncontrolled production of extracellular matrix,
-Stowasser teaches nintedanib as inhibiting PDGFR α and ß activation and proliferation of normal human lung fibroblasts to inhibit PDGF-BB, FGF-2, and BEGF induced proliferation of human lung fibroblasts, thus attenuating PDGF or FGF-2 stimulated migration of lung fibroblasts to myofibroblasts, 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). MPEP 2144.06
As such, an ordinary skilled artisan would have been motivated to make such an addition, to predictably arrive at a more therapeutically effective method of treating lung fibrosis.
Specifically regarding claim 2, since the combination of Fung and Stowasser treats lung fibrosis, the method would necessarily slow the rate of decline in pulmonary function and/or slow the progression of a fibrotic lung disease.
Moreover, as evidenced by [0010], [0016], [00192]-[00197], the instantly claimed method slows the rate of decline in pulmonary function in patients with a fibrotic lung disease.
Specifically regarding claim 111, since the combined method of Fung and Fujimoto teaches a method of treating the same patient population (patients with lung fibrosis), as instantly claimed, with therapeutically effective amounts of compounds of formula (IA) and nintedanib or pirfenidone, the combined method would necessarily inhibit TGF-ß.
Moreover, as evidenced by [00214] of the specification, fibrotic lung disease is a disease mediated by TGF-ß.
Regarding claims 123, 124, 128, 129, 133, and 134, Fung teaches B4 and B5.
Regarding claims 125-126, 130-131, 135-136, Stowasser teaches nintedanib monoethanesulphonate as the salt form of nintedanib (pg.5, claim 4) and Stowasser teaches pirfenidone.
Regarding claims 137-138 and 143, Stowasser teaches treating a method for treating idiopathic pulmonary fibrosis, such as idiopathic pulmonary fibrosis, wherein idiopathic pulmonary fibrosis belongs to a large group of more than 200 lung diseases known as interstitial lung diseases ([0001]-[0002]).
Regarding claims 139-140, Stowasser teaches idiopathic pulmonary fibrosis as a rare disease of unknown aetiology that is characterized by progressive fibrosis of the interstitium of the lung ([0003]).
Claims 122, 127 and 132 are rejected under 35 U.S.C. 103 as being unpatentable over US 9,604,924 to Fung (published 2017, IDS of 06/25/2024) in view of US 2019/0275032 to Stowasser (published 2019, PTO-892 of 03/10/2026), as applied to claims 1-2, 111, 123-126, 128-131, 133-140, and 143 above, and further in view of Patani (Bioisosterism: A Rational Approach in Drug Design, Chem. Rev. published 1996, PTO-892 of 10/06/2025), Perry (IBP Group Meeting 2019 PDF Unlayered from J. Med. Chem. 2012, 55, published 2019, PTO-892 of 10/06/2025).
Fung and Stowasser are applied as discussed above and incorporated herein.
While the combination of Fung and Stowasser teaches a method of treating lung fibrosis by administering a compound of
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, it differs from that of the instantly claimed invention, in that it does not teach a -OH at the 3 position of the 5-trifluoro-methylphenyl ring.
Patani teaches bioisosterism as a tool for the medicinal chemist for the rational modification of lead compounds into safer and more clinically effective agents (pg. 3147, “Introduction”). The ability of a group of bioisosteres to elicit similar biological activity is attributed to common physicochemical properties. Bioisosteres provide opportunities for the medicinal chemist to gain more specific insight into the quantitative structure-activity relationships associated with a specific class of drugs. Bioisosteric replacements often provide the foundation for the development of QSAR in drug design (pg. 3148, Col. 1).
Patani teaches OH and CF3, as known bioisosteres for a methyl group (pg. 3152, Col. 2).
In conclusion, Patani teaches that bioisosteres modulate biological activity by virtue of subtle differences in their physicochemical properties. Systematic correlation of physicochemical parameters with observed biological activity is very effective in highlighting subtle differences within bioisosteric groups which often increases activity. This systematic approach facilitates the use of bioisosteric replacements in structure-activity studies.
Perry IBP teaches CF3, and OH as bioisosteres of common functional groups on phenyl rings (pg. 15).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention to substitute the CF3 in
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of Fung, with -OH, to arrive at instant compound A18. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
-Patani and Perry IBP teach OH, and CF3 as bioisosteres,
-Perry IBP teach CF3, and OH as bioisosteres,
-Patani teaches bioisosterism as a tool for the medicinal chemist for the rational modification of lead compounds into safer and more clinically effective agents, and
-Patani teaches that systematic correlation of physicochemical parameters with observed biological activity is very effective in highlighting subtle differences within bioisosteric groups which often increases activity.
As such, an artisan having ordinary skill in the art would have been motivated to make such a substitution, to predictably arrive at a structurally and functionally similar compound that is effective in treating lung fibrosis; a prima facie case of obvious may be made when chemical compounds have very close structural similarities and similar utilities, MPEP 2114.09.
Claim 141 is rejected under 35 U.S.C. 103 as being unpatentable over US 9,604,924 to Fung (published 2017, IDS of 06/25/2024) in view of US 2019/0275032 to Stowasser (published 2019, PTO-892 of 03/10/2026), as applied to claims 1-2, 111, 123-126, 128-131, 133-140, and 143 above, and further in view of Cohen (Lung Pathology in US Coal Workers with Rapidly Progressive Pneumoconiosis Implicates Silica and Silicates, published 2016, PTO-892).
Fung and Stowasser are applied as discussed above and incorporated herein.
While the combination of Fung and Stowasser teaches a method of treating lung fibrosis by administering compounds B4 and B4, it differs from that of the claim 141, in that it does not teach coal workers pneumoconiosis as the fibrotic lung disease.
Cohen teaches progressive massive fibrosis and rapidly progressive pneumoconiosis in US coal miners (abstract).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to select coal workers pneumoconiosis as the fibrotic lung disease taught by the combination of Fung and Stowasser, to arrive at instant claim 141. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-the combination of Fung and Stowasser teaches a method of treating lung fibrosis, and
-Cohen teaches coal workers pneumoconiosis as characterized by lung fibrosis.
As such, an ordinary skilled artisan would have been motivated to make such a selection, to predictably arrive at a method that treats the lung fibrosis in coal workers pneumoconiosis.
Claim 142 is rejected under 35 U.S.C. 103 as being unpatentable over US 9,604,924 to Fung (published 2017, IDS of 06/25/2024) in view of US 2019/0275032 to Stowasser (published 2019, PTO-892 of 03/10/2026), as applied to claims 1-2, 111, 123-126, 128-131, 133-140, and 143 above, and further in view of Herzog (Interstitial Lung Disease Associated with Systemic Sclerosis and Idiopathic Pulmonary Fibrosis, published 2014, PTO-892 03/10/2026).
Fung and Stowasser are applied as discussed above and incorporated herein.
While the combination of Fung and Stowasser teaches a method of treating lung fibrosis by administering compounds B4 and B4, it differs from that of the claim 141, in that it does not teach systemic sclerosis-interstitial lung disease as the fibrotic lung disease.
Herzog teaches fibrosis of the lung as a common complication of systemic sclerosis associated interstitial lung disease (abstract; pgs. 2-3, Radiographic features, Lung pathology; pg. 4, Pathogenesis and genetic risk factors; pg. 6).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to select systemic sclerosis interstitial lung disease as the fibrotic lung taught by the combination of Fung and Stowasser, to arrive at instant claim 142. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-the combination of Fung and Stowasser teaches a method of treating lung fibrosis, and
-Herzog teaches systemic sclerosis associated interstitial lung disease as characterized by lung fibrosis.
As such, an ordinary skilled artisan would have been motivated to make such a selection, to predictably arrive at a method that treats the lung fibrosis in systemic sclerosis associated interstitial lung disease.
Response to Arguments
On pgs. 24-25 and 27, Remarks, Applicant argues that unexpected results have been achieved and specifically points the examiner to Tables 1-3 on pgs. 82-83 of the Specification.
These arguments have been fully considered, but are not found persuasive.
In Table 1, while a combination of a) 5µM nintedanib (N) and 5µM A18, b) 5µM N and 10µM A18, c) 200µM pirfenidone (P) and 5µM A18, d) 200µM P and 10µM A18, and e) 200µM P and 20µM A18, does show a synergistic effect on alpha-smooth muscle active (SMA) in lung fibroblasts, a combination of 5µM N and 20µM A18 does not.
In Table 2, while a combination of 5µM nintedanib (N) and 2µM B4, and a combination of 5µM N and 5µM B4, does show a synergistic effect on alpha-smooth muscle active (SMA) in lung fibroblasts, a combination of 5µM N and 10µM B4 does not. Table 2 shows no results for combinations of B4 and pirfenidone.
In Table 3, while a combination of a) 5µM nintedanib (N) and 5µM B5, b) 5µM N and 10µM B5, c) 200µM pirfenidone and 5µM B5, and d) 200µM P and 10µM B5, does show a synergistic effect on alpha-smooth muscle active (SMA) in lung fibroblasts, a combination of 5µM N and 20µM B5 and a combination of 200µM P and 20µM B5 does not.
In view of this data, the concentrations of the tested compounds appears to be critical to the synergistic effect on α -SMA levels.
In summary, Tables 1-3 only provide synergistic results for specific molar concentrations/molar ratios of A18, B4, or B5 in combination with N or B. Since the claims are not limited to such molar concentrations/ratios, Tables 1-3 are not sufficient as evidence of unexpected results.
MPEP 716.02 states that unexpected results must be commensurate in scope with the claimed invention and provide a comparison with the closest prior art.
On pgs. 29-30, Remarks, regarding the rejections over Patani and Perry, Applicant argues that bioisosteric replacement is unpredictable and that one of ordinary skill in the art would not have a reasonable expectation of success in predictably arriving at a safer and more clinically effective agent.
This argument has been fully considered, but is not found persuasive. Regarding the teachings of Perry pointed to on pgs. 29-30, Remarks, it is respectfully pointed out that Perry also teaches on pg. 48, that “Bioisosteres are frequently employed in a medicinal chemistry setting to improve or alter physico-chemical properties of lead compounds,” and on pg. 15, Perry teaches -C(CH3)2, CF3, and OH as bioisosteres of common functional groups on phenyl rings (pg. 15). Regarding the teachings of Meanwell pointed to on pg. 30, Remarks, which is no longer relied upon in the prior art rejection, it is respectfully pointed out that Meanwell also teaches on pg. 2529 that “In the contemporary practice of medicinal chemistry, the development and application of bioisosteres have been adopted as a fundamental tactical approach useful to address a number of aspects associated with the design and development of drug candidates. The established utility of bioisosteres is broad in nature, extending to improving potency, enhancing selectivity, altering physical properties, reducing or redirecting metabolism, eliminating or modifying toxicophores.” Thus, Meanwell teaches bioisosteres as known in the art and as useful. And Patani teaches “bioisosterism as a tool for the medicinal chemist for the rational modification of lead compounds into safer and more clinically effective agents (pg. 3147, “Introduction”). The ability of a group of bioisosteres to elicit similar biological activity is attributed to common physicochemical properties. Bioisosteres provide opportunities for the medicinal chemist to gain more specific insight into the quantitative structure-activity relationships associated with a specific class of drugs. Bioisosteric replacements often provide the foundation for the development of QSAR in drug design (pg. 3148, Col. 1).”
Thus, while there is some unpredictability in bioisosteric replacement,
-Patani teaches OH and CF3 as known bioisosteres, and
-Perry IBP teach CF3, and OH as known bioisosteres.
Further, it is respectfully pointed out that obviousness does not require absolute predictability, but a reasonable expectation of success (see MPEP 2143.02). As such, it would reasonably be expected that replacing CF3 with a bioisostere known in the art, i.e., OH, would lead to a structurally and functionally similar compound that may be safer and/or more clinically effective; a prima facie case of obvious may be made when chemical compounds have very close structural similarities and similar utilities, MPEP 2114.09.
For these reasons, Applicant’s arguments are not sufficient to overcome the instant rejections.
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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.
Claims 1-2, 111, 123-126, 128-131, 133-140, and 143 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 9,604,924 to Fung (IDS of 06/25/2024) in view of US 2019/0275032 to Stowasser (published 2019, PTO-892 of 03/10/2026).
Fung claims a method of treating or ameliorating fibrosis in a subject comprising administering to a subject, compound of
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(claims 1-21), and specifically claims instant B4 and B5 (claim 22), and specifically teaches lung fibrosis as a specific fibrosis (pgs. 97-98; pg. 107, claim 1; pg. 111, claim 24; pg. 114, claim 44; [00209]).
Stowasser is applied as discussed above and incorporated herein.
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to add the nintedanib or pirfenidone of Stowasser to the method of Fung, to arrive at instant claims 1, 2, and 111. One of ordinary skill in the art would have been motivated to make such an addition, with a reasonable expectation of success, because:
-Fung and Stowasser are both directed toward methods of treating lung fibrosis,
-Stowasser teaches nintedanib as inhibiting PDGFR α and ß activation and proliferation of normal human lung fibroblasts to inhibit PDGF-BB, FGF-2, and BEGF induced proliferation of human lung fibroblasts, thus attenuating PDGF or FGF-2 stimulated migration of lung fibroblasts to myofibroblasts, 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). MPEP 2144.06
As such, an ordinary skilled artisan would have been motivated to make such an addition, to predictably arrive at a more therapeutically effective method of treating lung fibrosis.
Specifically regarding claim 2, since the combination of Fung and Stowasser treats lung fibrosis, the method would necessarily slow the rate of decline in pulmonary function and/or slow the progression of a fibrotic lung disease.
Moreover, as evidenced by [0010], [0016], [00192]-[00197], the instantly claimed method slows the rate of decline in pulmonary function in patients with a fibrotic lung disease.
Specifically regarding claim 111, since the combined method of Fung and Fujimoto teaches a method of treating the same patient population (patients with lung fibrosis), as instantly claimed, with therapeutically effective amounts of compounds of formula (IA) and an antifibrotic agent, the combined method would necessarily inhibit TGF-ß. See MPEP 2112.02.
Moreover, as evidenced by [00214] of the specification, fibrotic lung disease is a disease mediated by TGF-ß.
Regarding claims 123, 124, 128, 129, 133, and 134, Fung teaches B4 and B5.
Regarding claims 125-126, 130-131, 135-136, Stowasser teaches nintedanib monoethanesulphonate as the salt form of nintedanib (pg.5, claim 4) and Stowasser teaches pirfenidone.
Regarding claims 137-138 and 143, Stowasser teaches treating a method for treating idiopathic pulmonary fibrosis, such as idiopathic pulmonary fibrosis, wherein idiopathic pulmonary fibrosis belongs to a large group of more than 200 lung diseases known as interstitial lung diseases ([0001]-[0002]).
Regarding claims 139-140, Stowasser teaches idiopathic pulmonary fibrosis as a rare disease of unknown aetiology that is characterized by progressive fibrosis of the interstitium of the lung ([0003]).
Claims 1-2, 111, 123-126, 128-131, 133-140, and 143 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 9,156,781 to Fung (IDS of 06/25/2024) in view of US 2019/0275032 to Stowasser (published 2019, PTO-892 of 03/10/2026).
Fung claims a compound of
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(claims 1-23), and specifically claims instant compounds B4 and B5 (claim 24), and specifically teaches its compounds for the treatment of lung fibrosis (Col. 47, lines 22-29).
Consistent with Sun Pharmaceutical Industries v. Eli Lilly and Col, 611 F. 3d 1381, 1387 (CAFC 2010), it is permissible to use a compound claim to reject a method of use claim where that method of use is disclosed in the specification of the application claiming the compound. According to the Sun Pharma. Court, “[i]t would shock one’s sense of justice if an inventor could receive a patent upon a composition of matter, setting out at length in the specification the useful purposes of such composition, . . .and then prevent the public from making any beneficial use of such product by securing patents upon each of the uses to which it may be adapted. . .”.
Regarding claims 1, 2, and 111 while Fung claims instant compounds B4 and B5 and teaches it compounds for the treatment of lung fibrosis, it differs from that of instant claims 1, 2, and 111 in that it does not teach nintedanib or pirfenidone.
Stowasser is applied as discussed above and incorporated herein.
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to add the nintedanib or pirfenidone of Stowasser to the method of Fung, to arrive at instant claims 1, 2, and 111. One of ordinary skill in the art would have been motivated to make such an addition, with a reasonable expectation of success, because:
-Fung and Stowasser are both directed toward methods of treating lung fibrosis,
-Stowasser teaches nintedanib as inhibiting PDGFR α and ß activation and proliferation of normal human lung fibroblasts to inhibit PDGF-BB, FGF-2, and BEGF induced proliferation of human lung fibroblasts, thus attenuating PDGF or FGF-2 stimulated migration of lung fibroblasts to myofibroblasts, 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). MPEP 2144.06
As such, an ordinary skilled artisan would have been motivated to make such an addition, to predictably arrive at a more therapeutically effective method of treating lung fibrosis.
Specifically regarding claim 2, since the combination of Fung and Stowasser treats lung fibrosis, the method would necessarily slow the rate of decline in pulmonary function and/or slow the progression of a fibrotic lung disease.
Moreover, as evidenced by [0010], [0016], [00192]-[00197], the instantly claimed method slows the rate of decline in pulmonary function in patients with a fibrotic lung disease.
Specifically regarding claim 111, since the combined method of Fung and Fujimoto teaches a method of treating the same patient population (patients with lung fibrosis), as instantly claimed, with therapeutically effective amounts of compounds of formula (IA) and an antifibrotic agent, the combined method would necessarily inhibit TGF-ß. See MPEP 2112.02.
Moreover, as evidenced by [00214] of the specification, fibrotic lung disease is a disease mediated by TGF-ß.
Regarding claims 123, 124, 128, 129, 133, and 134, Fung teaches B4 and B5.
Regarding claims 125-126, 130-131, 135-136, Stowasser teaches nintedanib monoethanesulphonate as the salt form of nintedanib (pg.5, claim 4) and Stowasser teaches pirfenidone.
Regarding claims 137-138 and 143, Stowasser teaches treating a method for treating idiopathic pulmonary fibrosis, such as idiopathic pulmonary fibrosis, wherein idiopathic pulmonary fibrosis belongs to a large group of more than 200 lung diseases known as interstitial lung diseases ([0001]-[0002]).
Regarding claims 139-140, Stowasser teaches idiopathic pulmonary fibrosis as a rare disease of unknown aetiology that is characterized by progressive fibrosis of the interstitium of the lung ([0003]).
Claims 122, 127, and 132 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 9,604,924 to Fung (IDS of 06/25/2024) in view of US 2019/0275032 to Stowasser (published 2019, PTO-892 of 03/10/2026), as applied to claims 1-2, 111, 123-126, 128-131, 133-140, and 143 above, and further in view of Patani (Bioisosterism: A Rational Approach in Drug Design, Chem. Rev. published 1996, PTO-892 of 10/06/2025), Perry (IBP Group Meeting 2019 PDF Unlayered from J. Med. Chem. 2012, 55, published 2019, PTO-892 of 10/06/2025).
Claims 122, 127, and 132 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 9,156,781 to Fung (IDS of 06/25/2024) in view of US 2019/0275032 to Stowasser (published 2019, PTO-892 of 03/10/2026), as applied to claims 1-2, 111, 123-126, 128-131, 133-140, and 143 above, and further in view of Patani (Bioisosterism: A Rational Approach in Drug Design, Chem. Rev. published 1996, PTO-892 of 10/06/2025), Perry (IBP Group Meeting 2019 PDF Unlayered from J. Med. Chem. 2012, 55, published 2019, PTO-892 of 10/06/2025).
Fung ‘924 and Stowasser, and Fung ‘781 and Stowasser are applied as discussed above and incorporated herein.
While the combinations of a) Fung ‘942 and Stowasser and b) Fung ‘781 and Stowasser teach a method of treating lung fibrosis by administering a compound of
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, they differ from that of the instantly claimed invention, in that they do not teach a -OH as the 3 position of the 5-trifluoro-methylphenyl ring.
Patani and Perry IBP are applied as discussed above and incorporated herein.
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention to substitute the CF3 in
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of the Fung references, with -OH, to arrive at instant compound A18. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
-Patani and Perry IBP teaches OH, and CF3 as bioisosteres,
-Perry IBP teach CF3 and OH as bioisosteres,
-Patani teaches bioisosterism as a tool for the medicinal chemist for the rational modification of lead compounds into safer and more clinically effective agents, and
-Patani teaches that systematic correlation of physicochemical parameters with observed biological activity is very effective in highlighting subtle differences within bioisosteric groups which often increases activity.
As such, an artisan having ordinary skill in the art would have been motivated to make such a substitution, to predictably arrive at a structurally and functionally similar compound that is effective to treat lung fibrosis; a prima facie case of obvious may be made when chemical compounds have very close structural similarities and similar utilities, MPEP 2114.09.
Claim 141 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 9,604,924 to Fung (IDS of 06/25/2024) in view of US 2019/0275032 to Stowasser (published 2019, PTO-892 of 03/10/2026), as applied to claims 1-2, 111, 123-126, 128-131, 133-140, and 143 above, and further in view of Cohen (Lung Pathology in US Coal Workers with Rapidly Progressive Pneumoconiosis Implicates Silica and Silicates, published 2016, PTO-892).
Claim 141 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 9,156,781 to Fung (IDS of 06/25/2024) in view of US 2019/0275032 to Stowasser (published 2019, PTO-892 of 03/10/2026), as applied to claims 1-2, 111, 123-126, 128-131, 133-140, and 143 above, and further in view of Cohen (Lung Pathology in US Coal Workers with Rapidly Progressive Pneumoconiosis Implicates Silica and Silicates, published 2016, PTO-892).
Fung ‘924 and Stowasser, and Fung ‘781 and Stowasser are applied as discussed above and incorporated herein.
While the combinations of a) Fung ‘924 and Stowasser, and b) Fung ‘781 and Stowasser teach a method of treating lung fibrosis by administering compounds B4 and B4, they differ from that of claim 141, in that they do not teach coal workers pneumoconiosis as the fibrotic lung disease.
Cohen teaches progressive massive fibrosis and rapidly progressive pneumoconiosis in US coal miners (abstract).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to select coal workers pneumoconiosis as the fibrotic lung disease taught by the combination of Fung ‘924 and Stowasser, and Fung ‘781 and Stowasser, to arrive at instant claim 141. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-the combinations of Fung and Stowasser teach a method of treating lung fibrosis, and
-Cohen teaches coal workers pneumoconiosis as characterized by fibrosis.
As such, an ordinary skilled artisan would have been motivated to make such a selection, to predictably arrive at a method that treats the lung fibrosis in coal workers pneumoconiosis.
Claim 142 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 9,604,924 to Fung (IDS of 06/25/2024) in view of US 2019/0275032 to Stowasser (published 2019, PTO-892 of 03/10/2026), as applied to claims 1-2, 111, 123-126, 128-131, 133-140, and 143 above, and further in view of Herzog (Interstitial Lung Disease Associated with Systemic Sclerosis and Idiopathic Pulmonary Fibrosis, published 2014, PTO-892).
Claim 142 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 9,156,781 to Fung (IDS of 06/25/2024) in view of US 2019/0275032 to Stowasser (published 2019, PTO-892 of 03/10/2026), as applied to claims 1-2, 111, 123-126, 128-131, 133-140, and 143 above, and further in view of Herzog (Interstitial Lung Disease Associated with Systemic Sclerosis and Idiopathic Pulmonary Fibrosis, published 2014, PTO-892).
Fung ‘924 and Stowasser, and Fung ‘781 and Stowasser are applied as discussed above and incorporated herein.
While the combinations of a) Fung ‘924 and Stowasser, and b) Fung ‘781 and Stowasser teach treating lung fibrosis by administering compounds B4 and B4, it differs from that of the claim 141, in that it does not teach systemic sclerosis-interstitial lung disease as the fibrotic lung disease.
Herzog is applied as discussed above and incorporated herein.
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to select systemic sclerosis interstitial lung disease as the fibrotic lungs taught by the combinations of Fung and Stowasser, to arrive at instant claim 142. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-the combinations of Fung and Stowasser teach a method of treating lung fibrosis, and
-Herzog teaches systemic sclerosis associated interstitial lung disease as characterized by fibrosis.
As such, an ordinary skilled artisan would have been motivated to make such a selection, to predictably arrive at a method that treats the lung fibrosis in systemic sclerosis associated interstitial lung disease.
Response to Arguments
On pgs. 32-33, Remarks, Applicant argues that for the reasons stated in the arguments toward the 35 USC 103 rejections, the claims of ‘781 and ‘924, are distinguished from the instantly claimed invention.
These arguments have been fully addressed above. For the reasons stated above, these arguments are not persuasive to overcome the Double Patenting Rejections.
Conclusion
No claims are allowed.
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/LAUREN WELLS/Examiner, Art Unit 1622
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