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
This Office Action is in response to Applicant’s Arguments and Amendment filed, 01/06/2026, wherein the Amendment amended claims 1-2, 10-11, 41-42, 71, 111, cancelled claims 29, 32, and 36-37, and added claims 113-121.
Claims 1-3, 8-14, 19, 24, 41-42, 71, 111, and 113-121 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.
Claims 8 and 71 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and subject matter, there being no allowable generic or linking claim.
Claims 1-3, 9-14, 19, 24, 41-42, 111, and 113-121 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REJECTIONS WITHDRAWN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 amendments to the claims are sufficient to overcome these objections.
35 U.S.C. § 112(a)
On pgs. 25-27, Remarks, Applicant successfully argues that the instant specification demonstrates that compounds A1-A22 and B4-B5, decrease α-SMA (smooth muscle actin) levels, wherein a decrease in α-SMA is an indicator of lung health in reference to lung fibrosis. As such, Applicant’s arguments are successful to demonstrate that compounds A1-A22 and B4-B5 are enabled for a) a method of treating or ameliorating one more symptoms of fibrotic lung disease; b) a method of slowing the rate of decline in pulmonary function in a subject with fibrotic lung disease or slowing the progression of a fibrotic lung disease; and c) a method of inhibiting TFG-ß in a subject, by administering an antifibrotic agent and compound of formula (IA).
Applicant’s amendments to independent claims 1 and 2 that delete the term “preventing” from the preamble, and which amend the compound of formula (IA) to limit its scope, most particularly to X is -NH- and Y is -S(O)2, is sufficient to overcome this rejection over independent claims 1-2, and those claims which depend from them.
35 U.S.C. § 112(d)
Applicant’s amendments to claims 41-42 that modify the claims’ dependency from claim 2 to claim 1, is sufficient to overcome this rejection.
REJECTIONS—MAINTAINED, MODIFIED, & NEW
Applicant’s amendments to the claims and addition of claims 113-121, have resulted in the below new and modified rejections. The same prior art references continue to be relied upon in the 35 USC 103 rejections. PGPub US20190275032 to Stowasser is added to address the limitations of new claims 118-121.
Claim Objections
(New) Claim 115 is objected to because of the following informalities:
-In claim 115, in the definition of R’’, groupings of Markush group members are separated by Roman Numerals such as (i) and (ii), which is improper. The Roman Numerals should be deleted, and replaced with commas, and the “or” prior to “hydroxyl” and the “or” prior to (ii) in lines 1-2 should be deleted.
See MPEP 2173.05(h) for guidance on proper Markush language.
Appropriate correction is required.
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.
(Modified) Claim 111 is 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 a) a method of treating or ameliorating one more symptoms of fibrotic lung disease; b) a method of slowing the rate of decline in pulmonary function in a subject with fibrotic lung disease or slowing the progression of a fibrotic lung disease; and c) a method of inhibiting TFG-ß in a subject, by administering an antifibrotic agent and compound of formula (IA), wherein
X is NH, and
Y is S(O)2,
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.
Note: In claim 111, X is not limited to -NH-, and Y is not limited to -S(O)2-, though Applicant argues on pg. 23 Remarks, that 111 has been limited to X is -NY- and Y is -S(O)2-.
The criteria for enablement set out in the In re Wands, MPEP 2164.01(a), considers the following factors:
Breadth of the Claims
Independent claim 111 recites:
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Thus, the breadth of the claim is great.
Level of Skill in Art
The level of skill in the art is a clinician or an artisan with PhD.
State of the Prior Art
US 9,604,924 to Fung (published 2017, IDS of 06/25/2024) 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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, (Cols. 85-86, claim 22), and Fung specifically teaches lung fibrosis as a type of fibrosis.
However, Fung does not teach the compounds of instant formula (IA), wherein the instant R’’ position is other than -CF3, and does not exemplify any compound other than X is NH, Y is S(O)2, n is 2 or 3, R is alkyl, and R’ and R’’ are H, CH3, Cl, or Br.
Thus, the prior art does not teach compounds of instant formula (IA) for treating lung fibrosis, and the closest prior art structure for the treatment of lung fibrosis, only teaches compounds wherein the instant R’’ position is always -CF3, and only exemplifies compounds wherein X is NH, Y is S(O)2, n is 2 or 3, R is alkyl, and R’ and R’’ are H, CH3, Cl, or Br.
Cleveland Clinic (Pulmonary Fibrosis, PTO-892 of 10/06/2025) teaches that there is no cure for pulmonary fibrosis and that treatment focuses on easing symptoms, slowing down progression, and improving quality of life. Cleveland Clinic teaches antifibrotic medications, such as nintedanib and pirfenidone, for slowing down lung scarring and preserving lung function, corticosteroids to reduce inflammation, oxygen therapy to increase oxygen to a patient’s blood and tissues, pulmonary rehabilitation to increase lung strength, and lung transplant, as treatments for pulmonary fibrosis (pg. 6).
Thus, Cleveland Clinic only teaches two drugs, nintedanib and pirfenidone, as treating the disease, itself, and while Fung teaches compounds similar to the instantly claimed compounds for the treatment or amelioration of lung fibrosis, it does not teach the instantly claimed compounds.
Predictability in the Art
Terrie (A Review of the Treatment and Management of Idiopathic Pulmonary Fibrosis, published 2021, PTO-892 of 10/06/2025) teaches that idiopathic pulmonary fibrosis (IPF) is defined as an unpredictable, irreversible, progressive, and fatal lung disease developing from an unknown cause that affects the tissue surrounding the air sacs or alveoli (abstract). Terrie further teaches that since there is no cure for IPF, the goal is to preserve patient lung function, decrease progression of the disease, and improve overall health related quality of life for the patient. Terrie further teaches that there are only two approved therapies used to slow the progression of the disease (pg. 4).
In view of Terrie’s teachings and those of the prior art, treating pulmonary fibrosis is unpredictable, and there are only two approved treatments.
And as can be seen by the IC50 values for MDA-MB-468 cells, for the compounds of Fung, structurally similar compounds, having a core structure encompassed by instant formula (IA), have drastically different IC50 values.
As such, the method of treating lung fibrosis and the activity of compounds of formula (IA), is unpredictable.
Working Examples
The instant specification exemplifies the effects of compounds A1-A22, B4, and B5,
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, on smooth muscle actin levels in fibroblasts (pgs. 82-84, specification).
“Normal human lung fibroblasts were plated. . .The cells were incubated overnights. . .The cells were treated with a test compound in DMEM. . . α smooth muscle actin levels were determined by Western blot and normalized to ß tubulin levels” ([00274]-[00275]).
As can be seen in Tables 1 and 4, A18, A7, and A9 at 5µM increase α-SMA, thus appearing to have an adverse effect on lung fibrosis.
Regarding the examples directed toward compounds B4 and B5, it is noted that these compounds are outside of the scope of instant claims 2-3, 9-14, 19, 24 and 113-121.
Direction and Guidance
In view of the single example which is directed toward compounds A1-A21, B4, and B4, wherein three of the compounds appears to have an adverse effect on lung fibrosis at 5µM, the unpredictability of the treatment of lung fibrosis, and the unpredictability of the activity of compounds of formula (IA), the instant specification lacks sufficient direction and guidance to use the invention as instantly claimed.
Quantity of Experimentation
The amount of experimentation required to determine what amounts of which species of compounds of formula (IA) inhibit transforming growth factor-ß, would be astronomical. This amount of experimentation amounts to invention, not development; it is an undue amount of experimentation.
Thus, while being enabling for a) a method of treating or ameliorating one more symptoms of fibrotic lung disease; b) a method of slowing the rate of decline in pulmonary function in a subject with fibrotic lung disease or slowing the progression of a fibrotic lung disease; and c) a method of inhibiting TFG-ß in a subject, by administering an antifibrotic agent and compound of formula (IA), wherein
X is NH, and
Y is S(O)2,
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.
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.
(Slightly Modified) Claims 1, 41, 42, and 111 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 2006/0105995 to Fujimoto (published 2006, PTO-892 of 10/06/2025).
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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, (Cols. 85-86, claim 22), which is instant B5.
Fung specifically teaches lung fibrosis as a type of fibrosis 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).
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is instant compound B5, and meets the limitations of instant formula (IA) when:
n is 3
R is CH3 and C(CH3)3, a C1 alkyl and a C4 alkyl
Y is S(O)2
X is NH
R’ and R’’’ is H
R” is CF3, a C1 alkyl substituted with halo.
Regarding claims 1 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 an antifibrotic agent.
Fujimoto teaches TAFI inhibitors and their use in treating pulmonary fibrosis (abstract; pg. 30, claim 42). Fujimoto teaches that these compounds may also be combined and/or co/administered with other therapeutic agents ([0080]).
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 FAFI inhibitor of Fujimoto to the method of Fung, to arrive at instant claims 1 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:
-Fujimoto teaches combining treatments for pulmonary fibrosis,
-Fung teaches adding one or more additional active agents to its compositions (Col. 4, lines 5-16; 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 artisan would have been motivated to make such a combination to predictably arrive at a more therapeutically effective method of treating lung fibrosis.
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 41-42, Fung teaches B5.
(Slightly Modified) Claims 1-3, 9-14, 19, 24, 41-42, 111, and 113-117 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 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), Mitsos (Isosteres in Medicinal Chemistry, Group Meeting, published 2006, PTO-892 of 10/06/2025), and US 2006/0105995 to Fujimoto (published 2006, PTO-892 of 10/06/2025).
Fung and Fujimoto are applied to claims 1, 41, 42, and 111 as discussed above and incorporated herein.
Regarding claim 2, while Fung 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 R” as instantly claimed.
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 NH2, OH, 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 (C)(CH3)2, CF3, and OH as bioisosteres of common functional groups on phenyl rings (pg. 15).
Mitsos teaches CH3 and CF3 as isosteres in medicinal chemistry:
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(pg. 2).
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 modify the instant R’’ position in
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of Fung, by substituting the CF3 with -OH, -CH3, -C(CH3)2, or NH2, to arrive at instant formula (IA). One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
-Patani teaches NH2, OH, and CF3 as bioisosteres,
-Perry IBP teach C(CH3)2, CF3, and OH as bioisosteres,
-Mitsos teaches CH3 and CF3 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 substitutions, to predictably arrive at a safer and more clinically effective agent with increased activity.
Moreover, a prima facie case of obvious may be made when chemical compounds have very close structural similarities and similar utilities, MPEP 2114.09.
Further regarding claim 2, while the combination of Fung, Patani, Perry IBP, and Mitsos teaches a method of treating fibrotic lung disease by administering a compound of Formula (IA), it differs from that of instant claim 2, in that it does not teach additionally administering an antifibrotic agent.
Fujimoto teaches TAFI inhibitors and their use in treating pulmonary fibrosis (abstract; pg. 30, claim 42). Fujimoto teaches that these compounds may also be combined and/or co/administered with other therapeutic agents ([0080]).
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 FAFI inhibitor of Fujimoto to the combined method of Fung, Patani, Perry IBP, and Mitsos, to arrive at instant claim 2. One of ordinary skill in the art would have been motivated to make such an addition, with a reasonable expectation of success, because:
-Fujimoto teaches combining treatments for pulmonary fibrosis,
-Fung teaches additional one or more additional active agents to its compositions (Col. 4, lines 5-16; 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 artisan would have been motivated to make such a combination to predictably arrive at a more therapeutically effective method of treating lung fibrosis.
Specifically regarding claim 2, since the combination of Fung, Patani, Perry IBP, Mitsos, and Fujimoto treat 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.
Regarding claims 3, 9-14, 19, 24, 113-117 the combination of Fung, Patani, Perry IBP, Mitsos, and Fujimoto teaches:
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, and
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.
(New) Claims 2-3, 9-14, 19, 24, and 113-121 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 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), Mitsos (Isosteres in Medicinal Chemistry, Group Meeting, published 2006, PTO-892 of 10/06/2025), and US 2019/0275032 to Stowasser (published 2019, PTO-892).
Fung, Patani, Perry IBP, and Mitosis are applied to claims 2-3, 9-14, 19, 24, and 113-117, as discussed above and incorporated herein.
Further regarding claim 2, and claims 118, and 120-121 while the combination of Fung, Patani, Perry IBP, and Mitsos teaches a method of treating fibrotic lung disease by administering a compound of instant formula (IA), it differs from that of instant claim 2, in that it does not teach additionally administering 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 combined method of Fung, Patani, Perry IBP, and Mitsos, to arrive at instant claims 2, 118, and 120-121. 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, Patani, Perry IBP, Mitsos, and Stowasser treat 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.
Regarding claim 119, Stowasser teaches nintedanib monoethanesulphonate as the salt form of nintedanib (pg. 5, claim 4).
Response to Arguments
On pg. 24, Remarks, Applicant outlines the requirements for prima facie obviousness rejections, and outlines the importance of unexpected results to rebut a prima facie obviousness rejection.
On pg. 25, Remarks, regarding the rejection of Fung in view of Fujimoto, Applicant argues that a prima facie case of obviousness has not been established because the combination of references do not arrive at a compound of formula (IA) acting synergistically with an antifibrotic agent in reducing an α-SMA level. Applicant further argues that there is no reasonable expectation of success.
This argument has been fully considered, but is not found persuasive. It is respectfully pointed out that none of the claims recite “synergism” or “reducing an α-SMA level.” And for the reasons discussed below, Applicant’s data is not sufficient to show an unexpected result of synergism.
On pgs. 25-26, Remarks, Applicant argues, that the instant application discloses compounds A18, B4, and B5 as acting synergistically with antifibrotic agent nintedanib and/or pirfenidone in reducing α-SMA levels. Applicant additionally argues that in Table 4, on pg. 84, the instant application also discloses compounds A1 to A22 as reducing α-SMA levels.
These arguments have been fully considered, but are not found persuasive.
Applicant is respectfully reminded that unexpected results a) are greater than expected results, b) show superiority of a property shared with the prior art, c) exhibit the presence of an unexpected property, and/or d) exhibit the absence of an expected property. MPEP 716.02 additionally states that unexpected results must be commensurate in scope with the claimed invention and provide a comparison with the closest prior art.
Compound A1-A22 and B4-B5 meet the limitations of the instantly claimed compound of formula (IA) when:
Compound
R
n
R’’
R’
R’’’
X
Y
A1
C(H)(CH3)3
3
CH3
H
H
NH
S(O)2
A2
C(H)(CH3)3
3
C(O)OCH3
H
H
NH
S(O)2
A3
C(H)(CH3)3
3
C(O)OH
H
H
NH
S(O)2
A4
C(H)(CH3)3
3
C(O)NHnBu
H
H
NH
S(O)2
A5
C(H)(CH3)3
3
NHBoc
H
H
NH
S(O)2
A6
C(H)(CH3)3
3
NH2
H
H
NH
S(O)2
A7
C(H)(CH3)3
3
NHC(O)CH3
H
H
NH
S(O)2
A8
C(H)(CH3)3
3
N(Et)2
H
H
NH
S(O)2
A9
Me
C(CH3)3
3
O(CH2)3CN
H
H
NH
S(O)2
A10
Me
C(CH3)3
3
O(CH2)4NH2
H
H
NH
S(O)2
A11
CH(CH3)2
3
O(CH2)4NH2
H
H
NH
S(O)2
A12
Me
C(CH3)3
3
O(CH2)2N(CH3)2
H
H
NH
S(O)2
A13
Me
C(CH3)3
3
(CH2)3N(CH3)2
H
H
NH
S(O)2
A14
Me
C(CH3)3
3
(CH2)3-morpholine
H
H
NH
S(O)2
A15
Me
C(CH3)3
3
Piperidine ring
H
H
NH
S(O)2
A16
Me
C(CH3)3
3
Br
H
H
NH
S(O)2
A17
Me
C(CH3)3
3
OCH3
H
H
NH
S(O)2
A18
Me
C(CH3)3
3
OH
H
H
NH
S(O)2
A19
CH(CH3)2
3
OCH3
CH3
H
NH
S(O)2
A20
CH(CH3)2
3
OH
CH3
H
NH
S(O)2
A21
CH(CH3)2
3
Br
H
CH3
NH
S(O)2
A22
Me
C(CH3)3
3
Piperidine
H
H
NH
S(O)2
B4
CH(CH3)2
3
CF3
CH3
H
NH
S(O)2
B5
Me
C(CH3)3
3
CF3
H
H
NH
S(O)2
Regarding these compounds and Tables 1-4, the following is noted:
-Compounds B4 and B5 are outside of the scope of instant claims 2-3, 9-14, 19, 24, and 113-121,
-compounds A4, A6, A7, A9 and A18, at 5µM, increase α-SMA, thus having no effect on fibrosis or having a pro-fibrotic effect (Table 1), and
-pirfenidone, as recited in instant claims 120 and 121, increases α -SMA, thus having no effect on fibrosis or having a pro-fibrotic effect (Tables 1 and 3).
The data on pgs. 82-84 of the specification is not commensurate in scope with the instantly claimed methods. As seen from the above chart, the scope of the compounds of Formula (IA) is much greater than the scope of tested compounds. Additionally, the effectiveness of the compounds vary in a dose-dependent manner, such that some of the tested compounds at a 5µM concentration demonstrate a pro-fibrotic effect, i.e., an increase in α-SMA levels, which is contrary to Applicant’s arguments that the combination of instant compounds of formula (IA) and nintedanib or pirfenidone, synergistically reducing α-SMA levels. Moreover, independent claims 1, 2, and 111, recite “a therapeutically effective amount of an antifibrotic agent,” and are not limited to either nintedanib or pirfenidone.
Table 2 demonstrates the effectiveness of a single antifibrotic agent, nintedanib, on B4 at concentrations of 2, 5, or 10µM, and nintedanib at a concentration of 5µM. Table 2 only shows a synergistic effect when 5µM nintedanib is combined 2µM B4. The combination of N(5µM) + B4 (5µM or 10µM) shows no synergistic effect, though N(5µM) + B4 (5µM) does appear to show an additive effect. Table 2 does not provide additional results on the effect of B4 with pirfenidone or any other antifibrotic agent.
Table 2 demonstrates the effectiveness of nintedanib or pirfenidone, on B4 at concentrations of 2, 5, or 10µM, and nintedanib at a concentration of 5µM and pirfenidone at a concentration of 200 µM. While a few combinations do show a synergistic effect, the combination of N(5µM) + B5 (20µM) and P(200µM) + B5(20µM), do not show a synergistic effect.
Thus, the amounts of the tested compounds in combination with nintedanib or pirfenidone appear to be critical to the synergistic effect on α -SMA levels. And as discussed above, compounds B4 and B5 are outside of the scope of instant claims 2-3, 9-14, 19, 24, and 113-121
Regarding Table 4, it is respectfully pointed out that no comparison with the closest prior art, i.e., Fung, is provided. As such, it is not known if the instantly claimed compounds have an unexpected effect on α-SMA levels in comparison to the compounds of Fung.
For these reasons, the data provided on pgs. 82-84 of the Specification is not persuasive to overcome the instant rejections.
On pg. 26, Remarks, Applicant argues that “Fujimoto fails to disclose a single biological data for TAFI inhibitors of Formula (I) disclosed therein to substantiate their useful in treating any disease including a fibrotic lung disease and inhibiting any biological target including TGF-ß.
This argument has been fully considered, but is not found persuasive. Applicant is respectfully reminded that the arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965). Examples of attorney statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the inventor or at least one joint inventor. See MPEP 716.01(c).
As discussed in the above rejection, Fujimoto teaches TAFI inhibitors and their use in treating pulmonary fibrosis (abstract; pg. 30, claim 42). Applicant has provided no evidence that the invention of Fujimoto is inoperable.
Regarding TGF-ß, as discussed above, 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.
On pg. 27, Remarks, Applicant additionally argues that there is no reasonable expectation of success because of the highly unpredictable nature of the chemical art.
This argument has been fully considered, but is not found persuasive. Applicant is respectfully reminded that obviousness does not require absolute predictability, but a reasonable expectation of success (MPEP 2143.02). As discussed in the above rejection:
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 FAFI inhibitor of Fujimoto to the method of Fung, to arrive at instant claims 1 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:
-Fujimoto teaches combining treatments for pulmonary fibrosis,
-Fung teaches adding one or more additional active agents to its compositions (Col. 4, lines 5-16; 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 artisan would have been motivated to make such a combination to predictably arrive at a more therapeutically effective method of treating lung fibrosis.
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 the rejection over Fung in view of Patani, Perry, Mitsos, and Fujimoto, Applicant argues that on pgs. 29-30, Remarks, Perry and Meanwell teach that bioisosteres are unpredictable.
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, 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. Regarding the reference to Tables 19 and 22 of Meanwell, in the Remarks, it is respectfully pointed out that Table 19 is “substituting a CH3 by CF3,” wherein the replacement is effective and both compounds are shown to be effective NK1 antagonists, while Table 22 is “Structure Activity Relationships Associated with Variation of the Alkyl Chain Terminus in a Series of MMP-9 Inhibitors,” wherein H or OCH3 is substituted with CH3 or CF3. Thus, Table 22 does not replace a CH3 group with a CF3 group, or replace a CF3 group with a CH3 group. Further, Mitsos and Patani teach CH3 and CF3 as isosteres in medicinal chemistry (see above rejection). 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 NH2, OH, and CF3 as known bioisosteres,
-Perry IBP teach C(CH3)2, CF3, and OH as known bioisosteres, and
-Mitsos teaches CH3 and CF3 as known bioisosteres.
And as discussed above, Patani and Perry IBP all teach that bioisosteric replacement is well known in the art and is beneficial for the medicinal chemist to arrive at compounds with increased activity, to provide specific insights into structure-function activity, and to improve or alter physico-chemical properties of lead compounds.
And as discussed above, 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 bioisosteres known in the art would lead to compounds that are safer and 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.
On pgs. 31-32, Remarks, regarding the arguments over Fujimoto and unexpected results, these arguments have been fully addressed above in reference to the response to arguments of Fung in view of Fujimoto.
For these reasons, Applicant’s arguments are not persuasive 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.
(Modified) Claims 1-3, 9-14, 19, 24, 29, 41-42, 111, and 113-121 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 Patani (Bioisosterism: A Rational Approach in Drug Design, Chem. Rev. published 1996, PTO-892 of 10/06/2025), Stephan (IBP Group Meeting 2019 PDF Unlayered from J. Med. Chem. 2012, 55, published 2019, PTO-892 of 10/06/2025), Mitsos (Isosteres in Medicinal Chemistry, Group Meeting, published 2006, PTO-892 of 10/06/2025), and US 2006/0105995 to US 2019/0275032 to Stowasser (published 2019, PTO-892).
Fung claims a compound of
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(claims 1-23), and specifically claims compounds such as
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(claim 24), 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]).
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meets the limitations of instant formula (I) when:
n is 3
R is CH3 and C(CH3)3, a C1 alkyl and a C4 alkyl
Y is S(O)2
X is NH
R’ and R’’’ is H.
Fung claims the compound in a composition comprising one or more additional active agents (claims 25-26).
Fung teaches its compounds for the treatment of lung fibrosis (Col. 47, lines 22-25)
Fung specifically teaches its compounds as inhibiting α -smooth muscle actin in normal human lung fibroblasts (Col. 4, lines 55-61).
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 claim 2, while Fung claims 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 claim instant R’’.
Patani, Perry IPM, and Mitsos, 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 modify the instant R’’ position in
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of Fung, by substituting the CF3 for -OH, -CH3, -C(CH3)2, or NH2, to arrive at instant formula (I). One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
-Patani teaches NH2, OH, and CF3 as bioisosteres,
-Perry IBP teach C(CH3)2, CF3, and OH as bioisosteres,
-Mitsos teaches CH3 and CF3 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 agent, 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 substitutions, to predictably arrive at a safer and more clinically effective agent with increased activity.
Moreover, a prima facie case of obvious may be made when chemical compounds have very close structural similarities and similar utilities, MPEP 2114.09.
Regarding claims 1 and 111, and further regarding claim 2, while Fung, and the combination of Fung, Patani, Perry IBP, and Mitsos respectively, teaches a method of treating fibrotic lung disease, it differs from that of instant claim 1-2, and 111 in that it does not claim the additionally active agent as an antifibrotic agent.
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 combined method of Fung, Patani, Perry IBP, and Mitsos, to arrive at instant claims 1-2, 111, 118, and 120-121. 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. 84, claim 26);
-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 (Col. 2, line 61-Col. 3, line 34),
-Stowasser teaches nintedanib as inhibiting PDGFRα 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 artisan would have been motivated to make such a combination to predictably arrive at a more therapeutically effective method of treating lung fibrosis.
Specifically regarding claim 2, since the combination of Fung, Patani, Perry IBP, Mitsos, and Stowasser treat 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 Stowasser 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.
(Modified) Claims 1-3, 9-14, 19, 24, 41-42, 111, and 113-121 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 9,604,924 to Fung (published 2017, IDS of 06/25/2024) in view of Patani (Bioisosterism: A Rational Approach in Drug Design, Chem. Rev. published 1996, PTO-892 of 10/06/2025), Stephan (IBP Group Meeting 2019 PDF Unlayered from J. Med. Chem. 2012, 55, published 2019, PTO-892 of 10/06/2025), Mitsos (Isosteres in Medicinal Chemistry, Group Meeting, published 2006, PTO-892 of 10/06/2025), and US 2019/0275032 to Stowasser (published 2019, PTO-892).
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 compounds such as
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(claim 24), 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]).
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meets the limitations of instant formula (I) when:
n is 3
R is CH3 and C(CH3)3, a C1 alkyl and a C4 alkyl
Y is S(O)2
X is NH
R’ and R’’’ is H.
Fung defines fibrosis as including lung fibrosis (Col. 43, lines 41-48). As such, an ordinary skilled artisan would have been motivated to select lung fibrosis as the fibrosis since Fung teaches lung fibrosis as a type of fibrosis to be treated by its methods.
Regarding claim 2, while Fung claims 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 claim instant R’’.
Patani, Perry IPM, and Mitsos 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 modify the instant R’’ position in
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of Fung, by substituting the CF3 for -OH, -CH3, -C(CH3)2, or NH2, to arrive at instant formula (I). One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
-Patani teaches NH2, OH, and CF3 as bioisosteres,
-Perry IBP teach C(CH3)2, CF3, and OH as bioisosteres,
-Mitsos teaches CH3 and CF3 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 agent, 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 substitutions, to predictably arrive at a safer and more clinically effective agent with increased activity.
Moreover, a prima facie case of obvious may be made when chemical compounds have very close structural similarities and similar utilities, MPEP 2114.09.
Regarding claims 1 and 111, and further regarding claim 2, while the combination of Fung, Patani, Perry IBP, and Mitsos teaches a method of treating fibrotic lung disease, it differs from that of instant claims 1-2, and 111, in that it does not claim the additionally active agent as an antifibrotic agent.
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 FAFI inhibitor of Fujimoto to the combined method of Fung, Patani, Perry IBP, and Mitsos, to arrive at instant claims 1-2, 111, and 118-121. One of ordinary skill in the art would have been motivated to make such an addition, with a reasonable expectation of success, because:
-Stowasser and Fung teaches methods of treating pulmonary fibrosis,
-Fung teaches administering additional active agents (Col. 58, lines 27-36), 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 artisan would have been motivated to make such a combination to predictably arrive at a more therapeutically effective method for treating lung fibrosis.
Specifically regarding claim 2, since the combination of Fung, Patani, Perry IBP, Mitsos, and Fujimoto treat 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 Stowasser 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.
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.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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//LAUREN WELLS/ Examiner, Art Unit 1622