DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The instant application, filed 4/26/2023, is a continuation of International Application No. PCT/US2021/057048, filed 10/28/2021, which claims the benefit of priority to U.S. Provisional Patent Application No. 63/106,725, filed on 10/28/2020.
Information Disclosure Statement
The Information Disclosure Statement filed on 04/26/2023, is acknowledged and found to be in compliance with the provisions of 37 CFR § 1.97. Accordingly, the Information Disclosure Statement has been considered.
Application History
Claims 1-35 were originally presented on 04/26/2023. The preliminary amendments to the claims, also filed on 04/26/2023, were received and entered. Claims 2-29 were cancelled. Claims 1 and 30-35 were pending.
An Election/Restriction requirement was mailed on 10/09/2025, and a response was filed on 02/09/2026. In the response, Applicant added claims 36-38.
Accordingly, claims 1 and 30-38 are pending.
Election/Restriction
Claims 1 and 30-35 were subject to a restriction/election requirement dated 10/09/2025. Newly added claims 36-38 are subject to this requirement. Applicant’s election of “the compound of Example 8, i.e., N-(4-hydroxynaphthalen1-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide, without traverse”, in the reply filed on 02/09/2026 is acknowledged.
Applicant states that the elected compound appears in the Specification at 25, and has the following structure:
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Elected species/compound, or Ex. 8 compound.
Applicant further states that pending claims 1 and 30-37 read on the elected compound.
Applicant is correct that the elected compound is recited by name in claims 1 (5th compound recited), and claim 37 (first compound recited). Further, it is a species of the Markush grouping in claim 36, in view of Applicant adding the limitation “oxo” for the substituent R5 for formula (I). The “oxo” limitation for the substituent R5 is not recited in the “formula (I)” of claim 1.
If the elected species is not anticipated by or obvious over the prior art, the examiner will extend the search and examination to a non-elected species or group of species that falls within the scope of a proper Markush grouping that includes the elected species. A proper Markush grouping that includes the elected species requires single structural similarity and common use. Accordingly, the proper Markush grouping that includes the elected species requires that the chemicals all bear what the examiner will refer to as the “N-(4-Hydroxy-1-naphthalenyl)-sulfonamide moiety” and the “benzimidazolone moiety”, as indicated below. In other words, the compounds must be built from the below chemical scaffold.
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Proper Markush grouping that includes the elected species
Status of Claims
Claims 1 and 30-38 are pending. Claim 38 is withdrawn from further consideration pursuant to 37 CFR § 1.142(b), as being drawn to a non-elected invention and species. Therefore, claims 1 and 30-37 read on an elected invention and species and are therefore under consideration in the instant application.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1 and 30-35 Indefinite – Improper Markush Grouping
Claim 1 and 30-35 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of the compounds recited in claim 1 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
First, claim 1 recites:
A method of treating cystic fibrosis, the method comprising administering to a subject in need of such treatment one or more compounds selected from
[ forty named compounds of different chemical structures ]
and
one or more compounds of formula (I):
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wherein,
[n, R1, R2, R3, R4, R5, R6, R7 variables recited];
and, pharmaceutically acceptable salts thereof.
Second, the forty named compounds, in the order recited in claim 1, correspond to example numbers, 10, 9, 12, 13, 8, 36, 37, 38, 39, 1, 2, 3, 4, 5, 6, 7, 9, 11, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, and 35 (compound 9 is indeed recited twice, (alutenusin)).
Third, Alternatives are not All Members of the Same Recognized Physical or Chemical Class or the same Art-recognized Class
“A recognized physical class, a recognized chemical class, or an art-recognized class is a class wherein there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. In other words, each member could be substituted one for the other, with the expectation that the same intended result would be achieved.” See MPEP 2117(II)(A).
The examiner grouped the forty named compounds according to their disclosed activity towards both CALP and Dab2, or only CALP, or only Dab2, see following pages. The examiner notes that compound 37 has no activity reported (see, e.g., Figure 1).
Therefore, as disclosed from Applicant’s experiments, there are four distinct art-recognized scientific classes: dual CALP and Dab2 inhibitors, sole CALP inhibitors, sole Dab2 inhibitors, and compounds with no disclosed activity. One would not expect that, by substituting an inhibitor of only CALP, with an inhibitor of only Dab2, one could inhibit CALP.
Moreover, the claims are drawn to administration of these compounds to humans. Among these forty named compounds, they vary from antibiotics like Naphthomycin B (compound 15), to plant extracts like Wedelolactone (compound 7), to proton pump inhibitors like tenatoprazole (compound 11), all of distinctly different structures. One would not expect, that by administering tenatoprazole instead of Naphthomycin B to patients, one would achieve the same intended result of inhibiting only CALP. See MPEP 2117(II)(A), discussing an example of interchangeable snaps and buckles. That example is very relevant here, because one would not expect that administering these alternative compounds would achieve the same result in cystic fibrosis patients.
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Napthomycin B
Disclosed CALP inhibitor,
art recognized antibiotic
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Wedelolactone,
disclosed CALP inhibitor,
art recognized plant extract
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Tenatoprazole
Disclosed Dab2 inhibitor,
art recognized proton pump inhibitor
Fourth, No Common Substantial Structural Feature and Common Use that Flows
Among these forty named compounds, there is very clearly, no common substantial structural feature. This is seen by looking at the structure of compound 15, i.e., Naphthomycin B. Naphthomycin B, as discussed, is an antibiotic isolated from Streptomyces sp. Naphthomycin B has no common substantial structural feature with compounds 7, 8, 38, 16, 36, and 39, despite having a “common use” of being able to inhibit only CALP.
Further, consider compound 7, which as discussed, is Wedelolactone. Wedelolactone is a coumestan extracted from plants. As shown below, Napthomycin B (compound 15) is not a coumestan, and neither are compounds 8, 38, 16, 36, or 39:
Inhibitors of only CALP
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Wedelolactone, bearing a coumestan structural motif
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And neither are any of the remaining compounds coumestans.
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No activity reported:
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As discussed above, the compounds may be grouped into what appears to be four broad categories, inhibitors of both CALP and Dab2, or only CALP, or only Dab2, or no disclosed use. Further, among each category, there are many subcategories of use of these compounds. The claims are drawn to administering these compounds to humans. The compounds claimed have entirely disparate activities in the human body. Napthomycin B and Tenatoprazole were given as simple examples. Further consider (S)-apomorphine hydrochloride (compound 12), a dopamine agonist, or propidium bromide (compound 29), used in fluorescence microscopy to stain nuclei. And then there are all of the compounds encompassed by formula (I), which encompasses massive breadth, and is supported by two compounds, 40 and 41, that inhibit only CALP (see Figure 1), and perhaps the N-(4-Hydroxy-1-naphthalenyl)-sulfonamide moiety of compounds like 8.
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The permitted variables for formula (I) are shown below. Given the variability shown in Applicant’s own data from forty diverse structures, single structural similarity and common use that might flow from the N-(4-Hydroxy-1-naphthalenyl)-sulfonamide moiety does not suggest that the breadth formula (I) are all just CALP inhibitors (see, e.g., R4 variable and breadth of R5).
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A proper Markush grouping is the one indicated in the Election/Restriction portion of this office action, reproduced below:
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Proper Markush grouping that includes the elected species
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Rejection Statement
Claim(s) 1 and 30-36 is/are rejected under both 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by US’933.1
Representative Claim
Claim 1 recites “A method of treating cystic fibrosis, the method comprising administering to a subject in need of such treatment one or more compounds selected from: the elected species compound
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Elected species/compound, or Ex. 8 compound, and
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Instant claim 1.
Claims 1 and 30-36 Anticipated by US’933
Regarding claims 1 and 36, US’933 teaches a method of treating fibrosis, including cystic fibrosis, the method comprising administering to a subject in need of such treatment one or more compounds of formula (I).
For example, US’933 discloses STAT3 inhibitors useful for treating fibrosis, including cystic fibrosis, see US’933 at page 58, last paragraph on col. 15, and methods for treating such patients using such compounds, see claim 1, page 206, col. 312.
As US’933 explains, its compounds prevent IL-6 signaling through STAT3, and that administration of its compounds “decreased fibrotic endpoints”. See US’933 at 51, background of the invention, and at 57, col. 14 (“C-188-9 administration decreased fibrotic endpoints”). See also, US’933 at cols. 14-15, under section III. Fibrosis (“Embodiments of the invention concern methods of treatment and/or prevention of any kind of fibrosis.”) (emphasis added).
Many/most of the compounds incorporate the N-(4-Hydroxy-1-naphthalenyl)-sulfonamide moiety. See US’933 at Example 10, beginning at col. 38, page 69. This scaffold/structural motif was therefore well known in the art at the time of filing to be a therapeutic target for developers of drugs seeking to treat fibrosis, including cystic fibrosis.
The compounds of US’933 accommodate a number of different substituents because the N-(4-Hydroxy-1-naphthalenyl)-sulfonamide moiety was found to effectively bind its target. See, e.g., Fig. 12, depicting an embodiment of the invention further described in US’933 at col. 4, page 52, shown below on the left and compared to the instant, non-elected compound 39 (right), which has the identical thioether functionalization.
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See also, Figures 16 and 17 (showing ways to make more STAT3 inhibitors useful for treating fibrosis, including cystic fibrosis).
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Accordingly, regarding claims 1 and 36, US’933 teaches a method of treating fibrosis, including cystic fibrosis, the method comprising administering to a subject in need of such treatment one or more compounds of formula (I).
Therefore, claims 1 and 36 are anticipated by US’933.
Regarding claim 30, US’933 explains how to formulate its compounds into pharmaceutical compositions. See US’933 at Title, and at pages 61-63, cols. 22-25. Pharmaceutically acceptable carriers are explicitly taught at the beginning of column 23.
Accordingly, claim 30 is anticipated by US’933.
Regarding claims 31 and 33, the Specification does not set forth a required definition for the term a “secondary therapeutic agent”, but explains that such secondary therapeutic agent includes agents like antibiotics, anti-inflammatory agents, mucoactive agents, and the like. However, regarding claim 33, it depends from claim 31, and recites that the secondary agent may be an antibiotic.
US’933 discloses that its compounds may be administered in combination therapies. See, e.g., US’933 at cols. 21-22, page 61, including with antibiotics, col. 22, lines 60-63.
Accordingly, claims 31 and 33 are anticipated by US’933.
Regarding claim 32, it depends from claim 31, and recites that the secondary agent is a CFTR modulator.
US’933 at col. 21, page 61, teaches with respect to combination therapies, “It is an aspect of this invention that a composition as disclosed herein is used in combination with another agent or therapy method, such as another fibrosis treatment.”
Further, regarding cystic fibrosis treatments, US’933 at cols. 15-16, page 58, teaches “Management of CF symptoms include intravenous, inhaled, and oral antibiotics; transplants; medications and/or mechanical techniques to dislodge and expectorate sputum, and so forth. Composition(s) of the invention may be utilized in conjuction with such management regimen(s).”
Accordingly, US’933 teaches combination therapies with “management regimen(s)” used for treating patients with cystic fibrosis. Such “management regimen(s)” encompass a CFTR modulator.
Accordingly claim 32 is anticipated by US’933.
Regarding claims 34 and 35, they both recite an intended use of administering a compound of claim 1, by carving out patient populations. Functionally, the claims just require administration of a compound of claim 1 to patients. US’933 teaches administration of one or more compounds of formula (I) to patients with fibrosis, including cystic fibrosis. Accordingly, claims 34 and 35 are anticipated by US’933.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
Rejection Statements
Claims 1 and 30-37 are rejected under 35 U.S.C. 103 as being unpatentable over US’933,2 in view of PubChem SID 1117633103 and Patani 1996.4
Claims 32 and 34 are rejected under 35 U.S.C. 103 as being unpatentable over US’933 in view of Patani 1996 and WO’263.5
Claim 35 is rejected under 35 U.S.C. 103 as being unpatentable over US’933 in view of Patani 1996 and WO’413.6
Discussion of the Invention and Relevant Background
The instant claims are drawn to Applicant’s discovery that the elected compound and its derivatives inhibit CALP. Applicant explains that inhibiting CALP may provide a therapeutic benefit to patients with cystic fibrosis by increasing the abundance of the transmembrane ion channel protein CFTR at the cell membrane, and thus restore proper fluid flow and ion balance in epithetical tissues. See Specification at 1-2, Technical Background.
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Elected species/compound, or Ex. 8 compound.
Specification at 35-36 explains that the elected example 8 compound was found to covalently modify CAL PDZ, i.e., CALP, in certain conditions, and hypothesize the following mechanism:
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Specification at 35.
US’933 is the closest prior art to Applicant’s claimed discovery.
As background to US’933, it discloses the compound C-188-9, also known as TTI-101. At the time of filing, clinical trials for C-188-9 were already ongoing to assess its viability in humans. See, e.g., clinical trial No. NCT03195699.
Claims 1 and 30-37 were Obvious over US’933 in view of PubChem SID 111763310 and Patani 1996
The findings of fact in the rejections of claims 1 and 30-36 under both 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by US’933 are incorporated herein.
Regarding claims 1, 36, and 37, drawn specifically to the elected compound, while US’933 does not expressly teach the elected compound, it teaches compounds bearing, what the examiner will refer to as a “N-(4-Hydroxy-1-naphthalenyl)-sulfonamide moiety” linked to an “oxindole moiety”, such as the one depicted below on the left and designated F5749-0350, at col 293, page 197, hereinafter “the US’933 compound”. See also, the following compounds in the footnote bearing the same “oxindole moiety”, but with further functionalization about the “N-(4-Hydroxy-1-naphthalenyl)-sulfonamide moiety”.7
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F5749-0350 / The US’933 compound
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Elected Compound
The elected compound differs from the US’933 compound by a single ring nitrogen, and a single chlorine atom. The chlorine atom is located at the specific location Applicant also functionalizes, as noted in the above rejections under 35 USC 102.
One of ordinary skill in the art at the time of filing seeking to design and use additional STAT3 inhibitors for treating fibrosis, including cystic fibrosis, without clearly infringing the claims of a valid US patent, would be motivated to design around the STAT3 inhibitors of US’933.
Accordingly, in view of the analogous “oxindole” compounds in US’933 cols. 69, 155, 193, and 248, one of ordinary skill in the art at the time of filing would envisage a chemical scaffold of STAT3 inhibitors useful for treating cystic fibrosis, based off the N-(4-Hydroxy-1-naphthalenyl)-sulfonamide moiety, covalently linked to the oxindole moiety, wherein C3 of the 4-Hydroxy-1-naphthalenyl group was a target for further functionalization, such as the one depicted below:
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US’933 oxindole Scaffold
While functionalization at C3 of the 4-Hydroxy-1-naphthalenyl group enhanced potency, see FIGs. 16 and 17, the group III compounds lacking polar functionalization at C3 still inhibited STAT3, and were thus useful for its methods of treating fibrosis, including cystic fibrosis (see US’933 at 207, claim 1, and at col. 15, page 58, and at col. 4, lines 53-59).
As such, the examiner finds that US’933 teaches the compound depicted by the above US’933 oxindole Scaffold, and teaches that the compound itself may be used in a method for treating cystic fibrosis. The difference between the US’933 oxindole Scaffold and the elected compound is a single ring nitrogen. Alternatively stated, the difference is between a “oxindole” moiety and a “benzimidazolone” moiety.
Now, further see US’933 at 67-68, cols. 33-34, wherein the inventors discuss in detail how to modify the compounds of their invention. The very first step in developing one of their STAT3 inhibitors is the selection of a sulfonyl chloride used to bind to the N-(4-Hydroxy-1-naphthalenyl)-sulfonamide moiety. See US’933 at col. 34, first paragraph. Here, the inventors state that such sulfonyl chlorides are “commercially available”, and “can be designed and synthesized and tested in an iterative manner until optimization of this modification.” US’933 a col. 34 (first paragraph). The inventors characterize this reaction as being “readily made in a simple two step reaction”.
Therefore, US’933 further teaches that, if the corresponding sulfonyl chloride required to form the elected species compound was commercially available at the time of filing, that by iterating over the course of commercially available sulfonyl chlorides to optimize activity, one of ordinary skill in the art at the time of filing would have a reasonable expectation of success in arriving at the elected species compound.
US’933 does not appear to expressly teach that the corresponding sulfonyl chloride used to obtain the elected species compound was commercially available at the time of filing, nor does it appear to expressly teach its bioequivalence between the “oxindole” moiety and the “benzimidazolone” moiety.
However, PubChem SID 111763310 teaches that the corresponding sulfonyl chloride was commercially available at the time of filing: See PubChem SID 111763310:
PubChem SID 111763310
See PubChem SID 111763310 (evidencing that the corresponding “2-oxo-1,3-dihydrobenzimidazole-5-sulfonyl chloride” was commercially available from the Chemical Vendor “ABI Chem" at least by 2011-03-08):
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Corresponding sulfonyl chloride to form the elected species
Moreover, Patani 1996 teaches that CH2 and NH are classical bioisosteres, and therefore one would reasonably expect bioequivalence between the “oxindole” moiety and the “benzimidazolone” moiety. See Patani 1996:
Patani 1996
See Patani 1996 at 3148-3149, teaching bioisosterism as a rational approach in drug design, and explaining that Grimm’s Hydride Displacement Law sets forth a series of classical bioisosteres:
The widespread application of the concept of isosterism to modify biological activity has given rise to the term bioisosterism. As initially defined by Friedman,2 bioisosteres were to include all atoms and molecules which fit the broadest definition for isosteres and have a similar type of biological activity, which may even be antagonistic. More recently this definition has been broadened by Burger as “Compounds or groups that possess near-equal molecular shapes and volumes, approximately the same distribution of electrons, and which exhibit similar physical properties...”.5 The critical component for bioisosterism is that bioisosteres affect the same pharmacological target as agonists or antagonists and, thereby, have biological properties which are related to each other.
Bioisosteres have been classified as either classical or nonclassical. 12 Grimm's Hydride Displacement Law and Erlenmeyer's definition of isosteres outline a series of replacements which have been referred to as classical bioisosteres.
Patani 1996 at 3148-3149.
See also Patani 1996 at 3148 (discussing Grimm’s classical bioisosteres, and note that NH and CH2 are in a column):
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Patani 1996 at 3148.
See also, Patani 1996 at 3158-3159 (providing a SAR, wherein a “oxindole” moiety and a “benzimidazolone” moiety were exchanged (compounds 52b and 52c):
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Patani 1996 at 3158-3159.
Accordingly, one of ordinary skill in the art at the time of filing would be motivated to select a benzimidazolone moiety, because
administering such a compound would not clearly infringe the patented methods of US’933,
it would be have been easy to synthesize from a commercially available sulfonyl chloride, and
one would reasonably expect bioequivalence between the “oxindole” moiety and the “benzimidazolone” moiety.
Therefore, the examiner finds that one of ordinary skill in the art at the time of filing would have a reasonable expectation of success synthesizing the elected species compound, because PubChem SID 111763310 teaches that the corresponding “2-oxo-1,3-dihydrobenzimidazole-5-sulfonyl chloride” was commercially available from the Chemical Vendor “ABI Chem" at least by 2011-03-08.
Further, the examiner finds that one having ordinary skill in the art at the time of filing would have a reasonable expectation of success using the elected species compound for treating cystic fibrosis, because Patani 1996 teaches that NH and CH2 were known bioisosteric equivalents, and therefore one would reasonably expect bioequivalence between the “oxindole” moiety and the “benzimidazolone” moiety. Therefore, one of ordinary skill in the art would reasonably expect that the elected species compound, when administered, would be effective for treating cystic fibrosis, as taught for its “oxindole” equivalent in US’933.
Any added benefit imparted from being able to functionalize the nitrogens of the benzimidazolone moiety, or tune the solubility or pharmacokinetics/pharmacodynamics of the drug substance, would have been clear driving factor to an ordinary chemist at the time of filing.
Accordingly, claims 1, 36, and 37 were obvious at the time of filing.
Regarding claim 30, US’933 explains how to formulate its compounds into pharmaceutical compositions. See US’933 at Title, and at pages 61-63, cols. 22-25.
One of ordinary skill in the art at the time of filing would have a reasonable expectation of success in utilizing the instructions of US’933 to obtain the subject matter of claim 30, because the elected compound 8 was reasonably within the scope of the invention of US’933, given its discussed bioisosteric equivalence.
Accordingly, claim 30 was obvious at the time of filing.
Regarding claim 31, the Specification does not set forth a required definition for the term a “secondary therapeutic agent”, but explains that such secondary therapeutic agent includes agents like antibiotics, anti-inflammatory agents, mucoactive agents, and the like.
Regarding claim 33, it depends from claim 31, and recites that the secondary agent may be an antibiotic.
US’933 discloses that its compounds may be administered in combination therapies. See, e.g., US’933 at cols. 21-22, page 61, including with antibiotics, col. 22, lines 60-63.
One of ordinary skill in the art at the time of filing would have a reasonable expectation of success in administering the elected compound 8 with a secondary therapeutic agent, like a antimicrobial agent, because US’933 explicitly considers such combinations at col. 22, lines 60-63, and the elected compound 8 was reasonably within the scope of the invention of US’933, given its discussed bioisosteric equivalence.
Accordingly, claims 31 and 33 were obvious at the time of filing.
Regarding claim 32, it depends from claim 31, and recites that the secondary agent is a CFTR modulator.
US’933 at col. 21, page 61, teaches with respect to combination therapies, “It is an aspect of this invention that a composition as disclosed herein is used in combination with another agent or therapy method, such as another fibrosis treatment.”
Further, regarding cystic fibrosis treatments, US’933 at cols. 15-16, page 58, teaches “Management of CF symptoms include intravenous, inhaled, and oral antibiotics; transplants; medications and/or mechanical techniques to dislodge and expectorate sputum, and so forth. Composition(s) of the invention may be utilized in conjuction with such management regimen(s).”
Accordingly, US’933 teaches combination therapies with “management regimen(s)” used for treating patients with cystic fibrosis. Such “management regimen(s)” encompass a CFTR modulator.
Therefore, one of ordinary skill in the art at the time of filing would have a reasonable expectation of success in adding a CFTR modulator in combination with the elected species compound, because US’933 reasonably teaches such combination therapies and the elected species compound was reasonably within the scope of the invention of US’933, given its discussed bioisosteric equivalence.
Accordingly, claim 32 was obvious at the time of filing.
Regarding claims 34 and 35, they both recite an intended use of administering a compound of claim 1, by carving out patient populations. Functionally, the claims just require administration of a compound of claim 1 to patients. One of ordinary skill in the art at the time of filing would have a reasonable expectation of success in using the elected species compound for the treatment of patients with cystic fibrosis, for the reasons previously stated.
Accordingly, claims 34 and 35 were obvious at the time of filing.
Claims 32 and 34 were Obvious over US’933 in view of PubChem SID 111763310 Patani 1996 and WO’263
The rejection of claims 1 and 30-37 under 35 U.S.C. 103 as being unpatentable over US’933, in view of PubChem SID 111763310 and Patani 1996 are fully incorporated herein.
The administration of the elected species in a method of treating cystic fibrosis was obvious at the time of filing for all of the reasons previously stated.
To the extent that Applicant may argue that US’933, in view of PubChem SID 111763310 and Patani 1996, does not teach a secondary therapeutic agent being a CFTR modulator, and/or does not teach a method of inhibiting protein interactions with CALP, WO’263 teaches these limitations. The examiner notes that Applicant’s data show that the compounds of US’933 are inherently CALP inhibitors.
Regarding claim 32, as discussed, it depends from claim 31 and recites that the secondary therapeutic agent is a CFTR modulator.
The Specification at 1, paragraph [0045] explains that ivacaftor is an example of a “CFTR modulator”. Thus, the broadest reasonable interpretation of that a CFTR modulator includes ivacaftor.
Accordingly, WO’263 at 61, claim 1, teaches a “method for preventing for treating cystic fibrosis comprising administering to a subject in need of treatment an effective amount of an agent that selectively inhibits the interaction between a degradation-prone Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) and CFTR- Associated Ligand, thereby preventing or treating the subject's cystic fibrosis.”
WO’263 at claim 2 teaches that the degradation-prone CFTR is ΔF508.
WO’263 at claim 4 teaches that the agent administered is a peptide comprising the amino acid sequence of SEQ ID NO : 1 , or a derivative or peptidomimetic thereof.
WO’263 at 46, Example 4, and paragraph [00105] teaches that “iCAL36 is a Highly Selective PDZ Inhibitor”, “that Rescues ΔF508-CFTR”.
Thus, iCal36, or variants thereof described in WO’263, may be administered in a method of treating cystic fibrosis, the method comprising administering to a subject in need of such treatment, a CALP inhibitor such as iCAL36.
Accordingly, WO’263 teaches a method of treating cystic fibrosis, the method comprising administering to a subject in need of such treatment a CALP inhibitor iCal36.
Further, WO’263 at 62, claim 6 teaches its methods in combination with “a CFTR corrector, CFTR potentiator, mucolytic, anti-inflammatory agent or combination thereof.”
WO’263 at 28, paragraph [0062] further teaches administering iCal36 in such a method with a “CFTR potentiator”, such as ivacaftor.
Accordingly, WO’263 teaches a method of treating cystic fibrosis, the method comprising administering to a subject in need of such treatment a CALP inhibitor iCal36, and a CFTR modulator, such as ivacaftor, and an anti-inflammatory agent.
In view of US’933 teaching that its STAT3 inhibitors prevent IL-6 signaling through STAT3, and that IL-6 is a proinflammatory and pro-fibrotic cytokine, see US’933 at 51, col 1, Background of the Invention, the STAT3 inhibitors of US’933 reasonably serve as an anti-inflammatory agent specifically tailored for fibrosis patients. Their administration would be reasonably expected to suppress inflammation and decrease fibrotic endpoints.
As such, one of ordinary skill in the art at the time of filing would have a reasonable expectation of success in utilizing the STAT3 inhibitors of US’933 as anti-inflammatory agents in the methods of WO’263, because both methods expressly contemplate combination therapies, and the STAT3 inhibitors of US’933 would reasonably be expected to suppress inflammation and decrease fibrotic endpoints. The elected species compound was reasonably within the scope of the invention of US’933, given its discussed bioisosteric equivalence.
Such a combination results in the subject matter of claims 32 and 34. For claim 34, the CALP inhibitor iCal36 serves the role of the secondary therapeutic agent in the recited method.
Accordingly, claims 32 and 34 were obvious at the time of filing.
Claim 35 was Obvious over US’933 in view of PubChem SID 111763310, Patani 1996 and WO’413
The rejection of claims 1 and 30-37 under 35 U.S.C. 103 as being unpatentable over US’933, in view of PubChem SID 111763310 and Patani 1996 are fully incorporated herein.
To the extent that Applicant may argue that US’933, in view of PubChem SID 111763310 and Patani 1996, does not teach a method of inhibiting protein interactions with the DH domain of Dab2, WO’413 teaches this limitation.
First, the instant claim 35 recites a method of inhibiting protein interactions with the DH domain of Dab2:
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Instant claim 35.
While the elected compound is a “compound[] recited in claim 1”, Applicant does not disclose that it is an inhibitor of the DH domain of Dab2. Instead, Applicant discloses that it is an inhibitor of the PDZ domain of CAL. Because Dab2 and CAL are distinct ligands/proteins that interact with a third protein CFTR, and the elected species does not inhibit the DH domain of Dab2, it is unclear how it can be used in “a method of inhibiting protein interactions with DH domain of … Dab2”, unless the method expressly requires a specific “secondary therapeutic agent” that “inhibit[s] protein interactions with DH domain of … Dab2”.
Accordingly, for this specific rejection, the examiner interprets the instant claim as a method of treating cystic fibrosis comprising administering a compound of claim 1, i.e., the elected species compound, and a secondary therapeutic agent that is an inhibitor of the DH domain of Dab2.
The administration of the elected species in a method of treating cystic fibrosis was obvious at the time of filing for all of the reasons previously stated.
WO’413 at Abstract teaches “Compositions and kits including an agent that inhibits the interaction between Disabled-2 and mutant CFTR proteins, optionally in combination with a CFTR corrector, CFTR potentiator, CAL inhibitor, mucolytic, anti- inflammatory agent or a combination thereof are provided as are methods for preventing or treating cystic fibrosis.” The agents of WO’413 inhibit the Dab2-DH domain. See, e.g., WO’413 at 45-46, Example 2.
In view of US’933 teaching that its STAT3 inhibitors prevent IL-6 signaling through STAT3, and that IL-6 is a proinflammatory and pro-fibrotic cytokine, see US’933 at 51, col 1, Background of the Invention, the STAT3 inhibitors of US’933 reasonably serve as an anti-inflammatory agents specifically tailored for fibrosis patients. Their administration would be reasonably expected to suppress inflammation and decrease fibrotic endpoints. As explained previously, the elected species compound is a STAT3 inhibitor of US’933.
As such, one of ordinary skill in the art at the time of filing would have a reasonable expectation of success in utilizing the STAT3 inhibitors of US’933 as anti-inflammatory agents in the methods of WO’413, because both methods expressly contemplate combination therapies, and the STAT3 inhibitors of US’933 would reasonably be expected to suppress inflammation and decrease fibrotic endpoints. The elected species compound was reasonably within the scope of the invention of US’933, given its discussed bioisosteric equivalence.
Such a combination results in the subject matter of claim 35, when the elected species compound is co-administered with the agents of WO’413 that inhibit the Dab2-DH domain.
Accordingly, claim 35 was obvious at the time of filing.
Prior Art Cited but not Applied
The prior art made of record and not relied upon is considered pertinent to applicant’s disclosure.
Singh 20018 teaches that simple benzimidazolones were a known and validated CFTR targeted scaffold, and effectively provides an entire SAR for such compounds.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Christopher Evan Redwood whose telephone number is (571)272-8882. The examiner can normally be reached Monday - Friday 6:15 AM - 4:45 PM.
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/C.E.R./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 Tweardy, David J., et al., “Methods and compositions for treatment of fibrosis”, U.S. Patent No. US 10112933 B2, published 2018-10-30, hereinafter “US’933”.
2 Cited in the section regarding 35 USC 102.
3 PubChem SID 111763310 for 2-oxo-1,3-dihydrobenzimidazole-5-sulfonyl chloride, Record Version 1, Dated 2011-03-08, hereinafter “PubChem SID 111763310”. Explanation of record dates annexed hereto.
4 George A. Patani and Edmond J. LaVoie, “Bioisosterism: A Rational Approach in Drug Design”, Chem. Rev., vol. 96, no. 8, pp. 3147-3176 (1996), hereinafter “Patani 1996”.
5 Madden, Dean R., “THERAPY AND KIT FOR THE PREVENTION AND TREATMENT OF CYSTIC FIBROSIS”, International Publication No. WO 2016191263 A1, published 2016-12-01, hereinafter “WO’263”.
6 Madden, Dean R., “Dab2 inhibitors for the prevention and treatment of cystic fibrosis”, International Publication No. WO 2016077413 A1, published 2016-05-19, hereinafter “WO’413”, cited in IDS received on 04/26/2023 as FOR cite 3.
7 See also, compound F5749-0421, col. 69, page 85; F5749-0127, col. 155, page 128; F5749-0203, col. 193, page 147; and F5749-0274, col. 247, page 174.
8 Singh, Sangeeta, et al. "Benzimidazolone activators of chloride secretion: potential therapeutics for cystic fibrosis and chronic obstructive pulmonary disease", The Journal of Pharmacology and Experimental Therapeutics, vol. 296, no. 2, pp. 600-611 (2001), hereinafter “Singh 2001”.
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