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 on 07/12/2024, is a national stage entry of International Application No. PCT/EP2023/051147, filed on 01/18/2023, which claims priority to European Patent Application Nos. EP22152325.1, filed on 01/19/2022, and EP22162769.8, filed on 03/17/2022. Receipt is acknowledged of certified copies of papers required by 37 CFR § 1.55.
Status of Claims
Claims 1-15 were originally presented on 07/12/2024. Applicant’s preliminary amendments received 05/15/2025, are acknowledged and entered. Claims 3-12, 14 and 15 were amended and claim 16 was added.
Accordingly, claims 1-16 are pending.
Information Disclosure Statement
The Information Disclosure Statement received on 07/12/2024 is acknowledged and found to be in compliance with the provisions of 37 CFR § 1.97. Accordingly, the Information Disclosure Statement has been considered.
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.
Claims 1-16 Anticipated by WO’298
Claim(s) 1-16 is/are rejected under both 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by WO’298.1
Representative Claim and Embodiment
The instant claims are drawn to N-(1,3-thiazol-2-yl)-4H-1,2,4-triazol-3-amines of Formula (I):
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and the intended use of such compounds as antagonists of adenosine receptors. The Example 9 compound (Specification at 67), which is recited solely in claim 16, is an embodiment of the claims. Its structure is below:
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Example 9 compound
The Example 9 compound is encompassed by the instant claims 1, 2 (R1 is H), 3 (optional R2 substitution not used), 4 (RA imidazolyl), 5 (RA1 is methyl), 6 (RA is a2, X is CH, RA4 is methyl), 7 (RB is phenyl), 8 (RB1 is 3-cyano), 9 (RB is b1, RB3 is 3-cyano), 10 (single RB1 being cyano), 11 (Formula Ia2b, R1 is H, X is N, R4A is methyl), 12 (Formula Ia2b1, R1 is H, X is N, R4A is methyl, RB3 is 3-cyano), 13 (9th compound named), and 14-16.
WO’298
WO’298 teaches aminothiazoles of formula (I), and the intended use of such aminothiazoles as antagonists of adenosine receptors. See, e.g., WO’298 at 28, claim 1. R2 is defined as a 5- or 6- membered monovalent heterocyclic group, which it defines at page 3 to mean “a monovalent 5- or 6- membered heterocyclic group having one, two or three ring hetero atoms selected from nitrogen, oxygen and sulfur, such as pyrrolyl, triazolyl, pyridyl, …” (emphasis added).
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aminothiazoles of formula (I) of WO’298
While the aminothiazoles of formula (I) of WO’298 appear to encompass many possible rings and structures, the inventors of these compounds teach preferred embodiments with particular biological significance. See WO’298 at 10:
Compounds of the Examples hereinbelow have KB values below 300nM in the reporter gene assay. For example, the compounds of Examples 12, 15, 16, 17, 27, 35, 36 and 38 have KB values of 31nM, 20nM, 24nM, 26.5nM, 10nM, 4nM, 17nM and 12nM respectively.
In general, compounds of formula I in free or pharmaceutically acceptable salt form also exhibit inhibition of adenosine A3 receptor activation, which may be demonstrated in the adenosine A3 receptor assay described in WO 99/64418. For instance, the compounds of Examples 7, 27, 30, 31, 34, 35 and 38 have KI values of 24nM, 16nM, 22nM, 11.5nM, 11nM, 10nM and 4nM in this assay.
WO’298 at 10 (emphases added).
The Example 35 compound of WO’298 (bolded above, structure last entry on page 21) has the following structure (left), which is compared to the embodiment of the instant claims (Instant Example 9, right):
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Example 35 of WO’298
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Instant Example 9 Compound
Among the aminothiazoles of formula (I) of WO’298 that bear a 1H-imidazoly-1-yl substituent for the heterocycle covalently attached to the thiazole, biological significance consistently requires a 3-cyano substituent (i.e., 3-benzonitrile). See, e.g., Examples 1, 17, 32-35 (pages 17-22), which are the disclosed compounds which bear a 1H-imidazoly-1-yl substituent for the heterocycle covalently attached to the thiazole. Examples 17, 34 and 35 were highlighted in WO’298 at 10 for having particular biological significance (examples 17 and 34 shown below, 35 above). These compounds (17, 34 and 35) all have a 3-benzonitrile substituent for Ar of formula (I) of WO’298.
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Example 17 of WO’298
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Example 34 of WO’298
Indeed, the vast majority of the aminothiazoles of formula (I) of WO’298 have a 3-benzonitrile (see pages 17-22). Accordingly, even though the aminothiazoles of formula (I) of WO’298 may seem to describe a large number of compounds, in fact, the aminothiazoles of formula (I) of WO’298 of biological significance that bear a 1H-imidazoly-1-yl substituent for the heterocycle covalently attached to the thiazole represent a more limited generic class covered by the preferred formula, wherein a 3-benzonitrile substituent for Ar imparted biological significance. Accordingly, WO’298 teaches the following aminothiazoles of formula (I) of WO’298 of a more limited generic class, which bear a large unchanging structural nucleus:
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Limited class of biologically significant aminothiazoles of formula (I) of WO’298 that bear a 1H-imidazoly-1-yl. The X and Y variables are added by the examiner.
Returning to the Specification where WO’298 defines “a monovalent 5- or 6- membered heterocyclic group”, it states that this claim term means:
a monovalent 5- or 6- membered heterocyclic group having one, two or three ring hetero atoms selected from nitrogen, oxygen and sulfur, such as pyrrolyl, triazolyl, pyridyl, oxopyridyl, piperidyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrazolinyl, piperazinyl, morpholinyl, furyl, pyranyl, thienyl or thiazolyl, …
WO’298 at 3.
For the monovalent 5-membered heterocyclic group having three ring hetero atoms, the only example given is triazolyl. There are two types of triazoles, 1,2,3-traizole or 1,2,4-triazole, that exist as tautomers, shown below. The heterocyclic group attached to the central amine group in the compounds disclosed in WO’298 required (NH)-C connectivity. That is, WO’298 did not teach the heterocyclic group attaching at a heteroatom of the heterocycle to the central amine group. Reviewing the structures of the only available triazoles, there is a total of four connection points, marked with asterisks (*) below.
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1,2,3-traizole
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1,2,4-triazole
Holding the above X variable constant (e.g., methyl due to exemplifying superior KB and KI values), connection to these triazoles as taught for this more limited generic class results in four total compounds, each of which one of skill in the art would at once envisage as if the inventors of WO’298 had fully drawn or named them in their specification. One of these four compounds is indeed the Instant Example 9 Compound.
Accordingly, the examiner finds that WO’298 teaches the Instant Example 9 Compound, and therefore the compound claims 1-13 and 16 drawn to this compound are anticipated by WO’298.
Regarding claim 14, WO’298 teaches pharmaceutical compositions comprising compounds of its invention and a pharmaceutically acceptable diluent or carrier. See, e.g., WO’298 at 33, claim 12. As stated, the examiner finds that the Instant Example 9 Compound is a compound of WO’298, and it is encompassed by the formula (I) of claim 1 of WO’298.
Accordingly, claim 14 is anticipated by WO’298.
Regarding claim 15, WO’298 teaches a method of treating a condition, disorder or disease mediated by activation of the adenosine A2B receptor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the Instant Example 9 Compound. See, e.g., WO’298 at claim 13, which the examiner interprets as a method of treatment, and WO’298 at 15-16 (last paragraph of page 15), which teaches exemplary daily dosages for oral administration.
Accordingly, claim 15 is anticipated by WO’298.
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.
Claims 1-16 Obvious over US’722 in view of WO’298
Claim(s) 1-16 is/are rejected under 35 U.S.C. 103 as being unpatentable over US’7222 in view of WO’298.3
The above findings of fact and discussion regarding WO’298 in the section regarding anticipation of claims 1-16 are fully incorporated herein.
US’722 at cols. 132-133, claim 1 teaches N-(1,3-thiazol-2-yl)-4H-1,2,4-triazol-3-amines of the instant Formula (I), of complete overlap. See variables X = NH, R1 substituted aryl, R2 substituted heterocycle, R3 H, R4 (H, halogen, alkyl, cycloalkyl, alkoxy, and cyano taught). US’722 teaches the intended use of such compounds for inhibiting cellular protein tyrosine phosphatase activity, cellular transduction, the treatment of cancers, and the treatment of diabetes. See, e.g., US’722 at cols 133-134, claims 4-12. While the exemplified compounds of US’722 typically bear a nitro substituent, the compounds do not require nitro substitution. See US’722 at claim 1. US’722 explicitly teaches that its compounds are active against protein tyrosine phosphatases (transmembrane and cytoplasmic enzymes). See, e.g., US’722 at col. 1, beginning at line 65 (discussing PTKs and PTPs), and at col. 4, under the detailed description of the invention (discussing inhibiting transmembrane and intracellular protein tyrosine phosphatase activity).
Accordingly, US’722 teaches the exact core scaffold of the instant Formula (I), albeit for a different purpose. Further, the scaffold incorporates more variability in substitution. See, e.g., R4 may be C1-20 alkyl, whereas the instant claims permit C1-C8 alkyl for the same substituent (labeled R1 in the instant claims).
However, as discussed in the section regarding anticipation of claims 1-16, the examiner finds that WO’298 teaches the Instant Example 9 Compound and its intended use as an antagonist of adenosine receptors.4 Indeed, as discussed in the section regarding anticipation, the examiner finds that WO’298 teaches a more limited generic class of N-(1,3-thiazol-2-yl)-4H-1,2,4-triazol-3-amines, and that for these compounds, they exhibit the ability to antagonize adenosine receptors. Adenosine receptors are also transmembrane. Pharmacologically affecting either protein tyrosine phosphatase activity or adenosine receptors may be therapeutically effective for treating diabetes. See, e.g., US’722 at col. 133, claim 8, and WO’298 at 13, second paragraph.
One of ordinary skill in the art at the time of filing, seeking to prepare more APIs for treating diabetes, would be motivated to combine the N-(1,3-thiazol-2-yl)-4H-1,2,4-triazol-3-amine scaffold of US’722 with the narrower scaffold of WO’298 and perform a SAR about the triazole R4 variable of US’722. Starting from the methyl-imidazolyl and 3-benzonitrile substituents configured for adenosine receptors (Example 35 of US’722), one of ordinary skill in the art at the time of filing would have a reasonable expectation of success in adding a simple alkyl (e.g., methyl) or cycloalkyl (e.g., cyclopropyl) at the R4 position because US’722 teaches that such compounds are effective for treating diabetes. Such a combination results in the Instant Example compounds 8 and 10.
One of ordinary skill in the art at the time of filing would have a reasonable expectation of success in preparing a pharmaceutical composition comprising such compounds with a carrier or a diluent because US’722 teaches pharmaceutical compositions that comprise compounds of claim 1 of US’722 and carriers. See US’722 at col. 133, claim 3. The Instant Example compounds 8, 9, and 10 are all compounds encompassed by claim 1 of US’722.
One of ordinary skill in the art at the time of filing would have a reasonable expectation of success in administering an effective amount of such compounds to treat a condition, disorder or disease mediated by activation of the adenosine A2B receptor, because US’722 teaches effective amounts (see, e.g., US’722 at cols. 39-40, specific dosing begins around line 40 of col. 39), wherein at least the condition, disorder or disease mediated by activation of the adenosine A2B receptor is diabetes, see US’722 at col. 133, claim 8.
Accordingly, claims 1-16 were obvious at the time of filing.
Secondary Considerations
Certain embodiments of the instant invention, while being clearly obvious over US’722 in view of WO’298 (or WO’298 alone), may not be species one of skill in the art would at once envision reading the specification of WO’298, and therefore secondary considerations tailored to certain species may be relevant.
The two references cited below in the prior art cited but not applied section teach more examples of aminothiazole adenosine receptor antagonists. Both WO’298 and WO’926 (full citation below) teach N-(1,3-thiazol-2-yl)-4H-1,2,4-triazol-3-amine scaffolds. Therefore, triazoles were an obvious choice, and there was a reasonable expectation of success in view of the inventors of these compounds teaching that triazoles work.
Unfortunately, Applicant provides no in vivo data and no comparison data to known compounds built off the known aminothiazole scaffold. As a result, the examiner cannot assess a secondary consideration, such as an unexpected result, because no comparison data were offered.
Prior art Cited but not Applied
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Press, Neil J., et al. "A new orally bioavailable dual adenosine A2B/A3 receptor antagonist with therapeutic potential." Bioorganic & medicinal chemistry letters 15.12 (2005): 3081-3085, cited in the IDS received on 07/12/2024 as NPL Cite 1, hereinafter “Press 2005”, at 3082-3083 teaches that the inventors of WO’298 discovered during its SAR studies of adenosine receptors that the 5- or 6- membered heterocycle simply requires a weakly basic nitrogen. It further teaches at 3082 that “the 3-cyanobenzene substituent at the 4-position generally bestowed the highest affinity for the A2B and A3 receptors, while giving some selectivity against A1 and A2A.”
Press, Neil, John, and Taylor, Roger, John, “THIAZOLE DERIVATIVES AS A2B ANTAGONISTS”, International Publication No. WO 2005070926 A1, published 2005-08-04, cited in the IDS received on 07/12/2024 as FOR Cite 1, hereinafter “WO’926”, at 22, claim 1 teaches N-(1,3-thiazol-2-yl)-4H-1,2,4-triazol-3-amines of the instant Formula (I). WO’926, WO’298, and Press 2005 form a collective body of work by the inventors of these compounds.
Conclusion
No claims 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 Press, Neil, John and Taylor, Roger, John, “AMINOTHIAZOLES AND THEIR USE AS ADENOSINE RECEPTOR ANTAGONISTS”, International Publication No. WO 0242298 A1, published 2002-05-30, cited in the IDS received on 07/12/2024 as FOR Cite 2, hereinafter “WO’298”.
2 Tang, Peng, C., et al, “Thiazole compounds and methods of modulating signal transduction”, U.S. Patent No. US 6080772 A, published 2000-06-27, hereinafter “US’772”.
3 Cited in the section regarding anticipation.
4 Moreover, to the extent that Applicant may argue that WO’298 does not either expressly or inherently teach the Instant Example 9 Compound for some reason, one of ordinary skill in the art at the time of filing would have a reasonable expectation of success in preparing such a compound because it represents one of four possible triazoles taught by the more limited generic class of biologically significant aminothiazoles of formula (I) of WO’298 that bear a 1H-imidazoly-1-yl substituent. One of ordinary skill in the art at the time of filing would have been motivated to select the methyl-imidazolyl substituent because it exemplified superior biological activity in WO’298, as taught for the Example 35 of WO’298.
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