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 .
Summary
Receipt of Applicant’s Amendments/Remarks filed on 01/30/2026 is acknowledged.
Claims 1-21 and 23-34 are pending.
Group II, claims 37, 40 and 41 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. The election is made FINAL filed 09/22//2025.
Claims 3, 13-20, 22, 24, 35, 36, 38, and 39 are cancelled.
Claims 1, 2, 4, 6, 8, 23 and 25 are amended.
Claims 1-2, 4-12, 21, 23 and 25-34 are pending and under examination in this application.
Modified Rejections
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 (i.e., changing from AIA to pre-AIA ) 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.
Claim(s) 1-2, 4-12, 21, 23 and 25-34 are rejected under 35 U.S.C. 103 as being unpatentable over Blagg (WO 2013/1903319 A1) in view of Surfactants: Pharmaceutical and Medicinal Aspects (hereinafter the reference is referred as Sekhon).
Blagg teaches compounds of formula (I)
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: wherein R1 and R2 are as defined herein, or a pharmaceutically acceptable salt or solvate thereof. The compounds of formula I are inhibitors of aurora kinase and/or FLT3. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which aurora kinase and/or FLT3 activity is implicated (abstract). Notably, Blagg discloses free base of formula (I) 6-Chloro-7-(4-(4-chlorobenzyl)piperazin-1-yl)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-3Himidazo[4,5-b]pyridine (page 26 and claim 6).
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And this particular compound (known as CCT137690) is a potent and orally bioavailable inhibitor of Aurora kinases that inhibits the growth of a SW620 human colon carcinoma xenograft in vivo with concomitant biomarker modulation consistent with target engagement (¶ 0007), and provide orally bioavailable inhibitors of Aurora kinase enzyme activity that possess acceptable human microsomal stability, reduced inhibition of cytochrome P450 activity and, in the case of certain compounds, a wider therapeutic index against hERG (¶ 0009).
Regarding claims 1, 32, Blagg teaches the synthesis of compound 6-Chloro-7-(4-(4-chlorobenzyl)piperazin-1 -yl)-2-(1 ,3-dimethyl-1 Hpyrazol-4-yl)-3H- imidazo[4,5-b]pyridine (¶ 0043, claim 6) corresponding to (compound of instant Formula (1 )) and the preparation thereof in (Example 1, ¶ 00116) or a pharmaceutically acceptable salt or a solvate thereof, in association with a pharmaceutically acceptable diluent or carrier (¶ 0074) and one or more pharmaceutically acceptable excipients (claim 7), and its use in the treatment of acute myeloid leukemia (claims 10, 12).
Regarding claims 27, 30, Blagg teaches oral dosage form (tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules or elixirs (¶ 0075) and oral route of administration (¶ 00101).
Regarding claim 28, Blagg teaches a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition (¶ 0078).
Regarding claims 31, Blagg teaches it shall also be appreciated that compounds of formula I may also be covalently linked (at any suitable position) to other groups such as, for example, solubilizing moieties (for example, PEG polymers), moieties that enable them to be bound to a solid support (such as, for example, biotin-containing moieties), and targeting ligands (such as antibodies or antibody fragments) (¶ 0055), and the synthetic methods that are used to prepare the starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be selected by a person skilled in the art, and It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions utilized, and Necessary starting materials may be obtained by standard procedures of organic Chemistry and the preparation of such starting materials is described in conjunction with the following representative process variants and within the accompanying Examples, and alternatively necessary starting materials are obtainable by analogous procedures to
those illustrated which are within the ordinary skill of an organic chemist (¶ 0056 – 0058). Therefore, the limitation of the compound of Formula (1) in a free base or a fumarate salt form can be selected by a person skilled in the art.
Regarding claim 33, Blagg teaches the composition comprises co-solvent DMSO, water, DMF, and alcohols e.g., EtOH (¶ 0065).
Regarding claim 34, Blagg teaches citric and maleic acid, which are considered suitable pharmaceutically acceptable antioxidants (¶ 0044).
Blagg fails to specifically teach a non-ionic surfactant in the composition.
Sekhon teaches surfactants are amphipathic substances with lyophobic and lyophilic groups and are critical components in pharmaceutical products. Surfactants have several uses in pharmaceuticals, i) for solubilization of hydrophobic drugs in aqueous media, ii) as components of emulsions ,iii) surfactant self-assembly vehicles for oral and transdermal drug delivery, iv) as plasticizers in semisolid delivery systems, and v) as agents to improve drug absorption and penetration. Non-ionic surfactants such as ethers of fatty alcohols are most commonly used in pharmaceuticals (Abstract). Moreover, Sekhon discloses surface-active agents (usually referred as surfactants, synthetic and biobased) are active at interfaces and possess both polar (hydrophilic) and non-polar (hydrophobic) characteristics in the same molecule and for pharmaceutical products poorly soluble in water, the use of surfactants becomes inevitable to reduce the interfacial tension between the medium and the drug and to increase solubility of drugs, and in drinks, surfactants are used as solubilizers to dissolve herbal medicinal materials, Vitamin E and other oil ingredients and Surfactants used in dental, oral, sublingual (under tongue) to form ointments, creams, gels, patches, tapes, and liquids, as well as dissolve, disperse, emulsify, and solubilize medicinal ingredients were found safe and ingestible, and depending on the nature of the polar group, surfactants can be classified into four groups: cationic, anionic, zwitterionic and non-ionic (Introduction to page 44, 1st and 2nd ¶).
Regarding claims 1, 2, 4-12, 21, 23, 25-26, Sekhon explicitly teaches
α-tocopheryl polyethylene glycol succinate, a vitamin E derivative as a commonly employed surfactant in pharmaceutical products (page 56, ¶ 4) and Tween 40, Tween 60, Tween 80, Cremophor EL, Cremophor RH40, Solutol HS15 (page 47). Sekhon further teaches that non-ionic surfactants with HLB values greater than about 12 are generally soluble in water and serve as emulsifiers, solubilizers and dispersants. The HLB range of about 10 to about 18 overlaps directly with the HLB ranges taught by Sekhon for non-ionic surfactants commonly used in pharmaceutical compositions. A PHOSITA reading Sekhon would have been directed specifically to TPGS and poloxamers as candidate surfactants.
More specifically, Sekhon teaches non-ionic surfactants can be classified as polyol esters, polyoxyethylene esters, poloxamers, polyol esters includes glycol and glycerol esters and sorbitan derivatives, and fatty acid esters of sorbitan (generally referred to as Spans) and their ethoxylated derivatives (generally referred to as Tweens) are perhaps one of the most commonly used non-ionics (page 46, ¶ 2), and the most commonly used non-ionic surfactants are ethers of fatty alcohol, wherein sorbitan esters are insoluble in water, but soluble in most organic solvents (low hydrophile–lipophile balance (HLB) value and are used as water-in-oil emulsifiers and as wetting agents, and the ethoxylated products are generally soluble in water and have relatively high HLB numbers (greater than about 12), wherein the nonionic surfactants products mainly serve as emulsifier, wetter, solubilizer and dispersant in pharmaceutical industry, and as gelling agent and foaming agent, they are used in the manufacture of several forms of drugs such as emulsion, cream, suppository, tablet and capsule etc., and the most frequently used surfactants are Polysorbate 20 and Polysorbate 80 and Poloxamer 188 in a concentration range between 0.001% and 0.1% (page 47, 1st ¶). Moreover, Sekhon teaches Vitamin E (introduction ¶), and commonly employed surfactants in pharmaceutical products include: fatty acid ester and α tocopherol polyethylene glycol succinate (page 56, ¶ 5).
Sekhon teaches the scope of non-ionic surfactants and reasons commonly known in the art to use these surfactants in pharmaceutical compositions. Therefore, a person having ordinary skill in the art, would have known all the advantages of these surfactant features and properties (emulsifier, solubilizer, dispersant, stabilizer) in order to select the desired non-ionic surfactant to achieve an effective composition.
The (6-chloro-7-[4-[(4-chlorophenyl)methyl]piperazin-1-yl]-2-(1,3-dimethylpyrazol-4-yl)-1H-imidazo[4,5-b]pyridine also known as mobinitinib) is known in the prior art. It is examiner position that a skilled artisan would have been capable of preparing salts of Formula (I) with nonionic surfactants in a composition as taught by Sekhon. Further, the skilled artisan would have been capable of testing the prepared salts and would pick a salt with good solubility, low hygroscopicity, and good processibility in order to improve drug absorption and penetration.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the compound of formula (I) or a pharmaceutically acceptable salt, and/or solvate thereof as taught by Blagg and combine with the non-ionic surfactant as taught by Sekhon in order to achieve solubilization of hydrophobic drugs, used as components of emulsions, surfactant self-assembly vehicles for oral delivery, and as plasticizers in semisolid delivery systems, and as agents to improve drug stability, absorption and penetration. One would have been motivated to do so because the combined teaching of Blagg in view of Sekhon discloses the claimed formula (I) and reasons to use non-ionic surfactants in pharmaceutical compositions. One of ordinary skill in the art would have been motivated to do this because both of the references are drawn to methods for using compositions and methods for the use of formula (I) and the preparation thereof with non-ionic surfactants. One of ordinary skill in the art would have found it obvious to apply the different methods of development, for example to include the claimed features of the non-ionic surfactants, glycerol derivative, block-co-polymer and the non-ionic surfactant selected from, for example Cremophor EL, RH35 and mixtures thereof, for the advantages mentioned above. From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention.
Double Patenting Maintained
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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-21 and 23-34 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8,10,12,14,16-18, 20, 21, 24, 25, 27-28 of copending Application No. 17/909,283 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select a fumarate as a pharmaceutical salt of Formula (I) and use it for the same purpose with a reasonable expectation of success. The skilled person would expect that all solid forms (and said forms of the salts) of Formula (I) possess antiproliferative activity (cancer, acute myeloid leukemia). Further, the skilled artisan would have been capable of preparing and testing salts of Formula (I) with the non-ionic surfactants as taught by Sekhon. Furthermore, the skilled artisan would have been capable of testing the prepared salts and picking a salt with good solubility, low hygroscopicity, good processibility, and to improve drug stability, absorption and penetration.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant’s arguments filed January 30, 2026 have been fully considered but are not persuasive. Regarding the amendment to claim 1, Applicant has narrowed the non-ionic surfactant to: (1) vitamin E derivatives, block co-polymers, and combinations thereof; and (2) having an HLB value of about 10 to about 18. Applicant's arguments have been considered but are not found persuasive for the reasons set forth below.
Response to Applicant's Unexpected Results Argument:
Applicant argues that TPGS (vitamin E derivative) and Poloxamer P124 (block co-polymer) unexpectedly outperformed other surfactants in solubilizing Formula (1) and providing a stable formulation. However, this argument is not persuasive for the following reasons:
1. As noted in the above rejections, Sekhon explicitly identifies TPGS (alpha-tocopherol polyethylene glycol succinate, a vitamin E derivative) as a 'commonly employed surfactant in pharmaceutical products' (Sekhon, page 56). Sekhon further teaches that non-ionic surfactants with HLB values greater than about 12 are generally soluble in water and serve as emulsifiers, solubilizers and dispersants. The HLB range of about 10 to about 18 overlaps directly with the HLB ranges taught by Sekhon for non-ionic surfactants commonly used in pharmaceutical compositions. A PHOSITA reading Sekhon would have been directed specifically to TPGS and poloxamers as candidate surfactants.
2. The unexpected results presented in the specification compare TPGS and Poloxamer P124 against Cremophor EL, Cremophor RH40, Solutol HS15, and Gelucire 44/14. However, these comparison surfactants are not the closest prior art surfactants that a PHOSITA would have selected based on the combined teachings of the cited references. Since TPGS and poloxamers are themselves specifically taught by Sekhon as surfactants for pharmaceutical compositions, any comparison must include a baseline from compositions that a PHOSITA would have arrived at from the prior art without modification.
3. The data showing TPGS provides a clear solution for 5 hours and Poloxamer P124 provides a stable suspension for 10 days, while desirable, does not demonstrate unexpected results beyond the level of ordinary skill. It is well-known in the art that vitamin E derivatives such as TPGS and poloxamers have favorable solubilizing properties for poorly water-soluble compounds (BCS Class II/IV drugs). The compound of Formula (1) (mobinitinib/CCT137690) is a hydrophobic compound, and TPGS is recognized in the art as a particularly effective solubilizer for such compounds. A PHOSITA would have had a reasonable expectation that TPGS would effectively solubilize Formula (1), and the results obtained are consistent with what would be expected from known properties of TPGS. See In re Expectation of Success, MPEP § 2143.02.
4. The limitation of HLB about 10 to about 18 is a broad range that encompasses a large number of known non-ionic surfactants beyond vitamin E derivatives and block co-polymers. A PHOSITA seeking to solubilize a hydrophobic drug in an aqueous pharmaceutical composition would routinely select non-ionic surfactants with HLB values in this range, as this range is well-recognized as suitable for oil-in-water emulsification and solubilization. See, e.g., Sekhon, pages 46-47.
Regarding Specific Dependent Claims:
In particular, the following dependent claims are specifically addressed:
Regarding claims 10 and 12: Claim 10 recites a vitamin E derivative; claim 12 recites alpha-tocopherol polyethylene glycol 1000 succinate (TPGS). As established above, Sekhon specifically discloses TPGS as a suitable non-ionic surfactant for pharmaceutical compositions. These claims remain unpatentable over the combination of Blagg and Sekhon.
Regarding claim 21: The claim recites a poloxamer (block co-polymer) with specific poloxamer numbers including P124. Sekhon teaches poloxamers, including Poloxamer 188, and the art recognized a wide variety of poloxamers for pharmaceutical use. Selection of specific poloxamer numbers would have been within the ordinary skill of an artisan optimizing a pharmaceutical formulation. See In re Aller, 220 F.2d 454 (CCPA 1955) (optimization of known result-effective variables is not inventive).
Regarding claim 23: The recites TPGS and/or Poloxamer P124 as the non-ionic surfactant. Both are specifically taught by Sekhon as pharmaceutical surfactants. This claim is unpatentable over Blagg in view of Sekhon.
Regarding claims 26-29: The surfactant concentration ranges and weight ratios recited in these claims represent routine optimization parameters within the skill of the art. Sekhon teaches concentration ranges between 0.001% and 0.1% and notes these may vary depending on the application. A PHOSITA would routinely optimize these parameters without inventive effort.
Blagg teaches the claimed active compound (6-chloro-7-[4-[(4-chlorophenyl)methyl]piperazin-1-yl]-2-(1,3-dimethylpyrazol-4-yl)-1H-imidazo[4,5-b]pyridine), pharmaceutically acceptable salts, solvates, oral dosage forms, and pharmaceutical compositions. Blagg further teaches oral administration, excipients and co-solvents, salt selection as a routine formulation choice, and formulation optimization would have been obvious performed by a PHOSITA.
The amended claims merely recite a finite number of predictable choices within a known class of surfactants, which constitutes routine optimization.
Alleged criticality of surfactant structure.
Applicant asserts that the claimed surfactant features confer critical advantages. However, Applicant has not provided comparative data or evidence of unexpected results demonstrating that the claimed surfactant achieve results different in kind from those expected from Sekhon’s teachings. Absent such evidence, the selections represent routine optimization, which is obvious as a matter of law.
There is motivation to combine.
It would have been obvious to one of ordinary skill in the art at the time of the invention to formulate the hydrophobic compound of Blagg with a non-ionic surfactant as taught by Sekhon in order to improve solubility, stability, and oral bioavailability, with a reasonable expectation of success. Both references are directed to pharmaceutical compositions and address the same formulation problems associated with poorly soluble small-molecule drugs. It would have been obvious to one of ordinary skill in the art at the time of the invention to select a non-ionic surfactant having the claimed structural characteristics as a result-effective variable, with a reasonable expectation of success.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANDRE MACH whose telephone number is (571)272-2755. The examiner can normally be reached 0800 - 1700 M-F.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert A Wax can be reached at 571-272-0323. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ANDRE MACH/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615