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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 6/10/2026 has been entered.
Summary
Receipt of Applicant’s Amendments/Remarks filed on 6/10/2026 is acknowledged. Claims 1-21 and 23-34,37, and 41 are pending. Claims 37, 40 and 41 are withdrawn from further consideration. Claims 2-25, 35, 36, 38, and 39 are cancelled. Claims 1 and 29 are amended.
Claims 1 and 26-34 are pending and under examination in this application.
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 and 26-34 are rejected under 35 U.S.C. 103 as being unpatentable over Blagg et al. (WO 2013/1903319 A1) (hereinafter the reference is referred as “Blagg”) in view of Surfactants: Pharmaceutical and Medicinal Aspects (hereinafter the reference is referred as “Sekhon”) and further in view of Kohara et al. (WO 2004/073692 A1) (hereinafter the reference is referred as "Kohara").
Blagg teaches compounds of Formula (I) — specifically the free base 6-chloro-7-(4-(4-chlorobenzyl)piperazin-1-yl)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine (CCT137690/mobinitinib) (pp. 26, claim 6), a potent and orally bioavailable inhibitor of Aurora kinases with activity in a SW620 human colon carcinoma xenograft model (¶ 0007), or a pharmaceutically acceptable salt and/or solvate thereof (claim 6), in association with a pharmaceutically acceptable carrier or diluent (¶ 0074) and one or more pharmaceutically acceptable excipients (claim 7), for use in the treatment of proliferative disorders including acute myeloid leukemia (AML) (claims 10, 12).
Regarding claims 27 and 30, Blagg teaches oral dosage forms including hard and soft capsules, aqueous or oily suspensions, emulsions, dispersible powders, granules, and elixirs (¶ 0075), and oral route of administration (¶ 0101).
Regarding claim 28, Blagg teaches formulations for oral administration to humans containing from 0.5 mg to 0.5 g of active agent (suitably 0.5–100 mg, e.g., 1–30 mg), compounded with an appropriate amount of excipients varying from about 5% to about 98% by weight of the total composition (¶ 0078).
Regarding claim 31, Blagg teaches the compound of Formula (I) may be prepared as a free base or in salt form, including fumarate salt, as a matter of routine pharmaceutical optimization by a PHOSITA (¶¶ 0056–0058).
Regarding claim 32, Blagg teaches pharmaceutical compositions comprising one or more pharmaceutically acceptable carriers, diluents, and excipients (¶ 0074, claim 7).
Regarding claim 33, Blagg teaches co-solvents including DMSO, water, DMF, and alcohols such as EtOH (¶ 0065).
Regarding claim 34, Blagg teaches citric acid and maleic acid as pharmaceutically acceptable components, recognized in the art as suitable antioxidants (¶ 0044).
Blagg fails to specifically teach a non-ionic surfactant in the composition, and fails to teach a specific weight ratio of surfactant to the compound of Formula (1).
Sekhon teaches that surfactants are amphipathic substances critical to pharmaceutical products, serving functions including: solubilization of hydrophobic drugs in aqueous media, components of emulsions, self-assembly vehicles for oral delivery, plasticizers in semisolid delivery systems, and agents to improve drug absorption and penetration (Abstract; pp. 43–44). Sekhon specifically identifies α-tocopheryl polyethylene glycol 1000 succinate (TPGS), a vitamin E derivative, as a commonly employed non-ionic surfactant in pharmaceutical products (p. 56, ¶ 4–5). Sekhon further teaches that non-ionic surfactants with HLB values greater than approximately 12 are generally water-soluble and serve as emulsifiers, solubilizers, and dispersants (pp. 46–47).
Regarding claims 1 and 26, Sekhon explicitly teaches TPGS as a commonly employed non-ionic surfactant in pharmaceutical products (p. 56, ¶ 4–5) and identifies it as suitable for oral, parenteral, topical, nasal, and rectal drug delivery. Sekhon further teaches that non-ionic surfactants are routinely used in capsule formulations and emulsions (pp. 46–47).
Sekhon fails to teach a specific weight ratio of TPGS to a drug compound, or to disclose the specific capsule fill formulation parameters for TPGS-containing hard capsules. Kohara is relied upon for these teachings.
Kohara teaches hard capsule preparations of poorly water-soluble drugs comprising a hydrophilic solubilizing agent and a quality-maintaining agent, where the hydrophilic solubilizing agent is specifically identified as including succinic acid vitamin E polyethylene glycol 1000 ester (TPGS/Tocophersolan) as a preferred surfactant (claims 1, 8; pp. 4–5 of the machine translation). Kohara specifically discloses TPGS as a preferred component of hard capsule fill formulations for poorly water-soluble drugs, noting it forms micelles and solubilizes drugs in physiological fluids without precipitation (pp. 3–5).
Regarding the weight ratio of TPGS to drug (as now recited in amended claim 1), Kohara teaches the following in the working examples:
Example 7 (danazol): 7 parts TPGS to 1 part drug — ratio of 7:1 (w/w)
Example 9 (tacrolimus): 1.4 g TPGS to 0.2 g drug — ratio of 7:1 (w/w)
Production Example 1: 9 parts TPGS to excipient (drug content variable from 0.1–50% per claim 5)
Kohara further teaches that the drug content in the hard capsule preparation is from about 0.1% to about 50% by weight (claim 5), and the hydrophilic solubilizing agent (including TPGS) is present in an amount of about 20% to about 99.8% by weight (claim 6). These ranges necessarily encompass TPGS:drug weight ratios spanning from well below 7:1 to well above 25:1, establishing that the ratio of surfactant to drug is a result-effective variable routinely optimized in the art.
A drug loading of 5% w/w with TPGS at 90% w/w, for example, corresponds to a TPGS:drug ratio of 18:1 — squarely within the claimed 7:1 to 25:1 range. Additionally, at a drug loading of approximately 3.8% w/w with TPGS at approximately 93% w/w — entirely within Kohara’s claimed drug loading range of 0.1–50% w/w (claim 5) and TPGS range of 20–99.8% w/w (claim 6) — the TPGS:drug ratio reaches approximately 24.5:1, which encompasses the upper boundary of the claimed 25:1 range. The full breadth of the claimed 7:1 to 25:1 range is therefore expressly encompassed within the compositional space taught by Kohara. Kohara thereby establishes that high TPGS-to-drug ratios in hard capsule formulations are a routine formulation parameter, not an inventive discovery.
Regarding claim 29 (currently amended): Claim 29 recites a weight ratio of non-ionic surfactant to compound of Formula (1). The Examiner notes that claim 29, as amended, now recites that the ratio is from about 7:1 to about 20:1 without the previously recited alternative sub-ranges. This limitation is encompassed by and obvious over the Kohara teachings discussed above regarding TPGS:drug ratios as a result-effective variable. Claim 29 is unpatentable.
Combined Rationale and Motivation to Combine:
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: (1) take the compound of Formula (1) (CCT137690/mobinitinib) as disclosed by Blagg, (2) formulate it with TPGS as the non-ionic surfactant as taught by both Sekhon and Kohara, and (3) optimize the TPGS-to-drug weight ratio within the range of 7:1 to 25:1 as a result-effective variable, as established by the working examples and compositional ranges of Kohara.
Motivation to combine exists because all three references are directed to pharmaceutical compositions of poorly water-soluble small-molecule drugs. The compound of Formula (1) (mobinitinib/CCT137690) is a known poorly water-soluble compound. Sekhon establishes TPGS as a commonly used non-ionic surfactant for such compounds in pharmaceutical compositions. Kohara establishes that TPGS is specifically the surfactant of choice for hard capsule fill formulations of poorly water-soluble drugs and demonstrates that the TPGS:drug ratio is a known, optimizable formulation parameter. A PHOSITA would have had a reasonable expectation of success in achieving the claimed composition based on the combined teachings of these references. See In re Aller, 220 F.2d 454 (CCPA 1955) (optimization of known result-effective variables does not require inventive effort).
Claim-Specific Analysis:
Claim 1 (currently amended): Blagg teaches the compound of Formula (1) and pharmaceutically acceptable salts/solvates thereof. Sekhon and Kohara teach TPGS as a preferred non-ionic surfactant for pharmaceutical compositions of poorly soluble drugs. The TPGS HLB value of approximately 13.2 falls squarely within the recited HLB range of about 10 to about 18. Kohara teaches hard capsule fill formulations of TPGS and poorly water-soluble drugs with TPGS:drug weight ratios that encompass and render obvious the claimed 7:1 to 25:1 range. The combined teachings of Blagg, Sekhon, and Kohara render claim 1 unpatentable.
Claims 26, 30, 31, 32, 33, 34 (previously presented, dependent on claim 1): These claims are unpatentable for the reasons set forth with respect to claim 1. Additionally, Blagg teaches oral dosage forms (¶ 0075), drug amounts (¶ 0078), free base and fumarate salt forms (¶¶ 0056–0058), excipients and carriers (¶ 0074), co-solvents (¶ 0065), and antioxidants (¶ 0044), all as discussed above.
Claims 27, 28 (previously presented): Blagg teaches pharmaceutical compositions in liquid-liquid dispersion, solid-liquid dispersion, and mixture forms (¶ 0075), and drug amounts of 1–30 mg per formulation (¶ 0078), rendering these claims obvious.
Response to Arguments
I. Response to Applicant's Unexpected Results Argument (TPGS Superiority over Poloxamer):
Applicant argues that the TPGS composition exhibits superior and unexpected dissolution performance compared to poloxamer P124, including avoidance of precipitation during pH shift (see spec. ¶ [0321]) and superior FaSSIF dissolution concentration (~22% at peak vs. ~5% plateau for poloxamer, spec. ¶ [0327]). Applicant further argues these results are surprising and sufficient to rebut any prima facie case of obviousness.
These arguments are not persuasive for the following reasons:
First, to constitute unexpected results, the comparison must be against the closest prior art — i.e., the composition a PHOSITA would have arrived at based on the cited references. In re Baxter Travenol Labs., 952 F.2d 388 (Fed. Cir. 1991). With the addition of Kohara to the rejection, TPGS is now not merely one of many surfactants in a broad category — it is the specifically preferred surfactant identified by the prior art for hard capsule fill formulations of poorly water-soluble drugs. Kohara expressly identifies TPGS as the hydrophilic solubilizing agent of choice for this dosage form (claims 1, 8) and demonstrates its use in working Examples 7 and 9 at a 7:1 TPGS:drug ratio. TPGS is therefore the closest prior art comparator — it is the surfactant a PHOSITA would have selected first. Applicant’s comparison between TPGS and poloxamer P124 accordingly does not demonstrate unexpected results relative to the closest prior art; it compares the expected choice against a surfactant a PHOSITA would have had less reason to select for hard capsule fill compositions of poorly water-soluble drugs.
Second, the unexpected results data is not commensurate in scope with the full breadth of the claimed range of 7:1 to 25:1. Applicant’s specification presents dissolution and viscosity data for formulations at approximately 9:1 (10% w/w drug loading) and 19:1 (5% w/w drug loading) ratios. No data is provided for compositions at or near the lower boundary of the claimed range (7:1, which is the ratio expressly exemplified by Kohara in Examples 7 and 9) or the upper boundary (25:1). To the extent the unexpected results argument rests on improved dissolution performance at these specific data points, that evidence does not establish that unexpected results are achieved across the entire claimed range. In re Harris, 409 F.3d 1339, 1344 (Fed. Cir. 2005) (unexpected results must be commensurate in scope with the claimed range). Notably, Kohara’s Examples 7 and 9 demonstrate satisfactory capsule fill performance at the 7:1 ratio, suggesting the result at the lower bound of the claimed range is entirely expected. Applicant should provide comparative data across the full claimed ratio range, and specifically at or near the 7:1 lower bound taught by Kohara, before unexpected results can be credited.
Third, TPGS is well-recognized in the art for its ability to maintain supersaturation of BCS Class II/IV compounds in aqueous and simulated intestinal media. Sekhon teaches TPGS as a "commonly employed surfactant in pharmaceutical products" (p. 56, ¶ 4), and Kohara specifically attributes TPGS’s suitability for capsule fill formulations to its ability to form micelles that maintain drug solubilization without precipitation (pp. 3–5 of machine translation). The dissolution behavior Applicant characterizes as unexpected — namely, maintenance of supersaturation through pH shift and superior FaSSIF dissolution relative to poloxamer — is entirely consistent with these well-known properties of TPGS. Results that are consistent with the known properties of a prior art compound cannot constitute unexpected results. See In re Merck & Co., 800 F.2d 1091, 1099 (Fed. Cir. 1986).
II. Response to Applicant's Argument Regarding the 7:1 to 25:1 TPGS:Drug Weight Ratio:
Applicant argues that the specific TPGS:drug weight ratio of 7:1 to 25:1 was specifically chosen based on unexpected experimental results showing that the 15% w/w (5:1 ratio) formulation had unacceptably high viscosity (spec. ¶ [0330]), while the 5% w/w (19:1) and 10% w/w (9:1) formulations provided acceptable capsule fill properties. Applicant therefore characterizes the 7:1 to 25:1 range as non-obvious.
These arguments are not persuasive for the following reasons:
First, Kohara expressly teaches TPGS-containing hard capsule fill formulations for poorly water-soluble drugs and discloses drug loading from 0.1–50% w/w and TPGS (hydrophilic solubilizer) content from 20–99.8% w/w. At 5% drug loading and 93% TPGS, the TPGS:drug ratio is approximately 18.6:1 — within the claimed range. At 10% drug loading and 87% TPGS, the ratio is approximately 8.7:1 — also within the claimed range. Kohara's Examples 7 and 9 explicitly demonstrate a 7:1 TPGS:drug ratio in a working hard capsule formulation. The claimed range of 7:1 to 25:1 is therefore squarely within the ratios disclosed and rendered obvious by Kohara.
Second, the selection of a maximum TPGS loading to avoid excessive viscosity in a capsule fill suspension is precisely the type of routine formulation optimization addressed by In re Aller, 220 F.2d 454 (CCPA 1955). Viscosity is a well-recognized result-effective variable in capsule fill formulation, and a PHOSITA would routinely screen formulations at varying drug/surfactant ratios to identify an acceptable viscosity range. No inventive step is required to exclude the high-viscosity 15% w/w formulation. Kohara itself instructs that the kinematic viscosity of the contents should be controlled to 100–2000 mpas (claim 2), confirming viscosity is a recognized optimization parameter.
Third, even accepting Applicant's characterization of the viscosity data, the claimed ratio range (7:1 to 25:1) is defined by exclusion of a single high-viscosity formulation. The identification of a single unacceptable data point and the selection of a ratio range that excludes it does not constitute an inventive discovery; it is routine optimization. See In re Peterson, 315 F.3d 1325 (Fed. Cir. 2003) (claiming a narrower range within the prior art range does not establish patentability absent evidence the narrower range achieves unexpected results).
III. Response to Applicant's Argument that Sekhon Does Not Teach TPGS as a Non-Ionic Surfactant for Compositions Containing Formula (1):
Applicant argues that Sekhon's mention of TPGS at page 56 is in the context of natural surfactants and does not specifically suggest TPGS as the non-ionic surfactant for use with the compound of Formula (1).
This argument was addressed in the prior Final Action and is reiterated here. Sekhon is not relied upon for a specific suggestion to use TPGS with the compound of Formula (1) in particular. Rather, Sekhon is relied upon for its teaching that TPGS is a "commonly employed surfactant in pharmaceutical products" (p. 56, ¶ 4), and Kohara is now additionally relied upon to confirm that TPGS is specifically the surfactant of choice for hard capsule formulations of poorly water-soluble small-molecule drugs. The combination of Blagg + Sekhon + Kohara provides an explicit motivation to use TPGS as the surfactant in a hard capsule formulation of the compound of Formula (1), with a reasonable expectation of success.
Nonstatutory Double Patenting Rejection
The prior Final Office Action contained a provisional nonstatutory double patenting (ODP) rejection over co-pending Application No. 17/909,283. The Examiner acknowledges, as noted in Applicant’s RCE Remarks, that Application No. 17/909,283 has since issued as U.S. Patent No. 12,624,027 on May 12, 2026. Upon reconsideration of the issued claims of U.S. Patent No. 12,624,027 in view of Applicant’s arguments, the provisional ODP rejection is WITHDRAWN.
The issued claims of U.S. Patent No. 12,624,027 are directed exclusively to crystalline solid-state forms (polymorphs) of Compound A fumarate, defined by crystallographic properties including XRPD peaks, unit cell parameters, and thermal data. Issued claims 1 and 2 recite specific polymorphic forms of the compound of Formula (1) (Forms 1–5 and 8) characterized solely by their physical solid-state properties. Issued claim 3 recites a process of preparing a pharmaceutical composition comprising such crystalline forms. Issued claims 4–6 recite methods of treating disease by administering such crystalline forms. None of the issued claims of U.S. Patent No. 12,624,027 recites a surfactant, a TPGS component, or any weight ratio of surfactant to active compound.
The pending claims of the instant application are directed to a pharmaceutical composition comprising the compound of Formula (1) in combination with α tocopherol polyethylene glycol 1000 succinate (TPGS) at a weight ratio of TPGS to compound of Formula (1) of from 7:1 to 25:1. This formulation invention is a distinct inventive concept from the crystallographic solid-state form inventions of U.S. Patent No. 12,624,027. The issued claims do not, alone, render obvious a pharmaceutical composition defined by a specific surfactant identity and a specific surfactant-to-drug weight ratio. A comparison of the claim scopes on their faces confirms that the pending claims require limitations wholly absent from any issued claim of U.S. Patent No. 12,624,027, and the issued claims require crystallographic limitations wholly absent from the pending claims. Accordingly, the claims are patentably distinct, and the provisional ODP rejection is not maintained.
Conclusion
No claims are allowed.
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/ANDRE MACH/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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