FINAL REJECTION
Receipt is acknowledged of Applicants' Amendments and Remarks, filed Dec. 31, 2025.
Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. The rejections and/or objections set forth below are either maintained or newly applied, and constitute the complete set presently applied to the instant claims.
STATUS OF THE CLAIMS
Claims 1-10, 16, and 18 have been canceled.
Claim 11 has been amended to incorporate the limitations of cancelled claims 16 and 18 and thus incorporate no new matter.
No new claims have been added.
Thus, claims 11-15, 17, 19, and 20 now represent all claims currently pending and under consideration.
INFORMATION DISCLOSURE STATEMENT
No new Information Disclosure Statements (IDS) have been submitted.
MAINTAINED REJECTIONS
The following rejection is maintained from the previous Office Action dated Oct. 1, 2025, on the ground that the references cited therein continue to read on the limitations of the amended claims.
Rejections under 35 USC §103
Claims 11-15, 17, 19, and 20 stand rejected under 35 U.S.C. 103 as being unpatentable over Li et al. (USPN 10,227,339) in view of Rao et al. (CN107281148A) and Niazi (Handbook of Pharmaceutical Manufacturing Formulations, 3rd Ed., Appendix B).
Li et al. exemplify the claimed compound, 2-(2-aminopyridine-4-yl)-5-(5-((5-(2-ethyl-2H-tetrazole-5-yl)pyridine-2-yl)oxy)-3,3-amyldimethyl)1,2,5-thiadiazolidin-1,1-dioxide, and the hydrochloride salt thereof (claims 6-7), an EV71 virus inhibitor having the structural formula shown below, as recited by claims 11 and 13.
Li et al. differs from the claims in that the compound is not disclosed in a pharmaceutical composition formulated as a granule together with a diluent, a solubilizer, and a suspending agent, as recited by claim 11.
Claimed compound (Li et al.)
EV71 virus inhibitor
Compound of Rao et al. (TJAB-1099)
EV71 virus inhibitor
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Rao et al. disclose methods of preparing solid dispersions, e.g., granules, comprising TJAB-1099, a water-insoluble EV71 virus inhibitor having the structural formula shown above,
which impart significantly improved solubility, GI drug absorption, and bioavailability (abstract; paras. [0005]-[0006]; claim 9).
In particular, Rao et al. disclose methods of combining the active ingredient with a dispersion carrier selected from povidone K30 and/or poloxamer 188, which is mixed evenly with a diluent, a disintegrant, a binder, and a lubricant, and then mixed evenly to prepare a soft material, which is sieved to form wet granules, dried, and tableted (claims 1-6).
The disintegrant includes, e.g., cross-linked polyvinylpyrrolidone (PVP), and the binder includes, e.g., povidone (claim 8).
For example, 0.1 g of the drug and 0.4 g of povidone K30 or Poloxamer 188 are dissolved in ethanol, then transferred to a rotary evaporator at 50°C to remove the ethanol, and vacuum dried for 24 hours to obtain 0.5 g of solid dispersion (Example 2, para. [0040] and Example 3, para. [0042]). The solid dispersion was then combined with additional excipients to obtain a soft material, which was sieved to obtain wet granules, dried, and tableted (Examples 6 and 8).
Rao et al. also exemplify a solid dispersion comprising an appropriate amount of strawberry essence (Example 9, para. [0054]), as recited by claim 17.
Thus, Rao et al. disclose pharmaceutical compositions comprising a granule, wherein the granule comprises, as the active agent, the structurally and functionally similar, water-insoluble EV71 virus inhibitor TJAB-1099; povidone K30; a diluent; poloxamer 188; cross-linked polyvinyl-pyrrolidone (crospovidone); and strawberry essence, as recited by claims 11, 12, 14, 15, and 17, in amounts falling inside the ranges recited by claim 11:
Claim 18
Rao et al. Example 6
1.0-3.0% (w/w) active ingredient
0.5%
0.3-2.0% (w/w) suspending agent (povidone)
2.0%
60-98% (w/w) diluent
68%
Regarding claim 16, Rao et al. disclose that the diluent is one or more combinations of starch, pregelatinized starch, microcrystalline cellulose, dextrin and lactose (claim 8).
Niazi discloses that, e.g., lactose, microcrystalline cellulose, and sucrose, as recited by claim 11, are art-recognized equivalents as fillers or diluents:
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(Table A1, Appendix B, pp. 87-88).
As recognized by MPEP §2144.06, it is predictable to substitute art-recognized equivalents, and an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982).
Regarding claims 19-20, Rao et al. exemplify the preparation of the solid dispersion granules in two parts. First, Rao et al. prepare the adhesive by weighing, mixing, and dissolving the active agent and filler in ethanol, then evaporating and vacuum drying to obtain a solid dispersion (Examples 1-5), which reads on part (a) of claims 19-20.
Second, Rao et al. formulate tablets by precisely weighing each additional excipient, combining them with the solid dispersions (adhesives) from Examples 1-5, mixing evenly, then adding a wetting agent to prepare a soft material, which is sieved to obtain wet granules, dried, and tableted (Examples 6-9), which reads on parts (b), (c), and (d) of claims 19-20.
Therefore, it would have been predictable to one of ordinary skill in the art as of the effective filing date to formulate the compound of Li et al. in pharmaceutical solid dispersion granules with the components taught by Rao et al. with a reasonable expectation of success, because TJAB-1099 is structurally and functionally similar to the compound of Li et al., and Rao et al. teach that the solid dispersion formed by TJAB-1099 and the dispersion carrier have the advantage of improving the hydrophilicity and lipophilicity of the drug, thereby improving the absorption capacity of the drug in the body and increasing the bioavailability (para. [0032]).
The rationale to combine the references is premised on the findings that (1) Li et al. and Rao et al. disclose each component claimed, with the only difference between the claimed invention and the prior art being the lack of actual combination of the elements in a single reference; (2) one of ordinary skill in the art could have combined the elements by known methods, and that in combination, each element merely performs the same function as it does separately; and (3) one of ordinary skill in the art would have recognized that the results of the combination were predictable.
As recognized by MPEP § 2143, combining prior art elements according to known methods to yield predictable results would motivate the skilled artisan to modify the references with a reasonable expectation of success. The rationale to support a conclusion of prima facie obviousness is that all the claimed elements were known in the prior art, and a skilled artisan could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. See KSR Int'l Co. v. Teleflex Inc. (550 U.S. 398, 409).
RESPONSE TO ARGUMENTS
Applicant's arguments filed Dec. 31, 2025 have been fully considered but they are not persuasive.
Applicant contends that the combination of Li et al., Rao, and Niazi fails to teach or suggest the claimed invention because Li et al. fail to disclose how to formulate the claimed compound into a dosage form, nor does it provide guidance on achieving a formulation that is both stable and fast-dissolving.
First, Applicant argues that the claimed compound is chemically distinct from the active ingredient disclosed in Rao. In the fields of medicinal chemistry and pharmaceutics, the chemical structure of an active ingredient is the primary determinant of its physicochemical properties. The solid dispersion approach of Rao was specifically designed to address the solubility issues of TJAB-1099, which is a water-insoluble inhibitor designed based on high-resolution 3D structures of EV71 and CVA16 viruses, and its solubility specifically limits its oral absorption. This teaching is highly specific and structure-dependent, and is not a transferable teaching that would lead a person of ordinary skill in the art to expect that the structurally different claimed compound could be successfully formulated via a simple direct-blend formulation to overcome its own unique challenges of solubility and stability (Remarks, p. 7).
Claimed compound (Li et al.)
EV71 virus inhibitor
Compound of Rao et al. (TJAB-1099)
EV71 virus inhibitor
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However, Applicant provides no evidence to support these assertions.
In fact, the claimed compound and the compound of Rao et al. are so structurally similar that they share identical biological activity. For example, Li et al. (ACS Med. Chem. Lett. 8, 841−846 (2017), cited on PTO-892) disclose that the viral protein VP1 is a well-known target for antiviral design because its hydrophobic pocket can be occupied by suitable compounds, which lead to stabilizing the virus capsid and preventing uncoating of virus for RNA release (p. 841, right col.). Li et al. note that the five-carbon alkyl linker and terminal pyridine play a very important role in influencing anti-EV71 activity, and so were left unchanged (p. 842, left col.).
In particular, the imidazolidinone (DBPR103) and 1,2,5-thiadiazolidine-1,1-dioxide (compound 14) are disclosed as the most potent against EV71 activity (abstract):
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Li et al. disclose additional structure-activity relationships in Table 1, again showing the imidazolidinone (compound 1) and the 1,2,5-thiadiazolidine-1,1-dioxide (compound 5) to be the most potent against the EV71 viral protein VP1.
Therefore, on the basis of their very close structural and functional similarities, one of ordinary skill in the art would have expected the compounds of Li et al. and the compounds of Rao et al. to have closely similar physical, chemical, and biological properties, and thus, similar formulation requirements.
Next, Applicant contends that Rao et al. teach a complex organic solvent process, which involves inherent drawbacks such as increased process steps, potential safety hazards from residual solvents, and risks of drug degradation, which present significant challenges for industrial-scale production. In contrast, through creative excipient screening and ratio optimization, the present application formulates the dosage form by directly mixing and granulating the active ingredient with meticulously selected solubilizers and diluents. This method is simple, robust, and readily scalable for industrial production. A skilled artisan would have had no reasonable motivation to apply Rao's complex, compound-specific solution to a structurally different compound while simultaneously abandoning the core solid dispersion technology in favor of the direct formulation strategy claimed herein (Remarks, p. 10).
However, again, Applicant provides no evidence to support these assertions.
As recognized by MPEP § 2145(I), the arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) (“An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness.”). See MPEP § 716.01(c) for examples of attorney statements which are not evidence and which must be supported by an appropriate affidavit or declaration.
Finally, Applicant argues that the claimed compositions are supported by unexpected results, specifically the Comparative Examples in Table 2 (para. [0078] of the specification). As demonstrated therein, formulations that utilized "obvious" excipient combinations or standard soluble granule techniques outside of the claimed weight ranges failed stability testing under stress conditions. In contrast, the claimed formulation, prepared via a simple, solvent-free direct-blend process rather than the complex "solid dispersion" path of Rao, unexpectedly achieved both high stability and rapid release, further underscoring the non-obviousness of the present invention (Remarks, p. 11).
Applicant argues that the technical solution of the claimed invention successfully resolves the conflict between achieving rapid dissolution and maintaining long-term chemical stability "through a precise, non-obvious 'sweet spot' of auxiliary materials - specifically the combination of 0.3% to 2.0% povidone and the identified diluents" (Remarks, pp. 10-11).
However, the examples presented in the specification do not support these assertions.
The specification presents Embodiments 1-9, of which only Embodiment 7 was evaluated in an accelerated stability test (Table 2) and a long-term stability test (Table 3), alongside Comparative Example 3, the components of which are shown below:
Claim 11
Exemplified Embodiment 7
Comparative Example 3
API
1.0% to 3.0% (w/w)
1.0%
1.0%
Diluent (sucrose, mannitol, sorbitol, and/or xylitol)
60% to 98% (w/w)
38%
(26 parts mannitol +
12 parts sorbitol)
38%
(38 parts sucrose)
Suspending agent
(povidone, CMC sodium, carragee-nan, crospovidone)
0.3% to 2.0% (w/w)
0.7%
(0.3 parts povidone K90 + 0.4 parts crospovidone)
--
Solubilizer (poloxamer 188 and/or polysorbate 80)
0.5% to 2.0% (w/w)
(claim 15)
0.4%
0.4 parts poloxamer 188
1.0%
(0.6 parts tartaric acid + 0.4 parts polysorbate 80
Essence
0% to 1% (w/w)
(claim 17)
0.08 parts
strawberry essence
0.08 parts strawberry essence
Notably, all nine embodiments contain 26 parts mannitol and 12 parts sorbitol. Thus, like Embodiment 7, ALL exemplified embodiments contain 26 + 12 = a total of 38% (w/w) diluent, which does not fall within the range of 60% to 98% as recited by claim 11.
Put differently, the claims are drawn to compositions comprising roughly twice as much diluent (60% to 98%) as all of the exemplified compositions (38%), which cannot support a finding of unexpected results commensurate with the claims sufficient to overcome the prima facie case of obviousness. As recognized by MPEP §716.02(d),
Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the “objective evidence of non-obviousness must be commensurate in scope with the claims which the evidence is offered to support.” In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980).
For these reasons, the rejection under 35 U.S.C. § 103 of claims 11-15, 17, 19, and 20 over Li et al., Rao et al. and Niazi is maintained.
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.
CORRESPONDENCE
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARA E. TOWNSLEY whose telephone number is 571-270-7672. The examiner can normally be reached on Mon-Fri from 9:00 am to 6:00 pm (EST). If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Jeff S. Lundgren, can be reached at 571-272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SARA ELIZABETH TOWNSLEY/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
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