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 .
CONTINUING DATA
This application is a 371 of PCT/EP2019/085912 12/18/2019
FOREIGN APPLICATIONS
EP 18213993.1 12/19/2018
EP 19159227.8 02/25/2019
EP 19159222.9 02/25/2019
This office action is in response to Applicant’s amendment submitted October 1, 2025. Claims 29-33, 35-41, and 43-52 are pending.
The following rejections of record are maintained.
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.
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) 29-33, 35-36, and 49-50 is/are rejected under 35 U.S.C. 103 as being unpatentable over Brimert (WO 2016/120403 A1, 2016, cited on IDS) in view of Duong (EXPERT OPINION ON DRUG DELIVERY, 2016, cited on IDS) and Van den Mooter (Technologies, volume 9, Issue 2, Summer 2012, pp. e79-e85, cited on IDS).
Brimert teaches the compound recited as formula I in the current claims. See pages 135-136. A pharmaceutical composition is claimed, and treatment of a disorder such as fibrosis is claimed. Claims 25-31. The dose was 10 mg/kg (page 88, top). The compound can be in the form of a tablet or a capsule (page 64). The pharmaceutical composition contains 1-99% of excipient or carrier and 1-99% of the compound and the composition may be amorphous (page 64).
Brimert is silent about whether the obtained compound was crystalline or amorphous, and does not teach the stabilizers recited in the claims or the amounts of stabilizer to use relative to the active agent.
Duong teaches that amorphous solid dispersions are used to formulate poorly soluble drugs. The API is dispersed at the molecular level in an amorphous polymeric carrier. See abstract. Polymers to be used as the carrier include hydroxylpropylmethylcellulose acetate succinate (HPMCAS), ethylcellulose (EC) (see Introduction) or methacrylic acid ethyl acrylate copolymer (MAEA) (page 3, right column). Amorphous carriers are shown in Figure 1.
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The dissolution rate is greatly affected by the drug/carrier ratio. Typically, decreasing carrier content is associated with a decrease in dissolution content and lower stability. Page 2, right column. In an example, the carrier weight fraction was started at as low as 20% and gradually increased to determine the optimal weight fraction (Figure 2). Carriers also stabilize the drug against nucleation and crystal growth. Section 5. Choosing a carrier is mostly empirical and Figure 4 illustrates how to carry out a carrier screen.
Van den Mooter teaches that amorphous solid dispersions are used to increase the bioavailability of poorly soluble drugs by improving their rate and extent of dissolution. See abstract. One of the most applied manufacturing methods is spray drying (end of first column on page e82), or spray drying the drug-polymer solution to inert beads (page e82, top of second column).
It would have been obvious to one of ordinary skill in the art at the time at the time the application was filed to prepare a solid dispersion comprising Brimert’s compound in amorphous form and a polymer such as HPMCAS because amorphous solid dispersions are commonly prepared in the art to improve solubility and bioavailability. Duong HPMCAS as one example of a polymer used to stabilize amorphous solid dispersions, so the skilled artisan would have used HPMCAS or any of Duong’s other examples. Regarding claims 30 and 35, Brimert teaches a dosage of 10 mg/kg. If an average human weighs about 60 kg and Brimert’s dosage is followed exactly, a single dose would be about 600 mg, which is well within the claimed range. Treatment of mammals as small as 0.01 kg or as large as 100 kg, at 10 mg/kg, would fall within the claimed range. Once or twice daily administration is very common in the art, so the skilled artisan would have administered the compound once or twice daily. Duong teaches that the ratio of carrier to drug is important and teaches how to gradually increase the carrier amount to find the optimal ratio. The skilled artisan would have arrived at the claimed ratios using routine experimentation.
Claim(s) 31-33, 35-41, and 46-51 is/are rejected under 35 U.S.C. 103 as being unpatentable over Brimert in view of Duong and Van den Mooter and further in view of Desieno (US 5,573,783, 1996, previously cited by the examiner) and Curatolo (US 8,026,286 B2, 2011, previously cited by the examiner).
Brimert and Duong teach as set forth above. Van den Mooter teaches spraying a drug-polymer solution to inert beads, but is silent about the size of the beads and the identity of the bead. Van den Mooter does not teach how much of the active agent to use relative to the polymer stabilizer or the inert core.
Desieno teaches a low solubility drug associated with a stabilizer and coated on a carrier particle (see abstract). The carrier particle is sugar or Avicel (microcrystalline cellulose) at 40-45, 30-35, 20-25, 18-20, or 16-18 mesh, preferably 20-25 mesh (claims 15-16). 20-25 mesh is about 800-840 micrometers. See also column 17, Example 3. In Example 3, the ratio of active compound to polymer stabilizer is about 10:1 to 1:1. The active agent is about 15% and the carrier is about 78%. The matrix contains 0.1-60% of the stabilizer based on the weight of the drug (column 4, lines 62-67). The drug can be any of a large number of classes (claim 3). The stabilizer includes many of the same polymers taught by Duong and Van den Mooter (claim 6), including the claimed hydroxyethylcellulose acetate succinate.
Curatolo teaches improvement of drug concentration by using a polymer to prevent drug aggregation, nucleation, or crystal-growth processes. Column 9, last paragraph. Polymer-drug aggregates generally contain from about 5 wt% to about 90 wt% polymer, the remainder comprising non-crystalline drug. Column 11, first paragraph. The concentration-enhancing polymers include cellulosic polymers such as hydroxypropyl methyl cellulose acetate succinate. Column 21, lines 40-46 and claim 1.
It would have been obvious to one of ordinary skill in the art at the time the application was filed to prepare the solid amorphous dispersion as set forth above, and to use as the inert solid core a sugar or microcrystalline cellulose of around 800 micrometers. The skilled artisan would have used such a core for preparing the composition suggested by Brimert and Van den Mooter because the prior art teaches a successful composition using the sugar sphere of 20-25 mesh. Desieno teaches guidance for the amounts of active agent, stabilizer, and inert core, so it would have been obvious to one of ordinary skill in the art to optimize the amounts using Desieno’s guidance for a successful formulation and routine experimentation. Curatolo provides further guidance for the amounts of stabilizing polymer to drug for the same purpose as taught by Desieno, so the skilled artisan would have optimized the amounts of polymer and drug using Curatolo’s guidance as well. The results would have been predictable because Desieno’s and Curatolo’s methods are applicable to a wide variety of drugs, and the polymer stabilizers used include the same stabilizers taught by Duong and Van den Mooter.
Regarding claim 35, Brimert teaches a dosage of 10 mg/kg. If an average human weighs about 60 kg and Brimert’s dosage is followed exactly, a single dose would be about 600 mg, which is well within the claimed range. Treatment of mammals as small as 0.01 kg or as large as 100 kg, at 10 mg/kg, would fall within the claimed range. Once or twice daily administration is very common in the art, so the skilled artisan would have administered the compound once or twice daily.
Claim(s) 50 and 52 is/are rejected under 35 U.S.C. 103 as being unpatentable over Brimert in view of Duong, Van den Mooter, Desieno, and Curatolo, and further in view of Girard (Trends in Glycoscience and Glycotechnology Vol. 30 No. 172 (January-May 2018) pp. SE211-SE220, previously cited by the examiner).
Brimert teaches as set forth above, but does not teach how often to administer the compound.
Girard is a review of clinical applications of galectin antagonists. One agent, the small molecule TD139, was administered once daily. See page SE217. The structure of TD139 is shown below.
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TD139 has structural similarities to Brimert’s compound (fluorinated phenyl ring attached to a triazine, which is attached to a thiosugar). Brimert mentions this compound in the background section of the publication (page 8).
It would have been obvious to one of ordinary skill in the art at the time the application was filed to prepare the solid amorphous dispersion as set forth above, and to administer the compound once daily. Brimert teaches administration of the compound for treatment of disease, and a compound having structural similarity to Brimert’s compound and the same utility is administered once daily. The results would have been predictable because TD139 is structurally similar to Brimert’s compound and has the same properties and the same utility.
Claim(s) 43-45 is/are rejected under 35 U.S.C. 103 as being unpatentable over Brimert in view of Duong, Van den Mooter, Desieno, and Curatolo, and further in view of Maincent (Drug Delivery and Translational Research (2018) 8:1714-1725, of record) and Livnah (WO2013/105092 A1, 2013, of record).
Brimert, Duong, Van den Mooter, Desieno, and Curatolo teach as set forth above, but do not teach that the drug layer contains a pore forming excipient.
Maincent teaches that the use of amorphous solid dispersions to overcome poor drug solubility is of interest in the pharmaceutical industry, and sustained release ASDs are desirable. See abstract.
Livnah teaches a pharmaceutical dose which comprises an inert pellet coated with the active agent, and contains an extended-release coating. See page 2. The pore-forming agent controls the diffusion of the active agent through the coating layer, and can include HPC or lactose in an amount of 0.1-20% [0037].
It would have been obvious to one of ordinary skill in the art at the time the application was filed to incorporate a pore-forming agent into the composition suggested by Brimert and Van den Mooter because sustained release ASDs are desirable, and pore-forming agents impart controlled release characteristics to a dosage form. Livnah provides guidance for which compounds, and in which amounts, can be used as pore-forming agents for controlled release, so the skilled artisan would have used Livnah’s guidance for preparing the composition.
Response to Arguments
Applicant argues that choosing a polymer and the ASD-polymer ratio are unpredictable because Duong and Van den Mooter only disclose general ASD-to-polymer ratios. Applicant points to paragraphs from Duong and Van den Mooter. The examiner summarizes these paragraphs as follows: Duong teaches that it is difficult to predict which carrier is best suited for a given API, and that a trial and error strategy is required, and Van den Mooter teaches that there is a lack of understanding of amorphous compounds’ physical chemistry and in vivo behavior. Applicant argues that the references make clear that optimization of polymer selection and ASD-to-polymer ratio cannot be accomplished through routine experimentation. This argument is not persuasive because Duong teaches that choosing a carrier is mostly empirical and Figure 4 illustrates how to carry out a carrier screen. Duong also teaches that decreasing carrier content is associated with a decrease in dissolution content and lower stability. One method is to start the carrier weight fraction as low as 20% and gradually increase to determine the optimal weight fraction. Because Duong teaches a finite number of carriers, teaches how to carry out a carrier screen, and teaches how to optimize carrier content, experimentation would have been routine.
Applicant argues that the current specification demonstrates unexpected and highly advantageous results. The solubility of API-HPMC603 SDD was higher than the solubility of API only. This argument is not persuasive because this result is not unexpected and is not commensurate in scope with the claims. MPEP 716 states that expected beneficial results are evidence of obviousness. Van den Mooter teaches that preparing amorphous solid dispersions is done to increase the solubility of poorly soluble drugs by improving their rate and extent of dissolution. Thus, the skilled artisan would have expected at least some improvement in solubility when preparing an amorphous dispersion. Applicant has not provided any evidence to suggest that the combination with HPMC603 was effective to an unexpected extent. MPEP 716.02 states that the issue is whether properties differ to such an extent that the difference is really unexpected. MPEP 716.02(d) states that evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support. In this instance, the polymer used in the specification, HPMC, is not among the claimed polymers. Applicant has argued that selection of polymer is unpredictable, so the skilled artisan would not have been able to discern whether the results obtained with HPMC could be extrapolated to different polymers.
For these reasons, the rejections are 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.
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/LAYLA D BERRY/ Primary Examiner, Art Unit 1623