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 .
Status of Application
Applicants' arguments/remarks filed 02/02/2026 are acknowledged. Claims 1 and 17 are currently amended. Claims 6, 15 and 19-20 are newly canceled. Claim 14 is amended to include the ratio of claim 15. Claims 1, 5, 7-8, 11, 13-14 and 17-18 are examined on the merits within and are currently pending.
Withdrawn Rejections
With applicants' amendment and with respect to the arguments/remarks filed 02/02/2026:
The rejection under 35 U.S.C. 103 of claims 6 and 19 are withdrawn in view of the cancellation of these claims.
The rejection under 35 U.S.C. 102(a)(1) of claims 15 and 20 are withdrawn in view of the cancellation of these claims.
Modified Rejections
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, 5, 7-8, 11, 13-14 and 16-18 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Adesuyi et al. (US 8367685-B2).
Claim 1,
Adesuyi et al. teach composition comprising propylsulfamic acid 5-(4-bromophenyl)-6-2- (5-bromo-pyrimidin-2-yloxy)-ethoxy-pyrimidin-4-yl-amide, which is macitentan, (col. 1, line 19-21), with the dosage strength for the treatment of pulmonary arterial hypertension (PAH), (col. 10, line 31-32), to be in the form of a tablet (col. 2, lines 36-37), involving direct compression (col. 11, line 10); the compound macitentan in a total amount of up to 50% in weight based on the total weight of the pharmaceutical composition. (col 7, lines 3-6); a filler (col 2, line 1); a filler (col. 4, lines 40-42, 47), such as a sugar alcohol mannitol (col. 6, line 30), can be in an amount of 10-95% or 30-85% in weight based on the total weight of the pharmaceutical composition (col. 8, lines 38-41); a filler can be mannitol, (col., 2, line 46, col. 4, lines 40-42 and 51, col 6, line 30); as a filler and/or a diluent; and a surfactant (col. 2, line 4), such as polysorbate (col. 4, line 32), more specifically polysorbate 80 (col. 5, line 14), in a total amount of up to 7% or 0.01 to 5%, in weight based on the total weight of the pharmaceutical composition (col. 3, lines 6, 36-37). The pharmaceutical compositions of Reference Examples RE1 to RE4 and of Examples 16 to 33, 40, 41 and 43 were prepared by following a wet granulation process (col. 11, lines 49-50).
With regards to claim 5, the compressed composition comprising a surfactant, in a total amount of up to 7% or 0.01 to 5% in weight based on the total weight of the pharmaceutical composition (col. 3, lines 6, 36-38).
With regards to claims 7-8 and 11, the filler/diluent can be non-sugar alcohols, microcrystalline cellulose (col. 4, lines 42, and 50), which can be in a total amount of 0-20% in weight based on the total weight of the pharmaceutical composition. (col. 3, line 61-63). One or more excipients selected from the group consisting of microcrystalline cellulose, in a total amount of 10 to 95% in weight based on the total weight of the pharmaceutical composition (e.g. in an amount from 30 to 90%, in weight based on the total weight of the pharmaceutical composition). (col 3, lines 17-24).
With regards to claim 13, the composition comprises c) a disintegrant, e) a lubricant (col. 2, lines 2 and 5) and a binder such as starch, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol (col 2, lines 43, 46, 49, 61).
With regards to claim 14, the composition comprises a non-sugar alcohol diluent, wherein the non-sugar alcohol diluent is microcrystalline cellulose (col. 4, line 50), c) a disintegrant e.g. crospovidone (col. 4, line 61), e) a lubricant (col. 2, lines 2 and 5) and a binder such as polyvinylpyrrolidone, (col 3, line 66) and the lubricant is magnesium stearate. (col. 4, lines 34-35).
With regards to claim 16, the pharmaceutical compositions with the dosage strength for the treatment of pulmonary arterial hypertension (PAH), (col. 10, line 31-32).
With regards to claim 18, the pharmaceutical compositions, in the form of a tablet (col. 2, line 37) taken orally, involving direct compression (col. 11, line 10) with the dosage strength for the treatment of pulmonary arterial hypertension (PAH), (col. 10, line 31-32).
Claim 17, Adesuyi et al. teach composition comprising propylsulfamic acid 5-(4-bromophenyl)-6-2- (5-bromo-pyrimidin-2-yloxy)-ethoxy-pyrimidin-4-yl-amide, which is macitentan, (col. 1, line 19-21), with the dosage strength for the treatment of pulmonary arterial hypertension (PAH), (col. 10, line 31-32), to be in the form of a tablet (col. 2, lines 36-37), involving direct compression (col. 11, line 10); the compound macitentan in a total amount of up to 50% in weight based on the total weight of the pharmaceutical composition. (col 7, lines 3-6); a filler (col 2, line 1); a filler (col. 4, lines 40-42, 47), such as a sugar alcohol mannitol (col. 6, line 30), can be in an amount of 10-95% or 30-85% in weight based on the total weight of the pharmaceutical composition (col. 8, lines 38-41); a filler can be mannitol, (col., 2, line 46, col. 4, lines 40-42 and 51, col 6, line 30); as a filler and/or a diluent; and a surfactant (col. 2, line 4), such as polysorbate (col. 4, line 32), more specifically polysorbate 80 (col. 5, line 14), in a total amount of up to 7% or 0.01 to 5%, in weight based on the total weight of the pharmaceutical composition (col. 3, lines 6, 36-37).
The process for the preparation of can be carried out according to the process flow chart: shown in FIGs 2, 3, 4, 5 and 6. (pg. 3-7) and wherein and a surfactant (col. 2, line 4), such as polysorbate (col. 4, line 32), more specifically polysorbate 80 (col. 5, line 14), in a total amount of up to 7% or 0.01 to 5%, in weight based on the total weight of the pharmaceutical composition (col. 3, lines 6, 36-37)..
The pharmaceutical compositions of Examples 1-15 were prepared according to a process Summarized by the flow chart shown in Figures 2-6, Sheets 2-6. For compressed composition into tablets: Blend intra-granular materials separately from extragranular materials, or blend all to form uniform granular materials with compound macitentan and excipients a filler, a disintegrant, a glidant (col. 4, lines 20-29); Addition of lubricant and blending; And compression into tablets. (Figure 3, sheet 3).
Response to Arguments
With Regard to 35 U.S.C. § 102 Rejection:
Applicant argues that Adesuyi does not disclose, either expressly or inherently, a compressed composition comprising macitentan in the claimed amount, mannitol as the sugar alcohol diluent, polysorbate 80 in an amount of 0.5 to 5 wt.%, and prepared by wet granulation. While Adesuyi generically states that a surfactant may be present in an amount of up to 7 wt.%, all tablet examples employing polysorbate 80 use only 0.10 to 0.20 wt.%, which is well below the lower limit of amended claim 1. Further, the only higher surfactant level disclosed in Adesuyi is 1 wt.% sodium lauryl sulfate, and this is used only in capsule formulations, not in compressed tablets. Adesuyi also fails to disclose the use of mannitol in the claimed context. A review of all formulation examples in Adesuyi shows that mannitol appears only one example-Example 35. In that example: macitentan is present at 1 .40 wt.%, which is outside the claimed range - 5 to 25% wt.% of macitentan; no surfactant is included; mannitol is present at 71.6 wt.%, which is outside the claimed range; and the composition is prepared by direct compression rather than by wet granulation. And no dissolution or stability data are reported for Example 35. All examples in Adesuyi that use polysorbate 80 do not contain any sugar alcohol, including mannitol. The only example containing mannitol does not include a surfactant and is not prepared by wet granulation.
This argument has been fully considered, but is found not persuasive, because Adesuyi teaches wet granulation, the compositions with the excipients and the percentages applicant recites in the claim limitations, the percentages of the API macitentan 40% (Example 15, 14.29% (Examples 16-20, 40, 41). Adesuyi teaches a filler (col. 4, lines 40-42, 47), such as a sugar alcohol mannitol (col. 6, line 30), can be in an amount of 10-95% or 30-85% in weight based on the total weight of the pharmaceutical composition (col. 8, lines 38-41); a filler can be mannitol, (col., 2, line 46, col. 4, lines 40-42 and 51, col 6, line 30); the claimed range overlaps or is adjacent to the prior art, creating a presumption of obviousness. And OSITA can learn from and select specific parts of several prior arts’ teachings before the effective filing date of the invention to achieve better outcome results even though some prior arts may teach more and may teach different things. Also, applicant has no limitation of dissolution and stability in any claims, so the argument of no dissolution or stability data are reported for Example 35 is not persuasive. In addition, a prior art reference does not need to provide an explicit example (working example) to render a claim obvious/anticipated, provided it offers sufficient teaching, suggestion, or motivation for one of ordinary skill in the art (OSITA) to arrive at the claimed invention. OSITA is known for solving the same problem, is represented with design choices, would have selected those specific excipients and percentages from the prior art, even without an explicit example of matching excipients and percentages, to achieve outcome results.
Applicant argues that in view of the foregoing, claim 1 is not anticipated by Adesuyi. Amended independent claim 17 is also not anticipated by Adesuyi for substantially the same reasons as discussed above for claim 1.
This argument has been fully considered, but applicant’s arguments about claim 1 is found not persuasive, so this argument is not persuasive either.
Applicant argues that nothing in Adesuyi suggests or motivates such a combination, nor does
Adesuyi provide any indication that such a formulation would be desirable or workable. Such a
reconstruction can only be made with impermissible hindsight or pos factum analysis.
This argument has been fully considered, but is found not persuasive, because obviousness/anticipation may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, adesuyi teaches all matching API, excipients and their compositions, even though even though adesuyi teaches more and may teach different things, OSITA can learn from and select specific parts of several prior arts’ teachings before the effective filing date of the invention to achieve better outcome results. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Applicant argues that a person of ordinary skill in the art would not have had a reasonable expectation of success in combining these features in the manner presented in the office action. Pharmaceutical formulation, particularly for poorly-soluble and chemically sensitive macitentan, is unpredictable. Adesuyi provides no teaching that increasing the amount of polysorbate 80 would improve formulation performance, no teaching that mannitol would be compatible with such surfactant levels in a wet-granulated system, and no stability data for mannitol-containing compositions.
This argument has been fully considered, but is found not persuasive, because as explain above that Adesuyi teaches a filler, such as a sugar alcohol mannitol, can be in an amount of 10-95% or 30-85% in weight based on the total weight of the pharmaceutical composition; a filler can be mannitol; the claimed range overlaps or is adjacent to the prior art, creating a presumption of obviousness/anticipation. When the reference relied on expressly anticipates or makes obvious all of the elements of the claimed invention, the reference is presumed to be operable. Once such a reference is found, the burden is on applicant to rebut the presumption of operability. In re Sasse, 629 F.2d 675, 207 USPQ 107 (CCPA 1980). See also MPEP § 716.07. See also In re Antor Media Corp., 689 F.3d 1282, 103 USPQ2d 1555 (Fed. Cir. 2012).
Applicant argues that Engelmeier likewise does not overcome these limitations, as it is directed primarily to crystalline forms of macitentan and does not disclose mannitol, polysorbate 80 in the claimed range, or a wet-granulated compressed composition.
This argument has been fully considered, but is found moot, because applicant canceled claims 6 and 19, so Engelmeier is removed from this office action.
Applicant argues that provides comparative dissolution data demonstrating bioequivalence of the claimed compositions with the reference product Opsumit®. These results confirm that the presently claimed compositions provide predictable and clinically relevant dissolution performance.
This argument has been fully considered, but is found not persuasive, because the data is not commensurate in scope with the claims. The claims cover a broad range, but the dissolution data only covers one exact point, the data does not prove unexpected results across the entire claimed range. The claimed formulation is not "unexpectedly superior" to the closest prior art with similar formulation. Adesuyi provides the exact active pharmaceutical ingredient (API) and excipients within similar percentage ranges, creating a prima facie case of obviousness/anticipated and that the alleged unexpected results are insufficient to overcome the prima facie case of anticipated. The dissolution characteristics are inherent to the combination of the API and excipients disclosed in the prior art, even if the prior art did not specifically test that exact formulation.
Applicant argues that Example 6 in the SPEC provides unexpected long-term stability results, as it comprises macitentan formulated with mannitol as the sugar alcohol diluent, polysorbate 80 as the surfactant, and is prepared by wet granulation, after 12 months of storage at 30 °C and 75 % relative humidity, the level of the MCT-IMA impurity was below 0.05 %, and the total impurities were also below 0.05 %. In contrast, Adesuyi reports stability data only up to a maximum of 6 months, and even those data relate to formulations that do not comprise mannitol. Adesuyi does not report impurity levels approaching those achieved by Example 6 after 12 months, nor does it disclose or suggest that such long-term chemical stability could be achieved by combining mannitol and polysorbate 80 in a wet-granulated compressed composition.
This argument has been fully considered, but is found not persuasive, because the data is not commensurate in scope with the claims. The claims cover a broad range, but the stability data only covers one exact point, the data does not prove unexpected results across the entire claimed range. The claimed formulation is not "unexpectedly superior" to the closest prior art with similar formulation. Adesuyi provides the exact active pharmaceutical ingredient (API) and excipients within similar percentage ranges, creating a prima facie case of obviousness/anticipated and that the alleged unexpected results are insufficient to overcome the prima facie case of anticipated. Also, Adesuyi provides stability data at 40°C with 75% relative humidity for up to 6 months. while the prior art provided stability data for 6 months, one with skill in the art (OSITA) would have expected a similar composition to remain stable for 1 year, making the 1-year stability a predictable result, not an "unexpected" one.
Conclusion
Applicants' amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 extension fee 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 date of this final action.
Correspondence
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NGOC-ANH THI NGUYEN whose telephone number is (571)270-0867. The examiner can normally be reached Monday - Friday 8:00 am.
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/NGOC-ANH THI NGUYEN/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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