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 .
Priority
This Application is a 371 of PCT/EP2021/052362, filed Feb. 2, 2021, and claims foreign priority to EP20155184.3, filed Feb. 3, 2020 in the European Union.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 March 12, 2026 has been entered.
Claim Status
Claims 1 and 4-16 are currently pending. Applicant’s election without traverse of Group I (claims 1-5) and PVP K10 to K50 in combination with SDS in the reply filed on July 11, 2025 is acknowledged. Claims 6-15 are withdrawn. Claims 1, 4-5 and 16 are currently active and subject to examination.
Claim Rejections – 35 USC § 103 – Previously Presented
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.
The rejection of claim(s) 1, 4-5 and 16 under 35 U.S.C. 103 as being unpatentable over Fey (US 8,802,847 B2) in view of Nakach et al. (International Journal of Pharmaceutics, Volume 476, Issues 1–2, 10 December 2014, Pages 277-288) is maintained.
Claim 16 is newly added but is rejected on the same grounds as previously presented.
Response to Arguments
The Applicant argues that the prior art teaches away from the combination as in the instant claims because Nakach teaches that “different drugs will require different wetting/dispersant agents” (Remarks, p. 7-8). These arguments were fully considered but are not persuasive. Nakach provides a roadmap for one of ordinary skill in the art to build a nanosuspension for hydrophobic and poorly soluble APIs. Nakach does not name a particular API and “describes a systematic approach to select optimum stabilizer for the preparation of nano crystalline suspensions of an active pharmaceutical ingredient (API)” (Nakach, Abstract). Rather, Nakach teaches a finite number of solutions for an ordinary artisan to apply to produce similar nanosuspensions for similar poorly soluble APIs. Nakach teaches a limited number of wetting/dispersant agents that may work (less than 20), and most of them overlap with the instant invention. Nakach teaches the claimed ratio of API: dispersant and the particle size as in the instant invention. The instant invention does not teach a single formulation, but rather claims a range of wetting/dispersant agents, which are taught by Nakach. The presence of non-preferred embodiments in Nakach does not constitute a teaching away because Nakach does “not criticize, discredit, or otherwise discourage the solution claimed” (MPEP § 2123). Nakach teaches that many types of formulations will work, as in the instant invention.
The Applicant argues that the claimed invention is non-obvious because Nakach provides concrete evidence of failure (Remarks, p. 7). These arguments were fully considered but are not persuasive. Nakach does not report that the preferred stabilizers of the claimed invention did not work (PVP/SDS is preferred) but rather that HPC and PEG did not work. Nakash therefore tells a person of ordinary skill in the art which stabilizers to avoid and pushes them towards the ones that worked. Nakash’s best performing embodiment (Fig. 17, SDS/PVP) is exactly what claim 1 recites as a lead option. The Applicant’s amendment deleted e.g. HPC and poloxamer, which are the exact stabilizers that Nakash states could be problematic, showing that the Applicant is following the prior art’s roadmap with a reasonable expectation of success.
The Applicant argues that the claimed invention succeeded under conditions that the prior art taught to avoid because it reports that stabilizer concentrations above the CMC (as high as 4-fold higher than the CMC) produced stable nanosuspensions and no Ostwald ripening was observed (Remarks, p. 7). These arguments were fully considered but are not persuasive. Nakach demonstrates that stabilizer/SDS concentrations several times greater than the CMC produced stable nanosuspension. Nakach’s preferred embodiment uses 1.2% w/w SDS/PVP in a 40:60 ratio (Nakach, Abstract). This corresponds to a 0.48% w/w concentration of SDS. Nakach Fig. 10 shows that the CMC of this suspension is less than 0.01%:
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Nakach, p. 285.
Therefore, Nakach teaches that stable nanosupensions can be produced with SDS concentrations at least 50 times greater than the CMC, and it is not surprising that an SDS concentration four times greater than the CMC produces a stable nanosuspension. Regarding Ostwald ripening, Nakach teaches that Ostwald ripening is absent at this concentration: “This demonstrates that 1–1.2% is sufficient to ensure the suspension stabilization. Any excess is undesired as it may increase micellar solubility and therefore promote Ostwald repining.” (Nakach, p. 286).
The Applicant argues that the amended claims define a specific, non-obvious and unexpectedly successful formulation and that the combination of vericiguat with a PVP/SDS system at a specific 16:1 to 1:2 w/w ratio is not a product of routine optimization (Remarks, p. 8). These arguments were fully considered but are not persuasive. Nakach explicitly teaches PVP/SDS as the preferred stabilizer and a ratio of approximately 6.7:1 API: stabilizer, clearly falling within the range of the claimed invention. Nakach teaches that these conditions produce a stable nanosuspension. As stated in the MPEP, “evidence of similar properties or evidence of any useful properties disclosed in the prior art that would be expected to be shared by the claimed invention weighs in favor of a conclusion that the claimed invention would have been obvious.” (MPEP § 2144.08).
Reiterated Rejection
Claim(s) 1, 4-5 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Fey (US 8,802,847 B2) in view of Nakach et al. (International Journal of Pharmaceutics, Volume 476, Issues 1–2, 10 December 2014, Pages 277-288).
The instant invention is directed towards a nanosuspension comprising the known cardiovascular agent vericiguat and one or more stabilizers in a dispersing agent. Nanosuspensions comprising an active pharmaceutical ingredient (API) and one or more stabilizers in a dispersing agent are commonly known in the art. Many APIs are poorly soluble in aqueous solutions and therefore have poor bioavailability (Nakach, col. 1, p. 277). Nanosuspensions have been applied in order to deliver these poorly soluble APIs (id.). It is well within the level of ordinary skill to produce a nanosuspension as instantly claimed.
Claim 1 is directed towards a stable nanosuspension comprising:
nanoparticles of vericiguat, having the following formula:
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, in crystalline form of modification I, characterized in that the x-ray diffractogram of the compound exhibits peak maxima of the 2 theta angle at 5.9, 6.9, 22.7, and
one or more stabilizers in a dispersing agent
wherein the stabilizer(s) is polyvinylpyrrolidone (PVP) in combination with sodium dodecylsulfate (SDS), or selected from the group consisting of sodium dodecylsulfate (SDS), hydroxypropylmethylcellulose (HPMC), polysorbate 20-80, and combinations thereof,
the maximum concentration of the one or more stabilizer(s) is the solubility limit of the stabilizer(s) in the suspension,
the dispersing agent is selected from the group consisting of water, ethanol propanol, isopropanol, butanol, isobutanol, tert-butanol and glycerol,
the ratio of the compound of formula (I):one or more stabilizers is 16:1 to 1:2 w/w,
the nanoparticles have an average particle size, expressed as d50, of 500 nm or less,
and the average particle size, expressed as d50, remains at 500 nm or less at storage for at least one week at a temperature of at least 40°C.
Vericiguat is a cardiovascular agent indicated for the treatment of disorders such as heart failure and myocardial infarction (Fey, Specification, col. I). Fey teaches vericiguat, in crystalline form of modification I, characterized in that the x-ray diffractogram of the compound exhibits peak maxima of the 2 theta angle at 5.9, 6.9, 22.7:
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Fey, Specification, col. 25-26.
While Fey does not teach a stable nanosuspension of the vericiguat polymorph, one of ordinary skill in the art would have a reasonable expectation of success to produce a stable nanosuspension of vericiguat because these nanosuspensions are commonly known in the art for producing highly stable and bioavailable oral dosage forms of poorly soluble APIs.
For example, Nakach teaches a systematic approach to produce nanocrystalline suspensions of APIs, comprising e.g. 20% (w/w) of API, 3% (w/w) of dispersant/wetting (stabilizer) agents, and 77% (w/w) of water for injection (WFI) (Nakach, col. 2, p. 278). This is ratio of approximately 6.7:1 API: stabilizer, falling within the claimed range of 16:1 to 1:2 w/w%.
The dispersing agent is water for injection.
The stabilizer is included at a concentration that is less than the solubility limit (up to 3% w/w). The stabilizers used by Nakach included polyvinylpyrrolidone (PVP) in combination with sodium dodecylsulfate (SDS), vinylpyrrolidone- vinyl acetate copolymer, ethylene oxide-propylene oxide block copolymer, sodium dodecylsulfate (SDS), hydroxypropylmethylcellulose (HPMC), polysorbate hydroxypropylcellulose (HPC), polyoxyl-35 castor oil, and polyoxyl 15 hydroxystearate, as shown below.
The stabilizers used by Nakach include the following:
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Nakach, p. 279, Table 2.
Nakach teaches that the average particle size, expressed as D50 is 500 nm or less:
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Nakach, p. 282, Fig. 3.
While Nakach does not teach that the average particle size remains at 500 nm or less at storage for at least one week at a temperature of at least 40 degrees Celsius, one of ordinary skill in the art would have a reasonable expectation that the particle size would remain at 500 nm or less at storage for at least one week at a temperature of at least 40 degrees Celsius because the formulation of the instant invention is substantially identical to that of Nakach (a crystalline nanosuspension of an insoluble API using the same dispersing agent, the same stabilizer, similar particle size and concentrations) and the behavior at 40 degrees Celsius is an inherent property of such compositions (see MPEP § 2112). Supporting this, Nakach demonstrates that the preferred embodiment with SDS/PVP and d50 of about 125 nm was highly stable and the particle size did not change over 57 days of storage in ambient conditions:
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Nakach, p. 286, Fig. 17.
Therefore, claim 1 was prima facie obvious at the time of filing.
Claim 4 is directed towards the stabilized nanosuspension of claim 1, wherein the nanoparticles have an average particle size (d50) of 300 nm or less. One of ordinary skill in the art would have a reasonable expectation of success to produce a nanosuspension containing nanoparticles of d50 of 300 nm or less because Nakach teaches an exemplary nanosuspension containing nanoparticles with a d50 of about 125 nm as shown in Fig. 17 cited above. Therefore, claim 4 was prima facie obvious at the time of filing.
Claim 5 is directed towards the stabilized nanosuspension of claim 1, wherein the average particle size (d50) remains at 300 nm or less at storage for at least one week at a temperature of at least 40 degrees Celsius. While Nakach does not teach that the average particle size remains at 300 nm or less at storage for at least one week at a temperature of at least 40 degrees Celsius, one of ordinary skill in the art would have a reasonable expectation that the particle size would remain at 300 nm or less at storage for at least one week at a temperature of at least 40 degrees Celsius because Nakach teaches formulations that are substantially identical to the claimed invention and would be expected to have the same properties under a theory of inherency. Furthermore, Nakach teaches a preferred embodiment with SDS/PVP wherein the d50 was about 125 nm and the particle size did not change over 57 days of storage in ambient conditions (Fig. 17). Therefore, claim 5 was prima facie obvious at the time of filing.
Claim 16 is directed towards the stable nanosuspension of claim 1, wherein the ratio of the compound of formula (I):one or more stabilizer(s) is 8:1 to 2:1 w/w. As shown in the rejection of claim 1, one of ordinary skill in the art would have a reasonable expectation of success to use such a ratio because they are commonly known in the art. For example, Nakach teaches a systematic approach to produce nanocrystalline suspensions of APIs, comprising e.g. 20% (w/w) of API, 3% (w/w) of dispersant/wetting (stabilizer) agents, and 77% (w/w) of water for injection (WFI) (Nakach, col. 2, p. 278). This is ratio of approximately 6.7:1 API: stabilizer, falling within the claimed range of 8:1 to 2:1 w/w. Therefore, claim 16 was prima facie obvious at the time of filing.
Given the above teachings, the invention as a whole was prima facie obvious at the time of filing. The claimed polymorph of vericiguat is well known in the art. The teachings of Nakach show that it is within the level of ordinary skill to produce highly stable crystalline nanosuspensions comprising a poorly soluble API, wherein the stabilizing agent is one such as PVP/SDS, the dispersing agent is water, and the average particle size (d50) is less than 500 nm.
Conclusion
No claim is found to be allowable.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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 HEATHER DAHLIN whose telephone number is (571)270-0436. The examiner can normally be reached 9-5.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Lundgren can be reached on (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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/HEATHER DAHLIN/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
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