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 on 01/26/2026 are acknowledged. Claim 1 is/are currently amended. Claims 1, 3, 6, 8-11, 14, 16, 18-23 are examined on the merits within and are currently pending.
Modified Rejections
Claim Rejections - 35 USC § 103
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 non-obviousness.
Claims 1, 3, 6, 8-11, 14, 16 and 18-23 are rejected under 35 U.S.C. 103 as being unpatentable over Powers et al. (WO 2019/006283 Al) in view of Dali et al. (WO 2010/120963 Al) and further in view of Guerrieri et al. (Guerrieri et al., Role of Salt and Excipient Properties on Disproportionation in the Solid-State. Pharmaceutical Research, Vol. 26, No. 8, August 2009), Mahhour et al. (US 2021/0290548 Al).
Claim 1
Powers et al. teach pharmaceutical compositions comprising: (R)-N-(4- chlorophenyl)-2-((IS,4S)-4-(6-fluoroquinolin-4-yl) cyclohexyl) propanamide (Compound 1, (0002)) and its salts and hydrates, processes (Abs), Compound 1 mono-methane sulfonic acid salt (MSA salt), Form 1. (0021). In certain embodiments, the compound or pharmaceutical composition is administered orally. (00104). Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 mg to about 2000 mg of active ingredient per dosage unit. In these
pharmaceutical compositions the active ingredient will ordinarily be present in an amount of
about 0.1-95% by weight based on the total weight of the composition, (00170)
Powers et al. teach magnesium stearate as the lubricant (00164) and disintegrant agents (00165), but do not teach crospovidone and nor their percentages in the compositions nor the ratio of salt disproportionation of compound 1 MSA salt form to compound 1 free base is less than 25% by weight.
Dali et al. teach a preferred method is provided for preparing the tablet of the invention which includes the steps of blending the one or more excipients such as bulking agents, glidant, buffering and wetting agent. Buffering agent and p38 inhibitor are added to the blend. Additional bulking agent, and disintegrant are then mixed with the blend. A lubricant will be preferably added to the blend to facilitate tablet formation. The resulting blend is then compacted and
sized to form an intragranular portion which is mixed with an extragranular portion of
crospovidone, lubricant, and flow-aid. The resulting granulation is compressed into tablets of the invention. (0018).
For 100 mg Tablets:
(a) an intra-granular phase comprising:
(i) API:
(ii) crospovidone as a disintegrant a disintegrant present in an amount 2% of the composition;
(iii) magnesium stearate as a lubricant present in amount 0.5% of the composition; and
(iv) microcrystalline cellulose as a first diluent and lactose anhydrous as a second diluent
present in a total amount 52.3% w/w of the composition; and
(b) an extra-granular phase comprising:
(i) crospovidone as a disintegrant present in an amount of 5% w/w of the composition; and,
(ii) magnesium stearate as a lubricant present in an amount of 0.5% w/w of the composition; (0033, Example 2).
The 10 mg tablet has 11 wt% API (0031, Example 1), and the 100 mg tablet has 27 wt% API (0033, Example 2), so the API wt% can be varied between 11-27 wt% depending on the doses.
When crospovidone is substituted by croscamellose sodium, the API is conversed HCl salt to free base, which is salt disproportionation, and which cause slow down in the dissolution. (0037-0040) and crospovidone 5% in the extragranular should not cause disproportionation for the API IDO. A 5% crospovidone should increase dissolution rate of IDO over 2-3% crospovidone.
The crospovidone disintegrant in an amount within the range from 4 to 10% by weight, based on the total weight of the tablet formulation. (0015). Magnesium stearate is used as a lubricant in tablet manufacture at concentration between 0.75%-1.0% w/w (Claim 5f, pg. 18, 7e, pg. 19, Claims 9-13, pg. 20-23). Tablet formulation is provided which includes a medicament which is a pharmaceutically acceptable salt of a p38 inhibitor, such as the p38 HCl salt of the structure Formula (I) and which has good physical stability when stored at up to C/60% RH in closed containers with desiccant. The tablet formulation will contain crospovidone as a tablet disintegrant, which, unlike croscarmellose sodium, will not cause disproportionation of the HCl salt to the free base of P38 inhibitor and thus will have acceptable dissolution properties even after storage at room temperature, . (Abs). Accordingly, A stable tablet formulation containing the p38 inhibitor HCl salt which has improved physical stability over previous tablet formulations containing croscarmellose sodium and which can be stored at room temperature and 60% relative humidity in closed containers without disproportionation of the p38 inhibitor HCl salt to the free base (0005).
Guerrieri et al. teach the mesylate salts of two model pharmaceutical compounds were found to disproportionate to the free base form when physically mixed with certain common basic excipients and exposed to moderate relative humidities. The mesylate salts with higher solubilities showed significant levels of conversion to the free base. both the solubility and pH max (the pH of a solution where there is saturation of both ionized and unionized species) of the salts, as well as the base solubility, play important roles in determining the susceptibility of salts to disproportionate. The extent of conversion was also affected by excipient properties, including basicity, solubility, physical state and surface area. (Abs). Magnesium stearate did not cause free base conversion of micronazole mesylate and benzocaine mesylate salts. (pg. 2024, left par., last par.).
Mahhour et al. teach the present invention is directed to compressed tablets for oral administration, which comprise an intragranular component comprising the potassium salt of raltegravir, an inert superdisintegrant, and a binder; and an extragranular component comprising a superdisintegrant and a lubricant. (Abs). The granulation with crospovidone as the intragranular disintegrant showed about 0.4% disproportionation, whereas the granulation with sodium croscarmellose had about 2.2% free phenol. Thus, the use of the inert superdisintegrant crospovidone instead of sodium croscarmellose reduced the extent of disproportionation by about 5 times. (0094).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to prepare pharmaceutical compositions of compound 1 MSA salt form for oral delivery, taught by Powers et al. comprising crospovidone and magnesium stearate within range to not having disproportionation taught by Dali et al. and Gaerrieti et al. and Mahjour et al., since they have proven it would be suitable to do so.
With regard to claim 3,
Dali et al. teach the glidant or flow aid will be used in the tablet formulation of the invention to aid powder blend flow from manufacturing equipment into the tablet press and dies and also to reduce friction during compression and will be present in an amount within the range from 0.5 to 5% by weight, preferably from 0.5 to 2% by weight based on the tablet formulation of the invention. Examples of glidants or flow aids suitable for use in the tablet formulation of the invention include, but are not limited to, silicon dioxide. (0024).
With regard to claim 6,
Powers et al. teach A typical capsule for oral administration contains at least one of the compounds of the present invention (250 mg), lactose (75 mg), and magnesium stearate (15 mg). (00171). Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 mg to about 2000 mg of active ingredient per dosage unit. In these
pharmaceutical compositions the active ingredient will ordinarily be present in an amount of
about 0.1-95% by weight based on the total weight of the composition. (00170). When the active ingredient is at maximum 95%, or 95g in 100g total, the magnesium stearate can be 1 to 5% maximum, then the ratios between the salt to total magnesium is less than max 95/(1-5) = 19-95 by weight.
Dali et al. teach the API 10.89 wt% and Magnesium Stearate 0.75% (10 mg Tablet) or 27.23 wt% and Magnesium Stearate1.0% (100 mg Tablet), so ratios between the API and Magnesium Stearate are 14.5 or 27.23 by weight.
With regard to claim 11, Dali et al. teach the glidant or flow aid will be used in the tablet formulation of the invention to aid powder blend flow from manufacturing equipment into the tablet press and dies and also to reduce friction during compression and will be present in an
amount within the range from 0.5 to 5% by weight, preferably from 0.5 to 2% by weight based on the tablet formulation of the invention. Examples of glidants or flow aids suitable for use in the tablet formulation of the invention include silicon dioxide. (0024).
With regard to claim 14, Dali et al. teach the bulking agent is present in an amount within the range from 25 to 95% by weight of the composition. (Claim 6. B), pg. 19). All of the bulking agents are in the intragranular so the intra-granular phase further comprises silicon dioxide as a glidant present in an amount of 2.0% w/w of the composition. (Table 1, 0031).
With regard to claims 16 and 18-21, Example 3, the compound in the formulation with the disintegrant crospovidone is compared with the disintegrant Croscarmellose Sodium, were stored in close containers at 25°C/60% RH, Closed Container, for 2, 4, 8, 12-13 and 26 weeks (Table A and Table B, pgs. 13-16).
With regard to claim 22,
Dali et al. teach pharmaceutical formulation in the form of a tablet. (Claim 5f, pg. 18).
With regard to claim 23,
Dali et al. teach one or more buffering agents selected from the group consisting of citric acid. (Claim 5d, pg. 18).
Claims 1, 8-10 are rejected under 35 U.S.C. 103 as being unpatentable over Powers et al. (WO 2019/006283 Al) in view of Dali et al. (WO 2010/120963 Al) and further in view of Guerrieri et al. (Guerrieri et al., Role of Salt and Excipient Properties on Disproportionation in the Solid-State. Pharmaceutical Research, Vol. 26, No. 8, August 2009), Mahhour et al. (US 2021/0290548 Al) and Leibovici et al. (US 2003/0022921 Al).
The teachings of Powers et al., Dali et al., Guerrieri et al., and Mahhour et al. are described in claim 1.
Dali et al. teach that it is preferred that a) the bulking agent is selected from microcrystalline cellulose and lactose, and more preferably a combination of microcrystalline cellulose and lactose; (0016). The bulking agents or fillers will be present in the tablet formulations of the invention in an amount within the range from I to 95% by weight, preferably from 25 to 90% by weight of the tablet formulation. A combination of microcrystalline cellulose and lactose, preferably from 20 to 60%. (0021). And lactose is lactose anhydrous, NF. (0030-0031).
Powers et al., Guerrieri et al., and Mahhour et al. do not teach the first diluent
and the second diluent is present in a ratio ranging from 2:1 to 1:2 by weight; wherein the first diluent is present in amount ranging from 25% to 40% w/w of the composition; the second
diluent is present in amount ranging from 25% to 40% w/w of the composition.
Leibovici et al. teach novel, stable pharmaceutical formulations for the oral administration of high purity torsemide modification II are disclosed. These formulations release high purity torsemide modification II in water at a constant and high purity rate and the high purity torsemide modification II therein does not rearrange to torsemide modification I over time. (Abs). Unstable torsemide modification II described in the relevant art contains trace amounts of torsemide modification I, the presence of which facilitates the rearrangement of torsemide modification II into torsemide modification I. (0032), where the pharmaceutical composition of claim I further comprising microcrystalline cellulose as a first diluent and lactose anhydrous as a second diluent present in a total amount between 50.5% to 100% w/w of the composition. The first diluent Microcrystalline Cellulose NF is at 25-45% and the second diluent is Lactose Anhydrous is at 25.5-65%, which provide a ratio ranging close to 2: 1 to 1 :2 by weight. (0044).
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(0044).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to prepare pharmaceutical compositions of compound 1 MSA salt form for oral delivery, taught by Powers et al. comprising crospovidone and magnesium stearate without having disproportionation taught by Dali et al. and Gaerrieti et al. and Mahjour et al., and to have the pharmaceutical composition wherein the first diluent and the second diluent is present in a ratio ranging from 2: 1 to 1 :2 by weight, wherein the first diluent amount ranging from 25% to 40% w/w of the composition, wherein the second diluent is present in amount ranging from 25% to 40% w/w of the composition, taught by Dali et al. and Leibovici et al., since they have proven it would be suitable to do so.
Response to Arguments
Obviousness
Powers, Dali, Guerrieri, and Mahjour: Claims 1-3, 5-14, 16, and 18-23
Applicant argues that the cited references do not render obvious the specific simultaneous combination of seven ingredients in the amounts, ratios, and distribution claimed in claim 1 nor in any claim dependent thereon, because they do not satisfy: 1. No Motivation to Combine Powers, Dali, Guerrieri, and Mahfour.
Applicant's arguments have been fully considered but they are not persuasive because the obviousness 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, Powers teaches the active ingredient with its concentration; Dali teaches granular formulation with intra and extra granular phase, with similar active ingredient, salt of a p38 inhibitor, the same disintegrant, lubricant and filler with their same ranges of percentages and Dali, Gaerrieti and Mahjour teach to not having disproportionation. The ingredients for powder formulations, either tablets or capsules are very common, including active ingredients, filler, a disintegrant, and a lubricant combining granulations, with intra- and extra-granulations, especially with compounds having stability problems. And their percentages are also quite common in tablet or capsule formulations, except filler percentages, which filler percentages may be varied depending on active ingredient potency, efficacy and stability. The compound (R)-N-(4-chlorophenyl)-2-((1S, 4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide (also known as Linrodostat or BMS-986205) is an IDO1 inhibitor. The methane sulfonic acid salt (mesylate) form of this compound is associated with disproportionation (or "salt splitting"), which is a common stability concern for amine-based drug substances. Dali teach the compound with amine functional group and is having similar disproportionate problem, even though Dali’s active compound is different from Powers’ compound; Guerrieri teaches salts of the different chemical classes of the antifungal compound miconazole and the local anesthetic benzocaine, and Mahjour teaches to raltegravir potassium which is an HIV integrase inhibitor, but no one reference has to teach all the claim limitations for an obviousness rejection and therefore several references are combined to render the claims obvious. One with ordinary skill in the art 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. One with skill in the art, is known for solving the same problem, is represented with design choices, may modify the teachings of the prior arts until they can achieve better outcome results.
Applicant argues that the cited references do not render obvious the specific simultaneous combination of seven ingredients in the amounts, ratios, and distribution claimed in claim 1 nor in any claim dependent thereon, because they do not satisfy: 2. No Reasonable Expectation of Success.
Applicant's arguments have been fully considered but they are not persuasive because 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). Powers’, Dali’s, Guerrieri’s, or Mahjour’s compound maybe different having a different core structure, and may exhibit different acid/base behaviors but they have disproportionate problems, and they carry out the studies, and found the results reported above. Also, Dali teaches a tablet formulation of a pharmaceutically acceptable salt of a p38 HCl salt of the structure Formula (I) and which has good physical stability when stored in closed containers with desiccant. The tablet formulation will contain disintegrant crospovidone will not cause disproportionation of the HCl salt to the free base of P38 inhibitor. One with skill in the art, is known for solving the same problem, is represented with design choices, may modify the teachings of the prior arts until they can achieve better outcome results.
B. Powers, Dali, Guerrieri, Mahjour, and Leibovici
Applicant argues that Claims 1 and 8-10 are rejected under 35 U.S.C. § 103 as allegedly obvious over Powers, Dali, Guerrieri, Mahjour, and Leibovici et al. US 2003/0022921 (hereinafter, "Leibovici"). This rejection is identical to the rejection presented in the Final Office Action dated May 6, 2025. Applicant respectfully disagrees. As noted in the Response to Final Office Action
filed August 6, 2025 (the "FOA Response"), claim 1 had been previously amended to require the
elements of previously pending claim 13, which was not rejected on this basis. Accordingly,
amended claim 1 submitted in the FOA Response is not obvious in view of Powers, Dali, Guerrieri, Mahjour, and Leibovici. Accordingly, claims 8-10 depending from claim 1 submitted in the FOA Response is not obvious in view of Powers, Dali, Guerrieri, Mahjour, and Leibovici.
Applicant's arguments have been fully considered but they are not persuasive because the independent claim 1 is amended while the dependent claims are not amended, so the rejection of amended independent claim 1 does not automatically change the rejection of a dependent claim.
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
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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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