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 09/15/2025 are acknowledged. Claims 1, 5-15 and 17 are currently amended. Claims 2-4 are newly canceled. Claims 1, 4 and 5-20 are examined on the merits within and are currently pending.
Withdrawn Rejections
With applicants' amendment, filed 12-17-2024:
the 35 U.S.C. § 102(a)(2) rejection of Claims 3-4 has been withdrawn in view of the cancelation of the claims;
the 35 U.S.C. § 103 rejection of Claim 2 has been withdrawn in view of the cancelation of the claim;
the 35 U.S.C. § 102(a)(2) rejection of Claims 1, 5-6, 9 and 14 has been withdrawn in view of the amendment of the claims;
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.
Claim(s) 1, 5-6, 9 and 14 is/are rejected under 35 U.S.C. 103 as being obvious by He et al. (US 20230190762Al) in view of Khan et al. (US 20230133326Al) and Altreuter et al. (.US 20220387310 A1).
Claims 1, 5-6
He et al. teach a stable varenicline solid oral dosage form, (Abs), which comprises varenicline salt form, varenicline tartrate (0029). In certain embodiments, the stable varenicline solid oral dosage forms are prepared by first mixing or blending the varenicline or pharmaceutically acceptable salt thereof with a pharmaceutically acceptable excipient, such as a binder, filler / diluent, (0009), antioxidants, which are also stabilizers, which include the solid dosage forms of the present invention include ascorbic acid, butylated hydroxyanisole, butylated hydroxytoluene,
propyl gallate, tocopherol, and mixtures thereof. (0043).
The stable varenicline solid dosage forms of the present invention may comprise about 0.25 wt % to about 5 wt %, preferably about 0.5 wt % to about 2.5 wt %, and most preferably about 0.70 wt % to about 1.0 wt % of varenicline or a pharmaceutically acceptable salt thereof; (0034);
Antioxidants are also stabilizers are, butylated hydroxyanisole, butylated hydroxytoluene. The antioxidant/stabilizer may be present in the dosage forms of the present invention in an amount from about 0.01 wt % to about 20 wt % based upon the total weight of the dosage form, preferably from about 0.1 wt % to about 10 wt %, and most preferably from about 0.5 wt % to about 5 wt %. (0043);
Based on most preferably amount of varenicline about 0.70 wt % to about 1.0 wt % and of the antioxidant/stabilizer about 0.5 wt % to about 5 wt %, then the ratio of Varenicline over the antioxidant/stabilizer is about 1:1 to 1:10.
He et al. teach a stable varenicline solid oral dosage form and a method for making the stable varenicline solid oral dosage form wherein the varenicline solid oral dosage form that contains less than 50 ppm, preferably less than 25 ppm, and more preferably less than 20 ppm, of any varenicline nitroso impurity including N-nitroso or nitrosamine impurities (R1-N(-R2)-N=O). (0006).
He et al. does not teach the amount of nitrosamine impurity after exposure of the pharmaceutical composition to 40°C/75% RH for a period of six months is less than about 50 ppm.
Khan et al. teach stable pharmaceutical compositions of metformin with control on nitroso impurities. (Title). Metformin has the R1-NH-R2 structure with NH group, similar to Varenicline and is formulated with similar excipients dicalcium phosphate, magnesium stearate, and stabilizer Butylated Hydroxytoluene. The tablet formulation has stability stored at 40°C/75% RH for 6 months, with nitroso 0 ng/500 mg Metformin, (0086), which is equal 0 ppm.
He et al. and Khan et al. do not teach maltodextrin.
Altreuter et al. teach varenicline or its pharmaceutically acceptable salt is for use in formulations for gastric residence systems, (0017), which can be capsule or other container suitable for oral administration. (0102). Exemplary carrier polymers suitable for use in the release-rate modulating polymer films disclosed herein include, but are not limited to maltodextrin. (0118).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention, to prepare the solid formulation for Varenicline with excipients, taught by He et al. and especially with antioxidant Butylated Hydroxytoluene to have very low nitroso impurity in ppm taught by Khan et al. and with excipient maltodextrin, taught by Altreuter et al., since they have proven antioxidant can stabilize this group of compounds R1-NH-R2 to have low nitroso impurities.
With regard to claim 9,
The stable varenicline solid dosage forms may comprise about 0.25 wt % to about 5 wt %, preferably about 0.5 wt % to about 2.5 wt %, and preferably about 0.70 wt % to about 1.0 wt % of varenicline or a pharmaceutically acceptable salt thereof; (0034); and one or more excipients (0034); In certain embodiments, the stable varenicline solid oral dosage form is a tablet wherein the tablet is prepared by dry granulating varenicline with pharmaceutically acceptable excipients such as lubricants, fillers, binders, disintegrants, glidants, solubilizing agents, flavoring agents, pH adjusting agents, antioxidants, chelating agents, or mixtures of the foregoing, compressing the varenicline granules into a tablet, coating the tablet with a water soluble protective coating material and optionally coating the protective coating with a further cosmetic coating. (0008).
lubricant including magnesium stearate, sodium stearyl fumarate, stearic acid, glyceryl behenate, polyethylene glycols, polyoxyethylene stearate, magnesium lauryl sulfate, sodium oleate, and mixtures thereof. The lubricants may be present in an amount ranging from about 0.1 wt % to about 10 wt % based on the total weight of the dosage form, preferably about 0.2 wt % to about 7 wt %, and most preferably about 0.5 wt % to about 5 wt %. (0036);
disintegrants including croscarmellose sodium, starch, crospovidone, sodium starch glycolate, alginic acid, calcium carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, powdered cellulose, chitosan, guar gum, magnesium aluminum silicate, methylcellulose, sodium alginate, and mixtures thereof. (0039). Croscarmellose 3%, (0081), (Example 1); glidants including colloidal silicon dioxide, corn starch, talc and mixtures thereof, (0040);
fillers (diluents) including dibasic calcium phosphate (anhydrous), microcrystalline cellulose, calcium carbonate, magnesium carbonate, calcium sulfate, powdered cellulose, silicified microcrystalline cellulose, magnesium carbonate, magnesium oxide, starch, lactose anhydrous, mannitol and mixtures thereof; (0037); Anhydrous Dibasic Calcium, 34.6%; (0081), (Example 1); binders including acacia, povidone (polyvinylpyrrolidone (PVP)), hypromellose (Hydroxypropyl Methylcellulose (HPMC), hydroxypropyl cellulose, hydroxyethyl cellulose, polyethylene oxide, polymethacrylates, methyl cellulose, ethyl cellulose, pregelatinized starch, microcrystalline cellulose, gelatin, tragacanth, zein, or mixtures thereof. Microcrystalline Cellulose, which is a filler and also a binder, 60%; (0081), (Example 1);
Claim 14,
He et al. teach the stable varenicline solid oral dosage forms are prepared by a) first mixing or blending the varenicline or pharmaceutically acceptable salt thereof with a pharmaceutically acceptable excipient, such as a binder, filler or diluent, with a low moisture content. This two-component mixing of the varenicline and low moisture excipient(s) should provide a more uniform distribution of the varenicline within the low moisture excipient(s) and/or absorption or adhesion of the varenicline onto the surface of the low moisture excipient(s) in the dosage form and b) prior to the blending and/or granulation of the varenicline and low moisture excipient mixture with other pharmaceutically acceptable excipients; (0009); c) The granules may be compressed into tablets or the granules may be further blended with additional extra granular excipients such as lubricants, fillers, binders, disintegrants, glidants, solubilizing agents, flavoring agents, pH adjusting agents, antioxidants, chelating agents, or mixtures of the foregoing and compressed into tablets.
The stable varenicline solid dosage forms of the present invention may comprise about 0.25 wt % to about 5 wt %, preferably about 0.5 wt % to about 2.5 wt %, and most preferably about 0.70 wt % to about 1.0 wt % of varenicline or a pharmaceutically acceptable salt thereof; (0034);
Antioxidants are also stabilizers are, butylated hydroxyanisole, butylated hydroxytoluene. The antioxidant/stabilizer may be present in the dosage forms of the present invention in an amount from about 0.01 wt % to about 20 wt % based upon the total weight of the dosage form, preferably from about 0.1 wt % to about 10 wt %, and most preferably from about 0.5 wt % to about 5 wt %. (0043);
Based on most preferably amount of varenicline about 0.70 wt % to about 1.0 wt % and of the antioxidant/stabilizer about 0.5 wt % to about 5 wt %, then the ratio of Varenicline over the antioxidant/stabilizer is about 1:1 to 1:10.
Response to Arguments
Claim Rejections 35 U.S.C. § 102
Applicant argues that He does not disclose the following elements of claim 1 or claim 14:
(a) Use of maltodextrin as a specific excipient in the composition;
(b) Specific stabilizing agents selected from isomalt, meglumine, povidone, ascorbic acid,
tocopherol, 2,5-dihydroxy benzoic acid, butylated hydroxytoluene, butylated
hydroxyanisole, propyl gallates, pullulan, or a combination thereof;
(c) Specified impurity threshold under accelerated stability conditions, i.e., the amount of
nitrosamine impurity after exposure of the pharmaceutical composition to 40°C/75% RH
for a period of six months is less than about 50 ppm;
( d) Quantitative ratio of varenicline to stabilizing agent (1: 1 to 1: 10).
Applicant's arguments have been fully considered and they are persuasive according to 102 rejection, but not persuasive according to modified 103 rejection, since (a and b) with modified 103 rejection, Altreuter et al. teach varenicline or its pharmaceutically acceptable salt is for use in formulations for gastric residence systems, (0017), which can be capsule or other container suitable for oral administration. (0102). Exemplary carrier polymers suitable for use in the release-rate modulating polymer films disclosed herein include, but are not limited to maltodextrin. (0118)..
(c) Claim 14 does not recite Specified impurity threshold under accelerated stability conditions, i.e., the amount of nitrosamine impurity after exposure of the pharmaceutical composition to 40°C/75% RH for a period of six months is less than about 50 ppm;
(d) the antioxidant/stabilizer about 0.5 wt % to about 5 wt %, then the ratio of Varenicline over the antioxidant/stabilizer is about 1:1 to 1:10. (please see details in the rejection of claim 1 and 14 above).
Applicant argues that Claims 5, 6 and 9 depend from claim 1, and therefore He also fails to disclose the elements of claims 5, 6 and 9.
Applicant's arguments have been fully considered but they are not persuasive since
applicant does not list what claims 4, 6 and 9 fail on what specific points. Please see the modified rejection of Claims 1, 4, 6, 9 and 14 above and the rejection of Claims 1 and 14 are responded above.
Claim Rejections - 35 U.S.C. § 103
Applicant argues that "He et al. does not teach the amount of nitrosamine impurity after exposure of the pharmaceutical composition to 40°C/75% RH for period of six months is less than 50 ppm.". To make up for this deficiency, the Office Action at page 6, paragraphs 6-7, cites Khan.
Applicant's arguments have been fully considered but they are not persuasive since the basis for 103 rejection is that 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.
Applicant argues that Khan, however, fails to provide any teaching, suggestion, or motivation to apply its principles to varenicline. There is no articulated or inherent motivation, suggestion, teaching or rationale in either reference that would lead one of ordinary skill in the art to combine their respective disclosures to arrive at the present claims.
Applicant's arguments have been fully considered but they are not persuasive. In response to applicant' s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that 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, Khan teaches in some embodiments, the drug including the primary, secondary, and/or tertiary amino group includes, without limitation varenicline. (0092).
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
Claims 1, 5-6, 9 and 14 are not allowed. Claim 10 is dependent on claim 9, which is dependent on claim 1, and claims 11 and 12 are dependent on claim 10, so claims 10-12 are not cured to be rejected. Independent Claim 13 is allowed since there is not prior art rejection. Claims 7, 8 are dependent on claim 5, which is dependent on claim 1 and claim 15-18 are dependent on Claim 14, which is rejected by prior art, so Claims 7, 8 and 15-18 are not cured to be rejected also since independent claim 14 is rejected by prior art. Claim 19-20 are dependent on Claim 17, which is dependent on Claim 14, which is reject by prior art, so Claim 19-20 are not cured to be rejected also.
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/NGOC-ANH THI NGUYEN/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615