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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 5/5/2025 has been entered.
Claims Status
Receipt of Remarks/Amendments filed on 5/5/2025 is acknowledged. Claims 17-19, 22-28, 30-34, 38-40 and 42 are currently pending and under examination.
Receipt of Declaration under 37 C.F.R. 1.132 filed on 5/5/2025 is acknowledged.
Rejection(s) not reiterated from the previous Office Action are hereby withdrawn. The following rejections are either reiterated or newly applied. They constitute the complete set of rejections presently being applied to the instant application.
Withdrawn Rejections
Applicant’s arguments/amendments, filed 5/5/2025, with respect to the previous new matter rejection have been fully considered and are persuasive. The previous new matter rejection has been withdrawn due to claim amendments.
Modified Claim Objection(s) / Rejection(s) Necessitated by Claim Amendments
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 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.
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.
Claims 17-19, 25, 27-28 and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Mathiowitz et al. (US 2014/0120162 A1; May 1, 2014) in view of Dokou et al. (US10272046B2; Apr. 30, 2019) as evidenced by Muley et al. (Asian Journal of Pharmaceutical Sciences II (2016) 684-699).
Mathiowitz throughout the reference teaches drug delivery compositions containing one or more active agents wherein the active agent can be a therapeutic agent or a diagnostic agent (Abstract; Para 0027). The formulation is a solid oral dosage formulation which can be in the form of multiparticulate formulations, beads, granules and particles (Para 0131, 0142). Mathiowitz teaches the formulation can be prepared using the extrusion-spheronization method wherein the micronized drug, optionally containing one or more charge masking elements, is mixed with microcrystalline cellulose (i.e., synthetic polysaccharide), binder, diluents and water (i.e., a volatile/non-volatile liquid) and extruded as a wet mass. The extrusion method results in rods with diameter of 0.1 to 5mm and the rods are transformed into spherical shapes. This reads on the diameter recited in the claims and since Mathiowitz is teaching the formulation transformed into spherical shapes, it would necessarily have a sphericity factor of about 1. The resulting spheroids are then dried at 40-50 C for 24-48 hours using tray dries or fluidized bed dryers and the spheroids can then be coated. (see: Para 0161). Mathiowitz teaches the drugs can be dispersed in polymers to reduce particle size and increase dissolution (Para 0127). Also, the reference discloses polyethylene glycol as a polymer which can be used with the active drug component (Para 0083). Mathiowitz also teaches polyethylene glycol as a binder with which the drug is mixed (Para 0132). Further, as evidenced by Muley, extrusion-spheronization process of producing pellets is multi-step batch process (see: Conclusion of Muley). Therefore, the extrusion-spheronization batch process would necessarily produce at least two different strengths of the active ingredient as recited in instant claim 19. Mathiowitz also discloses adding further excipients such as fillers, disintegrant, surfactants and lubricants (Para 0121). The reference teaches the drug can be loading in the amount ranging from 1 to 90% w/w (Para 0143). As discussed supra, Mathiowitz teaches the solid dosage formulation can be in the form of beads or granules. Mathowitz also does not require a method step of lyophilizing and molding.
The teachings of Mathiowitz have been set forth above.
Mathiowitz does not expressly teach the specific weight of the bead and wherein the formed beads are of different size or weight having different concentrations of the active ingredient, separating the beads according to their size or weight, and wherein each bead is a solid unit dosage which is neither reconstituted into a capsule nor a tablet, and is not subjected to compression. However, Dokou addresses this these deficiencies.
Dokou throughout the reference discloses solid pharmaceutical formulation in the form of granules or mini-tablets (abstract). The granules can be produced through extrusion-spheronization process. (col. 89, line 30-37). Dokou teaches that the formulation is in a unit dose form comprising one or plurality of granules or mini-tablets wherein the unit dose comprises 1 mg to 250 mg of active. The solid unit dose forms range in size from about 1 mm to about 5 mm and this miniaturized versions of adult dosage forms can easily be administered to patient that have difficulty swallowing adult sized tablet form. (claim 1; col. 9, line 37-50; col. 18, line 55-59). Dokou discloses examples illustrating 2 mm to 4 mm mini-tablet having weights such as 35.7 mg and 44.7 mg. Dokou teaches that one skilled in the art would understand that any desired dosage can be achieved by adjusting the weight of the formulation. (col. 68, line 24-36). Dokou further teaches that the number of solid dose form required for each unit dose form depends on the amount of the active compound in each solid dose form, and the required final amount of the active compound. (col. 65, line 3 to col. 67, line 45). Dokou teaches admixture/powder blend comprising the ingredients can be processed in to granules, pellets or mini tablets wherein the admixture can be granulated using extrusion-spheronization method. The granules can also be compressed into tablets and mini tablets. (col. 89, line 5-40). Thus, Dokou teaches method which produces granules through extrusion-spheronization process wherein a granule can be used as a unit dose without requiring further compression step.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to have modified Mathiowitz to incorporate the teachings of Dokou and form the beads/granules of Mathiowitz wherein the formed beads/granules are of different size or weight, having different concentrations of the active ingredient, separating the beads/granules according to their size or weight, and wherein each bead or granule is a solid unit dosage which is neither reconstituted into a capsule nor a tablet, and is not subjected to compression. As discussed supra, Dokou also teaches solid pharmaceutical formulations in the form of granules which can be produced through extrusion-spheronization process. Dokou teaches that the formulation is in a unit dose form comprising either one or plurality of granules or mini-tablets and that the number of solid dose form required for each unit dose form depends on the amount of the active compound in each solid dose form, and the required final amount of the active compound. Therefore, one skilled in the art would have found it obvious to form beads/granules having different size or weight which would depend on the amount of the active ingredient required by the recipient/patient. Further, it would have been obvious to one skilled in the art to separate the individual beads/granules according to their size or weight based on the amount of the active ingredient required the recipient/patient. Also, as Dokou teaches that the number of solid dose form required in each unit dose depend on the amount of the active ingredient in each solid dose form and thus, one skilled in the art would have found it obvious to administer the solid unit dose comprising a single dose form based on the dosage required by the recipient/patient.
Additionally, the weight of the formulation would also depend on the amount of active ingredients and the amount of active ingredient can be manipulated based on the disease indication, dose requires, size of the subject, etc. Therefore, absence a criticality of the claimed weight range, it would have been obvious to have the weight of the formulation as recited in the instant claims.
Further, while Mathiowitz discloses compressed tablet and capsule as preferred delivery system (para 0162-163), Mathiowitz does not require the extruded and spheronized beads/granules are further compressed into a tablet or capsule. “Disclosed examples and preferred embodiments do not constitute a teaching away from the broader disclosure or non-preferred embodiment.” In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). MPEP 2123. Dokou teaches admixture/powder blend comprising the ingredients can be processed in to granules, pellets or mini tablets wherein the admixture can be granulated using extrusion-spheronization method. The granules can also be compressed into tablets and mini tablets. (col. 89, line 5-40). Thus, Dokou teaches method which produces granules through extrusion-spheronization process wherein a granule can be used as a unit dose without requiring further compression step. Therefore, it would have been obvious to one skilled in the art to use the extruded and spheronized beads/granules of Mathiowitz as the final dosage form without compressing the beads/granules into a tablet or capsule form. Specifically, one would have been motivated to do so because it would eliminate an extra step in the method of formulating a dosage form.
From the combined teaching of the cited references, one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Claims 26, 30-32 and 34 are rejected under 35 U.S.C. 103 as being unpatentable over Mathiowitz et al. (US 2014/0120162 A1; May 1, 2014) in view of Dokou et al. (US10272046B2; Apr. 30, 2019) as evidenced by Muley et al. (Asian Journal of Pharmaceutical Sciences II (2016) 684-699) as applied to claims 17-19, 25, 27-28 and 40 above and further in view of Backensfeld et al. (US 2007/0059359 A1; Mar. 15, 2007).
The teachings of above cited references have been set forth above.
Mathiowitz further teaches the formulation comprising a filler such as mannitol (Para 0131; 0121), a binding agent such as polyvinylpyrrolidone (0121; 0132), a disintegrant such as cross-linked povidone (0134). The reference does not expressly teach the amount of these excipients added in the formulation. Further, as discussed supra, Mathiowitz teaches the drug mixed with microcrystalline cellulose (i.e., synthetic polysaccharide), but does not expressly teach the amount thereof. However, these deficiencies are cured by Backensfeld.
Backensfeld throughout the reference teaches a solid pharmaceutical formulation comprising an active component and excipients which include fillers such as mannitol in the amount of 1-50%, binders such as polyvinyl pyrrolidone in the amount of 0.5-15%, disintegrant such as cross-linked povidone in the amount of 1-20% (0046-0053). Backensfeld also discloses microcrystalline cellulose in the amount of 1-10% (0049).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to have modified Mathiowitz to incorporate the teachings of Backensfeld and include the excipient components in the amount taught by Backensfeld. One would have been motivated to do so because Mathiowitz discloses adding such components in the formulation but is silent on the amounts to add and Backensfeld, which also teaches solid pharmaceutical formulations, discloses amount of such excipients that are known in the art. Thus, it would have been obvious to one skilled in the art to look towards the teachings of Backensfeld when adding the excipients taught by Mathiowitz in the formulation of Mathiowitz. For example, one skilled in the art would manipulate the amount of binder and disintegrant based on the hardness desired, and filler and carriers based on the amount of active ingredient and the size of the bead/granule desired. “The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.” In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969). See MPEP 2144.05.
From the combined teaching of the cited references, one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Claims 22, 24, and 38-39 are rejected under 35 U.S.C. 103 as being unpatentable over Mathiowitz et al. (US 2014/0120162 A1; May 1, 2014) in view of Dokou et al. (US10272046B2; Apr. 30, 2019) as evidenced by Muley et al. (Asian Journal of Pharmaceutical Sciences II (2016) 684-699) as applied to claims 17-19, 25, 27-28 and 40 above and further in view of Sadeghi (Iranian J Basic Med Sci, Vol. 14, No. 4, 2011) as evidenced by Bhavsar (Indo American Journal of Pharmaceutical Research, 2017:7(08)).
The teachings of Mathiowitz have been set forth above.
As discussed supra, Mathiowitz discloses mixing the active drug component with polyethylene glycol. The reference does not expressly teach wherein the polyethylene glycol is a non-volatile liquid and the amount of such a suitable medium in the formulation. As such, Mathiowitz also does not expressly teach the amount of non-volatile liquid before and after drying as recited in claims 38-39. However, Sadeghi helps cure this deficiency.
Sadeghi is also directed towards solid pharmaceutical formulations wherein the reference teaches the production of ibuprofen pellets using polyethylene glycol (PEG 400). Sadeghi discloses the ease in process of extrusion-spheronization, increasing the mean dissolution time and change in mechanical properties of pellets from brittle to plastic behavior were advantages of using PEG 400. Sadeghi teaches PEG 400 in concentration of 1, 3 or 5% was used in production of pellets (See: Abstract; Entire Document). As evidenced by Bhavsar, PEG 400 is a non-volatile liquid solvent. PEG 400 in concentration of 1, 3 or 5% reads on the claimed amount of non-volatile liquid before and after drying.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to have modified Mathiowitz to incorporate the teachings of Sadeghi and include particularly PEG 400 as the particular polyethylene glycol medium and in the amount taught by Sadeghi. One would have been motivated to do so because Sadeghi also discloses preparation of solid pharmaceutical formulation using the extrusion-spheronization method and Sadeghi teaches the advantages of using PEG 400 which include increasing the mean dissolution time and change in mechanical properties of pellets from brittle to plastic behavior. Thus, one skilled in the art looking to reduce the brittleness of the formulation of Mathiowitz would have been strongly motivated to particularly mix PEG 400, in the amount taught by Sadeghi, with the active drug component.
From the combined teaching of the cited references, one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Claims 23 and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Mathiowitz et al. (US 2014/0120162 A1; May 1, 2014) in view of Dokou et al. (US10272046B2; Apr. 30, 2019) as evidenced by Muley et al. (Asian Journal of Pharmaceutical Sciences II (2016) 684-699) as applied to claims 17-19, 25, 27-28 and 40 above and further in view of Gu et al. (US 2017/0007661 A1; Jan. 12, 2017).
The teachings of Mathiowitz have been set forth above.
Mathiowitz further teaches the formulation comprising surface active agent such as poloxamer (0136). The reference also teaches the method of making the solid compositions comprise solvent removal wherein the drug is dispersed or dissolved in a solution of selected polymer in a volatile organic solvent like methylene chloride (0159). Mathiowitz does not teach wherein the volatile solvent is methanol. The reference also does not expressly teach the amount of the surface active agent. However, these deficiencies are cured by Gu.
Gu throughout the reference teaches pharmaceutical compositions or solid dispersions comprising therapeutically active agent (Summary of Invention). Gu discloses extrusion method as one of the processes for preparing solid dispersions (0095). Gu teaches using a solvent comprising one or more volatile solvent to dissolve or suspend the drug compound. The one or more solvent is a volatile solvent which include methylene chloride and methanol. (0124; 0125). Gu also teaches including a surfactant/wetting agent such as poloxamer in the amount of between about 0.1% and 2% w/w (0139, 0140, 0093).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to have modified Mathiowitz to incorporate the teachings of Gu and include particularly methanol as the volatile solvent in which the drug is dispersed. One would have been motivated to do so because, as discussed supra, Mathiowitz teaches the method of making the solid compositions comprise solvent removal wherein the drug is dispersed or dissolved in a solution of selected polymer in a volatile organic solvent like methylene chloride. Gu also teaches using a solvent comprising one or more volatile solvent to dissolve or suspend the drug compound to prepare solid dispersion wherein the solid dispersion can be prepared by using extrusion method, as discussed above. Gu teaches the one or more solvent is a volatile solvent which include methylene chloride and methanol. It would have been obvious to one of ordinary skill in the art to try and substitute methylene chloride with methanol as the volatile solvent as a person with ordinary skill has good reason to pursue known options within his or her technical grasp. see MPEP 2141 KSR International CO. v. Teleflex Inc. 82 USPQ 2d 1385 (Supreme Court 2007).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to have modified Mathiowitz to incorporate the teachings of Gu and include poloxamer in the formulation of Mathiowitz in the amount taught by Gu. One would have been motivated to do so because while Mathiowitz teaches including poloxamer surface active agent, the reference is silent on the amount and it would have been obvious to look towards the teachings of Gu for the amount of poloxamer to add in the formulation of Mathiowitz since both references are directed to solid pharmaceutical formulations. “The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.” In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969). See MPEP 2144.05.
From the combined teaching of the cited references, one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Claim 42 is rejected under 35 U.S.C. 103 as being unpatentable over Mathiowitz et al. (US 2014/0120162 A1; May 1, 2014) in view of Dokou et al. (US10272046B2; Apr. 30, 2019) as evidenced by Muley et al. (Asian Journal of Pharmaceutical Sciences II (2016) 684-699) as applied to claims 17-19, 25, 27-28 and 40 above and further in view of Kohr et al. (US20180133160A1; May 17, 2018) and Szymczak et al. (US 2011/0319441A1; Dec. 29, 2011).
The teachings of Mathiowitz have been set forth above.
Mathiowitz does not expressly teach a particular hardness of the formulation measured using a texture analyzer as recited in instant claim 42. However, this deficiency is cured by Kohr et al. and Szymczak et al.
Kohr throughout the reference teaches pharmaceutical dosage forms wherein the dosage form is in the form of tablet and the hardness of tablet ranges from about 60 to about 150 N. (para 0026). Further, Szymczak teaches a more preferred test for measuring hardness is by using a texture analyzer (Para 0149).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Mathiowitz to incorporate the teachings of Kohr and make the hardness of Mathiowitz dosage form per the teachings of Kohr. One would have been motivated to do so because both Mathiowitz and Kohr teach pharmaceutical dosage forms which include tablets and since Mathiowitz is silent on the particular hardness of the dosage form, it would have been obvious to one skilled in the art to look towards the teachings of Kohr and make the hardness of the dosage form which is known in the art, as suggested by Kohr. Moreover, it would have been obvious to achieve the desired hardness by manipulating the amount of the binder in the formulation.
With respect to the hardness as measured by a texture analyzer, Szymczak teaches using texture analyzer for measuring hardness is a preferred method and thus, absence any unexpected results, it would have been obvious to one skilled in the art to measure the hardness of the formulation by a texture analyzer since Szymczak teaches this method being a preferred method in the art.
From the combined teaching of the cited references, one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Response to Arguments/Declaration
Applicant’s arguments/declaration, filed 5/5/2025, have been fully considered but they are not persuasive.
Applicant argued that Dokou merely discloses a broad list of pharmaceutical compositions, without suggesting to a person skilled in the art that compression should be avoided. It was argued that Dokou discloses tablets, minitablets, granules, sprinkles, pellets, beads, particulates or particles can also be compressed into other solid forms and that composition is in powder form or in a compressed form, such as granules, pellets, particles, and minitablets. Applicant argued that it is clear that non-compressed forms are limited to powder form. Applicant also presented declaration by Dokou and argued that Dokou in the declaration stressed that proper compressibility is needed for the granules to be manufactured.
In response, as discussed supra, while Mathiowitz discloses compressed tablet and capsule as preferred delivery system (para 0162-163), Mathiowitz does not require the extruded and spheronized beads/granules are further compressed into a tablet or capsule. Dokou teaches admixture/powder blend comprising the ingredients can be processed in to granules, pellets or mini tablets wherein the admixture can be granulated using extrusion-spheronization method. The granules can also be compressed into tablets and mini tablets. (col. 89, line 5-40). Thus, Dokou teaches method which produces granules through extrusion-spheronization process wherein a granule can be used as a unit dose without requiring further compression step. “Disclosed examples and preferred embodiments do not constitute a teaching away from the broader disclosure or non-preferred embodiment.” In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). MPEP 2123. While Dokou discloses compressed granules, beads, minitablets and tablets, Dokou also discloses wherein admixture/powder blend comprising the ingredients can be processed in to granules using extrusion-spheronization method without requiring further compression step. Therefore, it would have been obvious to one skilled in the art to use the extruded and spheronized beads/granules of Mathiowitz as the final dosage form without compressing the beads/granules into a tablet or capsule form. Specifically, one would have been motivated to do so because it would eliminate an extra step in the method of formulating a dosage form.
With respect to the declaration, while Dokou in paragraph 11 discloses identifying a combination of lactose and mannitol that provided the proper compressibility needed to provide granules, the declaration does not state that granules must be compressed to formulate the composition of Dokou. As discussed supra, Dokou discloses an embodiment where granules are produced through extrusion-spheronization method and the granules are not compressed granules. Thus, it appears that declaration states for compressed granules, combination of lactose and mannitol is provided for proper compressibility, however, Dokou discloses granules without compression and the declaration does not state that granules must be compressed to formulate the composition of Dokou.
Conclusion
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/A.S/Examiner, Art Unit 1616
/SUE X LIU/Supervisory Patent Examiner, Art Unit 1616