CTNF 18/272,796 CTNF 83500 Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia 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 The Preliminary Amendment filed on 07/18/23 is acknowledged. Claim 6 was amended. Claims 1-11 are included in the prosecution. References in the Specification 06-49-06 AIA The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered. Priority This Application is a 371 of PCT/CN2021/143500 filed on 12/32/21. This Application also claims foreign priority to cn202110063061.2 filed on 01/18/21. Receipt is acknowledged of certified copies of papers submitted under 35 U.S.C. 119 (a)-(d), which papers have been placed of record in the file. 23-19 AIA Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) an English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e). Failure to provide a translation may result in no benefit being accorded for the non-English application. Claim Objections Claims 1, 3, 4, 7, and 10 are objected to because of the following informalities: In claim 1 , line 1, it is recommended that the article “an” be added before the term “amlodipine.” In claim 1 , last line, it is recommended that the article “the” be added before the term “same.” In claim 1 , last line, it is recommended that the term “wherein” be added before the phrase “no surfactant is added during the process.” In claim 3 , line 2, there appear to be extra space(s) between the comma and the phrase “and the homogenization is.” The extra space(s) should be deleted. In claim 4 , line 2, the article “the” before the term “step a)” should be deleted. In claim 7 , line 1, the phrase “the amlodipine dry suspension” should be added after the term “wherein.” Alternatively, the terms “wherein comprises” should be replaced with “comprising.” In claim 10 , line 1, the phrase “the amlodipine dry suspension” should be added after the term “wherein.” Alternatively, the terms “wherein further comprises” should be replaced with “further comprising.” Notice for all US Patent Applications filed on or after March 16, 2013 07-06 AIA 15-10-15 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. Claim Rejections - 35 USC § 103 07-20-aia AIA 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 of this title, 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. 07-23-aia AIA The factual inquiries set forth in Graham v. John Deere Co. , 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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. 07-20-02-aia AIA 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. 07-21-aia AIA Claim s 1-7 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Wang (CN 101966181 A – English Espacenet Translation) in view of Wang et al . (Chem. Pharm. Bull. 56(1) 22-27 (2008) – “Wang ‘08”) and Efrati (US 2019/0008777 A1) . Instant claim 1 is drawn to a process for preparing an amlodipine dry suspension, the process comprising: preparing an aqueous mixture 1 containing amlodipine besylate by using a high-speed homogenization method; adding sodium benzoate to the mixture 1, and homogenizing same at a high speed to obtain a mixture 2; and granulating the mixture 2 and other components, and then drying the same; wherein no surfactant is added during the process. Wang teaches the process of making an oral solid preparation comprising 2-32 mg of candesartan or pharmaceutically acceptable salts or esters thereof, and 1.25-20 mg of amlodipine or pharmaceutically acceptable salts thereof and pharmaceutically acceptable carriers thereof (Abstract and claims 1-9). The oral solid preparation can be a granular formulation or a dry-mixed suspension prepared by wet granulation (Abstract, [0002], [0076], [0147], claims 1, 6, 8, and 9). Amlodipine besylate is disclosed as the pharmaceutically acceptable salt ([0043], [0068] and claim 2). Aqueous solutions are disclosed ([0056]). The constituents of the oral solid preparation are mixed until homogenous ([0131], [0183], [0190], [0202]). The preparation method comprises: (A) separately crushing candesartan cilexetil and amlodipine besylate through an 80 mesh sieve, then uniformly mixing candesartan cilexetil and amlodipine besylate in a V-type mixer according to an equivalent progressive addition method; (B) separately crushing sodium citrate, sodium carboxymethyl cellulose, sucralose and polyethylene glycol 6000 through an 80 mesh sieve, then uniformly mixing in a trough mixer; (C) uniformly mixing the uniformly mixed candesartan cilexetil and amlodipine besylate and the uniformly mixed sodium citrate, sodium carboxymethyl cellulose, sucralose and polyethylene glycol 6000 in the V-type mixer according to an equivalent progressive addition method; (D) dissolving a prescription amount of povidone K30 in an appropriate amount of purified water, so as to prepare a 10% povidone K30 solution for use as an adhesive; (E) taking the uniformly mixed raw and auxiliary materials and a strawberry powdered essence, adding a 10% povidone K30 solution to prepare a soft material, pass through a 30 mesh sieve to granulate, dry at 80°C, pass through a 18 mesh to granulate, and obtain candesartan cilexetil amlodipine granules. (G) sub-packaging the candesartan cilexetil amlodipine granules into dry suspensions by using a particle subpackaging machine to prepare 10,000 bags (Example 8).The surfactants polysorbate 80 and sodium lauryl sulfate are not included in the claimed preparations. Wang does not expressly teach a high-speed homogenization method or adding sodium benzoate. Wang ’08 teaches that: “High shear mixers have been widely used in the pharmaceutical industry. There are several advantages of granulation in a high shear mixer: a shorter processing time; a need for less liquid binders compared with fluid bed granulators and, thus, a shorter drying process is obtained; voluminous materials can be densified. Moreover, granulation is performed in a closed system, which can include drying (microwave or vacuum); the porosity of the product can be influenced by the massing time and impact of the impeller; cleaning operations can be carried out easily either manually or by a clean-in-place system” (Page 22, Col. 1, 1 st ¶). A laboratory-scale vertical high shear mixer was used, and the rotational speed of the impeller and chopper could be varied between 0-1800 rpm and 0-4000 rpm, respectively (Page 22, Col. 2, last ¶). The effect of impeller speed and chopper speed on granule size distributions was investigated (Tables 1-4 and Figures 1-5). Efrati teaches a method of making a composition comprising amlodipine (Abstract and claims 1-9). Amlodipine besylate is discloses as a pharmaceutically acceptable salt of amlodipine ([0030]-[0031]). Sodium benzoate is disclosed as a lubricant that is included in the composition ([0027], [0061], claims 11, 12, and 18). Hydroxypropyl methylcellulose (HPMC or hypromellose) is disclosed as a suitable binder and is included in the range of about 0.5% to about 10% ([0059]). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the process of making an oral solid granular preparation comprising amlodipine besylate by wet granulation where the constituents are mixed until homogenous, as taught by Wang, in view of the use of high speed, high shear mixers for pharmaceutical granulations, as taught by Wang ’08, and the use of sodium benzoate in a composition comprising amlodipine besylate, as taught by Efrati, and produce the instant invention. One of ordinary skill in the art would have been motivated to use high speed and high shear mixing in the process of Wang because Wang ’08 teaches advantages of granulation in a high shear mixer: a shorter processing time; a need for less liquid binders compared with fluid bed granulators and, thus, a shorter drying process is obtained; voluminous materials can be densified. Moreover, granulation is performed in a closed system, which can include drying (microwave or vacuum); the porosity of the product can be influenced by the massing time and impact of the impeller; cleaning operations can be carried out easily either manually or by a clean-in-place system” (Page 22, Col. 1, 1 st ¶). One of ordinary skill in the art would have found it obvious to include sodium benzoate in the preparation taught by Wang because Efrati teaches the inclusion of this component as a lubricant in a composition comprising the same active ingredient, i.e ., amlodipine besylate ([0027], [0061], claims 11, 12, and 18). Moreover, it is obvious to combine prior art elements according to known methods to yield predictable results. Please see MPEP 2141(III)(A). From the teachings of the references, it is apparent that 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 before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary. Regarding instant claim 1, the process for preparing an amlodipine dry suspension would have been obvious over the process of making an oral solid preparation comprising amlodipine besylate by wet granulation (Abstract [0002], [0076], [0147]), as taught by Wang. Regarding instant claim 1, the limitation of step a) preparing an aqueous mixture 1 containing amlodipine besylate by using a high-speed homogenization method would have been obvious over the aqueous solutions ([0056]), amlodipine besylate ([0043], [0068] and claim 2), and mixing the constituents of the oral solid preparation until homogenous ([0131], [0183], [0190], [0202]), as taught by Wang, in view of the high speed high shear mixing for preparing pharmaceutical granulations (Pages 22-26), as taught by Wang ’08. Regarding instant claim 1, the limitation of step b) adding sodium benzoate to the mixture 1, and homogenizing same at a high speed to obtain a mixture 2 would have been obvious over the inclusion of sodium benzoate in a formulation comprising amlodipine besylate ([0027], [0061], claims 11, 12, and 18), as taught by Efrati, in view of the high speed high shear mixing for preparing pharmaceutical granulations (Pages 22-26), as taught by Wang ’08. Regarding instant claim 1, the limitation of step c) granulating the mixture 2 and other components, and then drying the same would have been obvious over the wet granulation (Abstract, [0002], [0076], [0147], claims 1, 6, 8, and 9) which is dried ([0092]) to prepare granules for later use ([0092]), as taught by Wang. Regarding instant claim 1, the limitation of no surfactant being added during the process would have been obvious over the process taught by Wang since the surfactants polysorbate 80 and sodium lauryl sulfate are not included in the claimed preparations (claims 1-9 of Wang). Regarding instant claim 2, the limitation of the surfactant being polysorbate 80 or sodium lauryl sulfate would have been obvious over the process taught by Wang since the surfactants polysorbate 80 and sodium lauryl sulfate are not included in the claimed preparations (claims 1-9 of Wang). Regarding instant claim 3, the limitation of the rotating speed of the high-speed homogenization of between 4000 rev/min and 10000 rev/min, and the homogenization performed for between 2 minutes and 4 minutes would have been obvious over the upper limit of the rotational speed of the 4000 rpm (Page 22, Col. 2, last ¶), as taught by Wang ’08. Regarding instant claim 4, the limitation of the weight percentage of the amlodipine besylate in the aqueous mixture 1 in step a) of between 1% and 5% would have been obvious over the dosage of 1.25-20 mg of amlodipine ([0002]) as taught by Wang, and typical amounts of amlodipine in the composition ranging from about 0.01% to about 10% ([0040]), as taught by Efrati. One of ordinary skill in the art would have found it obvious to include an effective amount of amlodipine besylate in the aqueous mixture based on the ranges taught by Wang and Efrati and based on the desired dosage of the final dry suspension. The recited range would have been an obvious variant over the ranges taught by Wang and Efrati unless there is evidence of criticality or unexpected results. Regarding instant claim 5, the limitation of high shear wet granulation would have been obvious over the wet granulation (Abstract, [0002], [0076], [0147], claims 1, 6, 8, and 9), as taught by Wang in view of the high shear wet granulation (Title, Abstract, Page 22, Col. 1, 1 st ¶), as taught by Wang ’08. Regarding instant claims 6 and 11, the limitations of the weight percentage of the amlodipine besylate in the dry suspension of between 0.5% to 2% would have been obvious over the dosage of 1.25-20 mg of amlodipine ([0002]) as taught by Wang, and the overlapping amounts of amlodipine in the composition ranging from about 0.01% to about 10% ([0040]), as taught by Efrati. One of ordinary skill in the art would have found it obvious to include an effective amount of amlodipine besylate based on the ranges taught by Wang and Efrati and based on the desired dosage of the final dry suspension. The recited range would have been an obvious variant over the ranges taught by Wang and Efrati unless there is evidence of criticality or unexpected results. Regarding instant claims 6 and 11, the limitations of the ratio of the weight of sodium benzoate to amlodipine besylate of between 1:1 and 5:1 would have been obvious over the sodium benzoate used as a lubricant and the typical amount of lubricant of about 0.1% to about 5% ([0061]) and the 0.01% to about 10% of amlodipine besylate ([0040]), as taught by Efrati. Based on the ranges of sodium benzoate and amlodipine besylate taught by Efrati, given 0.1% of sodium benzoate and 0.1% of amlodipine besylate, a 1:1 ratio is calculated. Given 5% of sodium benzoate and 1% of amlodipine besylate, a 5:1 ratio is calculated. Regarding instant claim 7, the limitation of sodium benzoate and amlodipine besylate would have been obvious over the sodium benzoate ([0061]) and amlodipine besylate ([0030]-[0031]), as taught by Efrati. The limitation of a diluent would have been obvious over the diluents ([0049]-[0051] and claims 8-9), as taught by Wang, and the diluents ([0021]-[0022], claim 7), as taught by Efrati. The limitation of a suspending agent would have been obvious over the hydroxypropyl methylcellulose (HPMC or hypromellose) ([0053]), as taught by Wang, and the HPMC ([0059]), as taught by Efrati . 07-21-aia AIA Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Wang (CN 101966181 A – English Espacenet Translation) in view of Wang et al . (Chem. Pharm. Bull. 56(1) 22-27 (2008) – “Wang ‘08”), Efrati (US 2019/0008777 A1), and Sekiguchi et al . (US 2015/0110880 A1 – “Sekiguchi”) . Instant claim 8 is drawn to the dry suspension of claim 7, wherein the diluent comprises mannitol, erythritol or maltitol, or combinations thereof, the weight percentage of the diluent in the dry suspension is between 80% and 95%. The teachings of Wang, Wang ’08, and Efrati are discussed above. Wang, Wang ’08, and Efrati do not expressly teach that the weight percentage of the diluent in the dry suspension is between 80% and 95%. Sekiguchi teaches a process for producing an orally disintegrating tablet by using wet granulation which is fluidized bed granulation (claims 27-28). The active ingredient includes amlodipine besylate ([0052]). Mannitol is disclosed as a sugar alcohol incorporated at 20-95% by weight of the final orally disintegrating tablet ([0060]-[0061]). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the process of making an oral solid granular preparation comprising amlodipine besylate by wet granulation where the constituents are mixed until homogenous, as taught by Wang, in view of the use of high speed, high shear mixers for pharmaceutical granulations, as taught by Wang ’08, the use of sodium benzoate in a composition comprising amlodipine besylate, as taught by Efrati, and the use of an overlapping 20-95% by weight of mannitol, as taught by Sekiguchi, and produce the instant invention. One of ordinary skill in the art would have been motivated to do so because all the references teach methods of preparing wet granulations containing amlodipine besylate. It is obvious to combine prior art elements according to known methods to yield predictable results. Please see MPEP 2141(III)(A). Furthermore, Sekiguchi teaches that the final product using 20-95% mannitol is an orally disintegrating tablet ([0061]) which has the advantages of quick disintegration and solubility when it is placed in the oral cavity or put into water, provides favorable taste, has a sufficient hardness in the processes of general production, transportation and use, and is excellent in terms of storage stability ([0049]). Regarding instant claim 8, the limitation of the diluent comprising mannitol, erythritol or maltitol, or combinations thereof, the weight percentage of the diluent in the dry suspension of between 80% and 95% would have been obvious over the diluent mannitol ([0049] and [0051]), as taught by Wang, and the diluent mannitol ([0022], claim 13), as taught by Efrati, and mannitol incorporated at 20-95% by weight of the final orally disintegrating tablet ([0060]-[0061]), as taught by Sekiguchi . 07-21-aia AIA Claim s 9 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Wang (CN 101966181 A – English Espacenet Translation) in view of Wang et al . (Chem. Pharm. Bull. 56(1) 22-27 (2008) – “Wang ‘08”), Efrati (US 2019/0008777 A1), and Slugg et al . (US 2004/0005358 A1 – “Slugg”) . Instant claim 9 is drawn to the dry suspension of claim 7, wherein the suspending agent is hypromellose K4M, and the weight percentage of the suspending agent in the dry suspension is between 1% and 5%. The teachings of Wang, Wang ’08, and Efrati are discussed above. Although Efrati teaches that HPMC or hypromellose is a suitable binder and is included in the range of about 0.5% to about 10% ([0059]), Efrati does not expressly teach that the weight percentage of the suspending agent hypromellose K4M. Slugg teaches the preparation of formulations by using wet granulation ([0078]) and incorporating antihypertensive agents such as amlodipine besylate ([0143]). Hydroxypropyl methylcellulose (Methocel K4M) or hypromellose K4M is disclosed as a polymer that controls the rate of drug release ([0046] and [0156]). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the process of making an oral solid granular preparation comprising amlodipine besylate by wet granulation where the constituents are mixed until homogenous, as taught by Wang, in view of the use of high speed, high shear mixers for pharmaceutical granulations, as taught by Wang ’08, the use of sodium benzoate and HPMC or hypromellose in an amount of about 0.5% to about 10% in a composition comprising amlodipine besylate, as taught by Efrati, and the use of an hypromellose K4M, as taught by Slugg, and produce the instant invention. One of ordinary skill in the art would have been motivated to do so because all the references teach methods of preparing wet granulations containing amlodipine besylate. It is obvious to combine prior art elements according to known methods to yield predictable results. Please see MPEP 2141(III)(A). Furthermore, one of ordinary skill in the art would have found it obvious to use various suitable grades of the constituents, including the HPMC or hypromellose K4M taught by Slugg, in the process of preparing the dry suspension of Wang with a reasonable expectation of success since this component is known to be used with the same active, amlodipine besylate in a wet granulation. Also, Slugg teaches that hypromellose K4M has the advantage of controlling the rate of drug release ([0046] and [0156]). Regarding instant claim 9, the limitation of the hypromellose K4M would have been obvious over the HPMC (Methocel K4M) or hypromellose K4M ([0046] and [0156]), as taught by Slugg. The limitation of the weight percentage of the suspending agent in the dry suspension of between 1% and 5% would have been obvious over the HPMC or hypromellose included in the overlapping range of about 0.5% to about 10% ([0059]), as taught by Efrati. Regarding instant claim 10, the limitation of a pharmaceutically acceptable defoamer would have been obvious over the antifoam agent which is simethicone (claim 15, part (e)), as taught by Slugg. The limitation of a binder would have been obvious over the binders ([0050]), as taught by Wang, the HPMC or hypromellose ([0059]), as taught by Efrati, and the HPMC (Methocel K4M) or hypromellose K4M ([0046] and [0156]), as taught by Slugg. The limitation of a glidant would have been obvious over the glidant ([0021] and claim 7), as taught by Efrati, and the anti-adherent colloidal silicon dioxide (claim 15), as taught by Slugg. The limitation of a flavoring agent would have been obvious over the flavoring agents ([0050]), as taught by Wang. Conclusion No claims are allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to ARADHANA SASAN whose telephone number is (571)272-9022. 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If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /ARADHANA SASAN/Primary Examiner, Art Unit 1615 Application/Control Number: 18/272,796 Page 2 Art Unit: 1615 Application/Control Number: 18/272,796 Page 3 Art Unit: 1615 Application/Control Number: 18/272,796 Page 4 Art Unit: 1615 Application/Control Number: 18/272,796 Page 5 Art Unit: 1615 Application/Control Number: 18/272,796 Page 6 Art Unit: 1615 Application/Control Number: 18/272,796 Page 7 Art Unit: 1615 Application/Control Number: 18/272,796 Page 8 Art Unit: 1615 Application/Control Number: 18/272,796 Page 9 Art Unit: 1615 Application/Control Number: 18/272,796 Page 10 Art Unit: 1615 Application/Control Number: 18/272,796 Page 11 Art Unit: 1615 Application/Control Number: 18/272,796 Page 13 Art Unit: 1615 Application/Control Number: 18/272,796 Page 14 Art Unit: 1615 Application/Control Number: 18/272,796 Page 15 Art Unit: 1615