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 .
Formal Matters
Applicant’s claim amendments and response along with the declaration by Bo Sik Kim in the reply filed on 22 July 2026 are acknowledged and have been fully considered. Claims 1-2, 4, and 6-16 are pending. Claims 1-2, 4, 6-10, and newly added claim 16 are under consideration in the instant office action. Claims 11-15 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention and/or species, there being no allowable generic or linking claim. Claims 3 and 5 are canceled. Applicant amended claim 1 and added new claim 16. Applicant’s claim amendments and arguments did not overcome the rejections under 35 USC 103 for reasons set forth in the previous office action and herein below.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 28 May 2026 is noted and the submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the examiner has considered the information disclosure statement. A signed copy is attached herein.
Withdrawn Objections/Rejections
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn as are those rejections and/or objections expressly stated to be withdrawn.
Rejections Maintained
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 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 1, 4, 6-10, and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Abebe et al. (WO 2011/060256, previously cited) in view of Kweon et al. (WO 2018/124468, English machine translation provided, previously cited), Preskar et al. (WO 2012/131005), and Chawla et al. (US 2003/0104059, previously cited).
Applicant Claims
Applicant claims “A composite tablet comprising: a first layer comprising dry granules-that include, said dry granules comprising: a) sitagliptin phosphate, and b) dapagliflozin proline; and a second layer comprising wet granules that include metformin or a pharmaceutically acceptable salt thereof and colloidal silicon dioxide, wherein the colloidal silicon dioxide is present at 0.7 percent by weight (wt%) to 2.8 wt% relative to a weight of the metformin or a pharmaceutically acceptable salt thereof, wherein the wet granules in the second layer have a water content of 2.0 wt% to 3.5 wt% relative to a total weight of the wet granules.” Dependent claims thereof recite other features.
Determination of the Scope and Content of the Prior Art (MPEP §2141.01)
Abebe et al. teach a bilayer tablet comprising: (1) a first layer wherein the first layer is a metformin extended release formulation; (2) a second layer wherein the second layer is an SGLT2 inhibitor formulation; and (3) optionally a film coating that covers the first layer and the second layer (see claim 1). The bilayer tablet according to claim 1 wherein the SGLT2 inhibitor is canagliflozin, dapagliflozin, dapagliflozin (S) propylene glycol hydrate, or dapagliflozin (R) propylene glycol hydrate (see claim 2). The bilayer tablet according to claim 1 wherein the (1) first layer comprises metformin, a binder, a release modifier, a lubricant, and optionally a glidant; and (2) the second layer comprises dapagliflozin or dapagliflozin (S) propylene glycol hydrate, two or three fillers, a disintegrant, a glidant, and a lubricant (see claim 4). The bilayer tablet according to claim 4 wherein (1) the metformin is metformin hydrochloride, the binder is sodium carboxymethyl cellulose; the release modifier is hydroxypropyl methylcellulose; the lubricant is magnesium stearate; and optionally the glidant is silicon dioxide or colloidal silicon dioxide; (2) the SGLT2 inhibitor is dapagliflozin or dapagliflozin (S) propylene glycol hydrate; the two or three fillers are selected from lactose anhydrous, microcrystalline cellulose, pregelatinized starch, mannitol, and hydroxypropyl cellulose; the disintegrant is crospovidone; the glidant is silicon dioxide; and the lubricant is magnesium stearate; (3) the optional film coating is Opadry® II (see claim 5). The bilayer tablet according to claim 5 wherein (1) the first layer comprises about 64-82% metformin hydrochloride, about 3-5% sodium carboxymethyl cellulose; about 15-30% hydroxypropyl methylcellulose; about 0.1-0.75%> magnesium stearate; and about 0-2%) silicon dioxide or 0-1.5% colloidal silicon dioxide; (2) the second layer comprises about 0.5-4%) dapagliflozin or dapagliflozin (S) propylene glycol hydrate; about 14-18%> lactose anhydrous; about 50-80%> microcrystalline cellulose; about 0-20%> pregelatmized starch; about 0-20%> mannitol; about 0-15%>hydroxypropyl cellulose; about 2-6% crospovidone; about 0.5-2.5%) silicon dioxide; and about 0.5-2%. magnesium stearate; (3) the optional film coating is Opadry® II (claim 6). The bilayer tablet according to claim 5 wherein (1) the first layer comprises about 67-71 o metformin hydrochloride, about 3-5% sodium carboxymethyl cellulose, about 25-29%o hydroxypropyl methylcellulose 2208, and about 0.1-0.75%) magnesium stearate; and (2) the second layer is about 300 mgs to about 400 mgs (see claim 7). The bilayer tablet according to claim 7 wherein the second layer comprises: (A) about 0.5-4%) dapagliflozin or dapagliflozin (S) propylene glycol hydrate: about 14-18%o lactose anhydrous; about 72-80%) microcrystalline cellulose 302; about 2-6%o crospovidone; about 0.5-2.5%) silicon dioxide; and about 0.5-1.5%) magnesium stearate; (B) about 0.5-4%) dapagliflozin or dapagliflozin (S) propylene glycol hydrate; about 14-18%o lactose anhydrous; about 50-70%) microcrystalline cellulose 302; about 10-22%o pregelatmized starch; about 2-6% crospovidone; about 0.5-2.5%) silicon dioxide; and about 0.5-1.5%) magnesium stearate; (C) about 0.5-4%) dapagliflozin or dapagliflozin (S) propylene glycol hydrate; about 14-18%o lactose anhydrous; about 60-70%) microcrystalline cellulose 302; about 5-15%o hydroxypropyl cellulose EXF; about 2-6% crospovidone; about 0.5-2.5%) silicon dioxide; and about 0.5-1.5%) magnesium stearate; or (D) about 0.5-4%) dapagliflozin or dapagliflozin (S) propylene glycol hydrate; about 14-18%o lactose anhydrous; about 55-65%) microcrystalline cellulose 302; about 10-20%o mannitol; about 2-6% crospovidone; about 0.5-2.5%) silicon dioxide; and about 0.5-1.5% magnesium stearate (see claim 8). Examples of lubricants suitable for use herein include, but are not limited to, magnesium stearate, zinc stearate, calcium stearate, talc, carnauba wax, stearic acid, palmitic acid, sodium stearyl fumarate, sodium laurel sulfate, glyceryl palmitostearate, palmitic acid, myristic acid and hydrogenated vegetable oils and fats, as well as other known lubricants, and/or mixtures of two or more thereof (see page 42, lines 23-27). It is very clear both magnesium stearate and sodium stearyl fumarate are taught to be used as lubricant.
The examiner notes that the first layer is wet granulated, see Examples 4, 7, and 13 of the metformin hydrochloride section). The examiner notes that the second layer is dry granulated, see example 4 the Dapagliflozin (S) PGS section which teaches Dapagliflozin (S) PGS was blended with microcrystalline cellulose, anhydrous lactose, a portion of crospovidone, and a portion of silicon dioxide in a suitable tumble mixer and passed through a suitable conical mill. A portion of magnesium stearate (screened) was blended into the mixture and then compacted using an appropriate roller compactor. The compacted mixture was reduced to form granules. The granules were blended with the remaining amount of crospovidone and silicon dioxide in a suitable tumble mixer. The granules were then blended with the remaining amount of magnesium stearate in a suitable tumble mixer. Bilayer compression. In another aspect, the present invention provides combination therapies that comprise the bilayer tablet of the present invention in combination with one or more: anti-diabetics (page 32). Suitable DPP4 inhibitors include, but are not limited to, sitagliptin and vildagliptin (page 33). In one aspect, the present invention provides a coated tablet that comprises a tablet core coated with a first coating optionally containing saxagliptin, a second coating optionally containing saxagliptin, and an optional third coating. The tablet core comprises metformin where metformin hydrochloride is preferred. At least one of the first and second coatings contains saxagliptin (see page 30, lines 17-21). This teaching demonstrates the inclusion of a DPP IV inhibitor like sitagliptin being included with the layer that contains dapagliflozin. Saxagliptin and sitagliptin are both DPP IV inhibitors which are functionally equivalent and substituting one with the other is prima facie obvious. It should be very clear that Abebe et al. as described above teach sitagliptin.
The metformin XR layer (1000 mg) comprises metformin, a binder, a release modifier, a lubricant, and optionally a glidant. A preferred binder is sodium carboxymethyl cellulose. Hydroxypropyl methylcellulose 2208 is a preferred release modifier. Magnesium stearate is a preferred lubricant and silicon dioxide or colloidal silicon dioxide are preferred glidants. The SGLT2 inhibitor layer comprises an SGLT2 inhibitor, two or three fillers, a disintegrant, a glidant, and a lubricant. The preferred fillers are lactose anhydrous, microcrystalline cellulose 302, pregelatinized starch, and mannitol. A preferred disintegrant is crospovidone. Silicon dioxide is the preferred glidant and magnesium stearate is the preferred lubricant. Hydroxypropyl cellulose EXF is the preferred binder. The metformin XR layer (500 mg) comprises metformin, a binder, at least one release modifier, a filler, a lubricant, and optionally a glidant. A preferred binder is sodium carboxymethyl cellulose. The preferred release modifiers are hydroxypropyl methylcellulose 2208 in combination with hydroxypropyl methylcellulose 2910 (see page 3, lines 6-26). The present invention also provides bilayer tablets comprising metformin XR (500 mgs) formulations, SGLT2 inhibitor (2.5, 5.0, 10.0 mgs) formulations, and optionally a film coating (page 21, lines 17-19).
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP §2141.012)
Abebe et al. do not specifically teach sitagliptin phosphate as the sitagliptin type and dapagliflozin L-proline as the dapagliflozin type. These deficiencies are cured by the teachings of Kweon et al. and Preskar et al.
Kweon et al. teach a dapagliflozin L-proline-containing pharmaceutical composition. Specifically, the dapagliflozin L-proline-containing pharmaceutical composition, according to the present invention, exhibits excellent elution properties even when the d(0.9) of the dapagliflozin L-proline has a large particle size distribution of at least 60μm, and provides the advantages of enabling a simple production process and a small loss of active ingredients. Thus, the pharmaceutical composition, according to the present invention, may be used as a preventive or therapeutic agent, for diabetes, diabetes-related diseases and diabetes complications, which has an excellent elution rate and bioabsorption rate (see abstract).
Preskar et al. teach a pharmaceutical composition comprising amorphous sitagliptin, wherein the amorphous sitagliptin has been prepared from a solution comprising sitagliptin and a crystallization inhibitor (see claim 1). The pharmaceutical composition according to claim 1, 2, or 3, wherein the sitagliptin is a sitagliptin salt (see claim 4). The pharmaceutical composition according to claim 4, wherein the sitagliptin salt is selected from the group consisting of hydrochloride salt, hydrobromide , sulfate, citrate, phosphate, tartrate, lactate, fumarate, maleate and/or mandelate (claim 5). The pharmaceutical composition according to the invention as well as the method according to the present invention are advantageous over the known prior art in that, unexpectedly and surprisingly, a highly stable amorphous form of sitagliptin with a low content of impurities in the pharmaceutical composition is obtained (see page 18, lines 7-12).
Abebe et al., Kweon et al., and Preskar et al. do not specifically teach the metformin wet granules of the second layer have a water content of 2.0 wt% to 3.5 wt% relative to a total weight of the wet granules and also the amounts recited in claim 4. These deficiencies are cured by the teachings of Chawla et al.
Chawla et al. teach controlled-release metformin and processes for their preparation, using a combination of non-ionic and anionic hydrophilic polymers, wherein the total hydrophilic polymer concentration is at least about 16% by weight of the composition (see abstract). The blend could be wet granulated with water or with an aqueous dispersion of the binder. For granulation, water or an aqueous dispersion of the binder can be added to the blend while mixing. The powder mass is typically wetted with water or the binding solution until the mass has a suitable consistency. The wet mass is forced through 8 or 10-mesh screen, however for large quantities comminuting mills suitable for wet screening may be used (paragraph 0034). Wet granules can be dried in trays or in fluidized bed dryer. In a drying step, a residual amount of moisture may be maintained in the granulation, to maintain the various granulation ingredients, such as the polymers, in a hydrated state. Also, residual moisture content can contribute to the reduction of static electric charge on the particles. The stability of the product containing moisture sensitive active ingredients may be related to the moisture content of the product. Residual moisture content of the granules can be less than about 6.0%. Residual moisture content of the granules can be between about 3.5 and about 6.0% by weight in some embodiments (paragraph 0035).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been prima facie obvious before the effective filing date of the instant application to modify the teachings of Abebe et al. by utilizing dapagliflozin L-proline as the dapagliflozin type because Kweon et al. teach a dapagliflozin L-proline-containing pharmaceutical composition. One of ordinary skill in the art would have been motivated to do so because Kweon et al. teach that specifically, the dapagliflozin L-proline-containing pharmaceutical composition, according to the present invention, exhibits excellent elution properties even when the d(0.9) of the dapagliflozin L-proline has a large particle size distribution of at least 60μm, and provides the advantages of enabling a simple production process and a small loss of active ingredients. Thus, the pharmaceutical composition, according to the present invention, may be used as a preventive or therapeutic agent, for diabetes, diabetes-related diseases and diabetes complications, which has an excellent elution rate and bioabsorption rate (see abstract). One of ordinary skill in the art would have had a reasonable expectation of success in combining the teachings of Abebe et al. and Kweon et al. because both references teach dapagliflozin based compositions for the treatment of diabetes. Furthermore, in the case where the claimed ranges for the amounts and concentrations of active agent and other ingredients “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Similarly, a prima facie case of obviousness exists where the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have the same properties. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985). Furthermore, generally differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). It is within the purview of the skilled artisan to optimize the amounts of active agents and ingredients.
It would have been prima facie obvious before the effective filing date of the instant application to modify the teachings of Abebe et al. by utilizing d sitagliptin phosphate as the sitagliptin type because Preskar et al. teach a pharmaceutical composition comprising amorphous sitagliptin, wherein the amorphous sitagliptin has been prepared from a solution comprising sitagliptin and a crystallization inhibitor (see claim 1). The pharmaceutical composition according to claim 1, 2, or 3, wherein the sitagliptin is a sitagliptin salt (see claim 4). The pharmaceutical composition according to claim 4, wherein the sitagliptin salt is selected from the group consisting of hydrochloride salt, hydrobromide , sulfate, citrate, phosphate, tartrate, lactate, fumarate, maleate and/or mandelate (claim 5). One of ordinary skill in the art would have been motivated to do so because Preskar et al. teach that the pharmaceutical composition according to the invention as well as the method according to the present invention are advantageous over the known prior art in that, unexpectedly and surprisingly, a highly stable amorphous form of sitagliptin with a low content of impurities in the pharmaceutical composition is obtained (see page 18, lines 7-12). One of ordinary skill in the art would have had a reasonable expectation of success in combining the teachings of Abebe et al. and Preskar et al. because both references teach DPP IV inhibitor based compositions for the treatment of diabetes. Furthermore, in the case where the claimed ranges for the amounts and concentrations of active agent and other ingredients “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Similarly, a prima facie case of obviousness exists where the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have the same properties. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985). Furthermore, generally differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). It is within the purview of the skilled artisan to optimize the amounts of active agents and ingredients.
With regard to the limitation of instant claim 10 reciting “The composite tablet for oral administration of claim 1, wherein when the composite tablet is stored for 4 weeks under harsh conditions of 60 °C, total related substances of sitagliptin are 0.2 wt% or less, and total related substances of dapagliflozin are 2 wt% or less in the composite tablet.” "[I]nherency may supply a missing claim limitation in an obviousness analysis." PAR, 773 F.3d at 1194-1195 ; see also Endo Pharms. Sols., Inc. v. Custopharm Inc., 894 F.3d 1374 , 1381 , 127 U.S.P.Q.2D (BNA) 1409 (Fed. Cir. 2018) ("An inherent characteristic of a formulation can be part of the prior art in an obviousness analysis even if the inherent characteristic was unrecognized or unappreciated by a skilled artisan."). It is long settled that in the context of obviousness, the "mere recitation of a newly discovered function or property, inherently possessed by things in the prior art, does not distinguish a claim drawn to those things from the prior art." In re Oelrich, 666 F.2d 578 , 581 (C.C.P.A. 1981). The Supreme Court explained long ago that "[i]t is not invention to perceive that the product which others had discovered had qualities they failed to detect." Gen. Elec. Co. v. Jewel Incandescent Lamp Co., 326 U.S. 242 , 249 , 66 S. Ct. 81 , 90 L. Ed. 43 , 1946 Dec. Comm'r Pat. 611 (1945). We too have previously explained that "an obvious formulation cannot become nonobvious simply by administering it to a patient and claiming the resulting serum concentrations," because "[t]o hold otherwise would allow any formulation—no matter how obvious—to become patentable merely by testing and claiming an inherent property." Santarus, Inc. v. Par Pharm., Inc., 694 F.3d 1344 , 1354 (Fed. Cir. 2012). In In re Kao, we found that the claimed controlled-release oxymorphone formulation was obvious because an inherent pharmacokinetic property of oxymorphone that was present in controlled-release oxymorphone "add[ed] nothing of patentable consequence." In re Huai-Hung Kao, 639 F.3d 1057 , 1070 , 98 U.S.P.Q.2D (BNA) 1799 (Fed. Cir. 2011). In In re Kubin, we found an inherent property obvious, explaining that "[e]ven if no prior art of record explicitly discusses the [limitation], the . . . application itself instructs that [the limitation] is not an additional requirement imposed by the claims on the [claimed protein], but rather a property necessarily present in [the claimed protein]." In re Kubin, 561 F.3d 1351 , 1357 , 90 U.S.P.Q.2D (BNA) 1417 (Fed. Cir. 2009). Our predecessor court similarly concluded that it "is not the law" that "a structure suggested by the prior art, and, hence, potentially in the possession of the public, is patentable . . . because it also possesses an [i]nherent, but hitherto unknown, function which [the patentees] claim to have discovered." In re [*1191] Wiseman, 596 F.2d 1019 , 1023 (C.C.P.A. 1979). Inherency, however, is a "high standard," that is "carefully circumscribed in the context of obviousness." PAR, 773 F.3d at 1195 . Inherency "may not be established by probabilities or possibilities," and "[t]he mere fact that a certain thing may result from a given set of circumstances is not sufficient." Oelrich, 666 F.2d at 581 (emphasis added) (quoting Hansgirg v. Kemmer, 102 F.2d 212 , 214 , 26 C.C.P.A. 937 , 1939 Dec. Comm'r Pat. 327 (C.C.P.A. 1939); see also In re Rijckaert, 9 F.3d 1531 , 1533-1534 (Fed. Cir. 1993). Rather, inherency renders a claimed limitation obvious only if the limitation is "necessarily present," or is "the natural result of the combination of elements explicitly disclosed by the prior art." PAR, 773 F.3d at 119511 -96; see also Alcon Research, Ltd. v. Apotex Inc., 687 F.3d 1362 , 1369 (Fed. Cir. 2012) (relying on inherency where the claims recited "a property that is necessarily present" in the prior art). "If . . . the disclosure is sufficient to show that the natural result flowing from the operation as taught would result in the performance of the questioned function, it seems to be well settled that the disclosure should be regarded as sufficient" to render the function inherent. Oelrich, 666 F.2d at 581 (quoting Hansgirg v. Kemmer, 102 F.2d 212 , 214 , 26 C.C.P.A. 937 , 1939 Dec. Comm'r Pat. 327 (C.C.P.A. 1939)). On appeal, Persion contends that the district court erred in applying the inherency doctrine in its obviousness analysis because Devane does not teach administering its hydrocodone-only formulation to patients with mild or moderate hepatic impairment. Thus, Persion asserts, "'the natural result flowing from the operation as taught' in Devane cannot be the claimed [pharmacokinetic] values for [hepatically impaired] patients." Appellant's Br. 37 (quoting Oelrich, 666 F.2d at 581 ); Reply Br. 19. To the extent Persion contends that inherency can only satisfy a claim limitation when all other limitations are taught in a single reference, that position is contrary to our prior recognition that "inherency may supply a missing claim limitation in an obviousness analysis" where the limitation at issue is "the natural result of the combination of prior art elements." PAR, 773 F.3d at 1194-1195 (emphasis added, internal quotations omitted). Here, the district court specifically found that Devane, together with Jain, the state of the prior art at the time of invention, and the Vicodin and Lortab labels, taught the combination of elements that inherently result in the claimed pharmacokinetic parameters. The district court found that a person of ordinary skill in the art would have been motivated, with reasonable expectation of success, to administer an unadjusted dose of the Devane formulation to hepatically impaired patients. There was also no dispute that the Devane formulation, which was identical to the Zohydro ER formulation described in the patents in suit, necessarily exhibited the claimed parameters under these conditions. Pernix, 323 F. Supp. 3d at 607 , 610 . In this context, the district court did not err by finding that the pharmacokinetic limitations of the asserted claims were inherent and added no patentable weight to the pharmacokinetic claims. Since the combination teachings of Abebe et al., Kweon et al., and Preskar et al. met the claimed structure, the claimed property would necessarily be there.
It would have been prima facie obvious before the effective filing date of the instant application to modify the teachings of Abebe et al., Kweon et al., and Preskar et al. by making the metformin wet granules of the second layer having a water content of 2.0 wt% to 3.5 wt% relative to a total weight of the wet granules and the amounts recited in claim 4 because Chawla et al. teach controlled-release metformin and processes for their preparation, using a combination of non-ionic and anionic hydrophilic polymers, wherein the total hydrophilic polymer concentration is at least about 16% by weight of the composition (see abstract). The blend could be wet granulated with water or with an aqueous dispersion of the binder. For granulation, water or an aqueous dispersion of the binder can be added to the blend while mixing. The powder mass is typically wetted with water or the binding solution until the mass has a suitable consistency. The wet mass is forced through 8 or 10-mesh screen, however for large quantities comminuting mills suitable for wet screening may be used (paragraph 0034). One of ordinary skill in the art would have been motivated to do so because Chawla et al. teach that wet granules can be dried in trays or in fluidized bed dryer. In a drying step, a residual amount of moisture may be maintained in the granulation, to maintain the various granulation ingredients, such as the polymers, in a hydrated state. Also, residual moisture content can contribute to the reduction of static electric charge on the particles. The stability of the product containing moisture sensitive active ingredients may be related to the moisture content of the product. Residual moisture content of the granules can be less than about 6.0%. Residual moisture content of the granules can be between about 3.5 and about 6.0% by weight in some embodiments (paragraph 0035). Furthermore, in the case where the claimed ranges of ingredients “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Similarly, a prima facie case of obviousness exists where the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have the same properties. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985). Furthermore, generally differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). It is within the purview of the skilled artisan to optimize the amounts of active agents and ingredients. One of ordinary skill in the art would have had a reasonable expectation of success in combining the teachings of Abebe et al., Kweon et al., Preskar et al., and Chawla et al. because while Kweon et al. and Preskar et al. teach the drug types that can be included in a bilayer tablet composition Abebe et al. and Chawla et al. teach preparation of wet metformin granules.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim(s) 2 is/are rejected under 35 U.S.C. 103 as being unpatentable over Abebe et al. (WO 2011/060256, previously cited) in view of Kweon et al. (WO 2018/124468, English machine translation provided, previously cited), Preskar et al. (WO 2012/131005, previously cited), and Chawla et al. (US 2003/0104059, previously cited) as applied to claims 1, 4, 6-10, and 16 above, and further in view of Raveendra Babu et al. ( INTERNATIONAL JOURNAL OF PHARMACEUTICAL, CHEMICAL AND BIOLOGICAL SCIENCES, 2015, 5(3), 510-516, previously cited).
Applicant Claims
Applicant claims “A composite tablet comprising: a first layer comprising dry granules-that include, said dry granules comprising: a) sitagliptin phosphate, and b) dapagliflozin proline; and a second layer comprising wet granules that include metformin or a pharmaceutically acceptable salt thereof and colloidal silicon dioxide, wherein the colloidal silicon dioxide is present at 0.7 percent by weight (wt%) to 2.8 wt% relative to a weight of the metformin or a pharmaceutically acceptable salt thereof, wherein the wet granules in the second layer have a water content of 2.0 wt% to 3.5 wt% relative to a total weight of the wet granules.” Dependent claims thereof recite other features. Instant claim 2 recites the composite tablet of claim 1, wherein a shrinkage difference between the first layer and the second layer is within 1 percent (%).
Determination of the Scope and Content of the Prior Art (MPEP §2141.01)
The teachings of Abebe et al., Kweon et al., Preskar et al., Chawla et al. are described above in detail are incorporated herein by reference.
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP §2141.012)
Abebe et al., Kweon et al., Preskar et al., and Chawla et al. do not specifically teach a shrinkage difference between the first layer and the second layer is within 1 percent (%). This deficiency is cured by the teachings of Raveendra Babu et al.
Raveendra Babu et al. teach bilayer tablet is a new era for the successful development of controlled release formulation along with various features to provide a way of the successful drug delivery system. Bilayer tablets can be a primary option to avoid chemical incompatibilities between API by physical separation, and to enable the development of different drug release profiles like the immediate release with extended release. Bilayer tablet is a very different aspect of anti-inflammatory and analgesic. Bi-layer tablet is suitable for sequential release of two drugs in combination and also for sustained release tablet in which one layer is immediate release as initial dose and second layer is maintenance dose. Bilayer tablet is improved beneficial technology to overcome the short coming of the single layered tablet. There are various applications of the player tablet, it consists of monolithic partially coated or multilayered matrices (see abstract). Friction and shock are the forces that most often cause the tablets to chip, chop or break. The friability test is closely related to tablet hardness and is designed to evaluate the ability of the tablet to with stand abrasion in packaging, handling and shipping. It is usually measured by the use of the Roche friabilator. A number of tablets are weighed and placed in the apparatus where they are exposed to rolling and repeated shocks as they fall 6 inches in each turn within the apparatus. After four minutes of this treatment or 100 revolutions, the tablets are weighed and the weight compared with the initial weight. The loss due to abrasion is a measure of the tablet friability. The value is expressed as a percentage. A maximum weight loss of not more than 1% of the weight of the tablets being tested during the friability test is considered generally acceptable and any broken or smashed tablets are not picked up. Normally, when capping occurs, friability values are not calculated. A thick tablet may have fewer tendencies to cap where as thin tablets of large diameter, often show extensive cupping, thus indicating that tablets with greater thickness have reduced internal stress the loss in the weight of the tablet is the measure of variability and is expressed in percentages (see pages 514-515).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been prima facie obvious before the effective filing date of the instant application to modify the teachings of Abebe et al., Kweon et al., and Preskar et al. by making the shrinkage between the first and the second layers is not more than 1% because Raveendra Babu et al. teach bilayer tablet is a new era for the successful development of controlled release formulation along with various features to provide a way of the successful drug delivery system. Bilayer tablets can be a primary option to avoid chemical incompatibilities between API by physical separation, and to enable the development of different drug release profiles like the immediate release with extended release. Bilayer tablet is a very different aspect of anti-inflammatory and analgesic. Bi-layer tablet is suitable for sequential release of two drugs in combination and also for sustained release tablet in which one layer is immediate release as initial dose and second layer is maintenance dose. Bilayer tablet is improved beneficial technology to overcome the short coming of the single layered tablet. There are various applications of the player tablet, it consists of monolithic partially coated or multilayered matrices (see abstract). Friction and shock are the forces that most often cause the tablets to chip, chop or break. The friability test is closely related to tablet hardness and is designed to evaluate the ability of the tablet to with stand abrasion in packaging, handling and shipping. It is usually measured by the use of the Roche friabilator. A number of tablets are weighed and placed in the apparatus where they are exposed to rolling and repeated shocks as they fall 6 inches in each turn within the apparatus. After four minutes of this treatment or 100 revolutions, the tablets are weighed and the weight compared with the initial weight. One of ordinary skill in the art would have been motivated to do so because Raveendra Babu et al. teach that the loss due to abrasion is a measure of the tablet friability. The value is expressed as a percentage. A maximum weight loss of not more than 1% of the weight of the tablets being tested during the friability test is considered generally acceptable and any broken or smashed tablets are not picked up. Normally, when capping occurs, friability values are not calculated. A thick tablet may have fewer tendencies to cap where as thin tablets of large diameter, often show extensive cupping, thus indicating that tablets with greater thickness have reduced internal stress the loss in the weight of the tablet is the measure of variability and is expressed in percentages (see pages 514-515). Furthermore, Raveendra Babu et al. teach that in a double sided tablet the advantage is it is possible displacement weight monitoring for accurate and independent weight control of the individual layer can be accomplished (see page 512). Furthermore, in the case where the claimed ranges of any measurable properties such as shrinkage percentage “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is within the purview of the skilled artisan to measure and optimize the shrinkage percentage of each layer. One of ordinary skill in the art would have had a reasonable expectation of success in combining the teachings of Abebe et al., Kweon et al., Preskar et al., and Raveendra Babu et al. because while Kweon et al. and Preskar et al. teach the drug types that can be included in a bilayer tablet composition Abebe et al. and Raveendra Babu et al. tech bilayer tablet compositions.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant’s remarks and the Declaration under 37 C.F.R. § 1.132 of Bo Sik Kim have been fully considered. They are not persuasive. The rejection of claims 1, 2, 4, and 6–10 under 35 U.S.C. § 103 over Abebe et al. (WO 2011/060256) in view of Kweon et al. (WO 2018/124468), Preskar et al. (WO 2012/131005), and Chawla et al. (US 2003/0104059), and of claim 2 further in view of Raveendra Babu et al., is maintained. Newly added claim 16 is rejected on the same grounds as claim 1.
Applicant argues that the amendment of claims 1 and 12 and the addition of claim 16 are supported by paragraphs [0071]–[0072] of the published application and introduce no new matter.
The amendments have been entered. Support is acknowledged. However, entry of the amendment does not, by itself, overcome the obviousness rejection.
Applicant argues that the Kim Declaration supplies the missing formulas for Examples 5–7 and Comparative Examples 17–19, establishes that only metformin-granule water content and colloidal silicon dioxide (CSD) were varied from Table 1, and therefore converts Experimental Example 3/Tables 6–7 into a controlled comparison entitled to weight under § 1.132. Applicant points to Example 7 (2.8% CSD, 3.5% water: 0.18% sitagliptin related substances/1.24% dapagliflozin related substances after 4 weeks at 60 °C) versus Example 17 (3.5% CSD, 3.5% water: 0.42%/2.11%).
The above assertions are not persuasive because first the examiner points that the declaration is accepted as establishing the complete Table 1 formula and that, within Applicant’s own three-drug series, only water content and CSD were varied. However, that does not make the showing sufficient to rebut the prima facie case. First, Applicant relying upon a comparative showing to rebut a prima facie case must compare the claimed invention with the closest prior art. In re Holladay, 584 F.2d 384, 199 USPQ 516 (CCPA 1978); Ex parte Humber, 217 USPQ 265 (Bd. App. 1961). The closest prior art is Abebe’s two-drug (metformin + dapagliflozin) bilayer, optionally coated, optionally used with a DPP-4 inhibitor. The Declaration compares two points inside Applicant’s own three-drug formula. It does not compare the claimed tablet with Abebe. Second, any difference between the claimed invention and the prior art may be expected to produce some difference in properties. The question is whether the difference is unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Changing glidant level or residual moisture in a wet-granulated metformin layer is expected to affect impurity formation (Chawla, paragraph 0035). A movement from 0.18% to 0.42% sitagliptin related substances, or from 1.24% to 2.11% dapagliflozin related substances, is a difference of degree, not kind. In re Waymouth, 499 F.2d 1273, 182 USPQ 290 (CCPA 1974); UCB, Inc. v. Actavis Labs. UT, Inc., 65 F.4th 679, 2023 USPQ2d 448 (Fed. Cir. 2023). Third, objective evidence of nonobviousness must be commensurate in scope with the claims. In re Clemens, 622 F.2d 1029, 206 USPQ 289 (CCPA 1980); In re Peterson, 315 F.3d 1325, 65 USPQ2d 1379 (Fed. Cir. 2003); In re Grasselli, 713 F.2d 731, 218 USPQ 769 (Fed. Cir. 1983). Claim 1 recites sitagliptin or any pharmaceutically acceptable salt or hydrate and dapagliflozin or any pharmaceutically acceptable salt or hydrate, is not limited to the Table 1 excipients, and recites CSD from 0.7 wt% to 2.8 wt% relative to metformin. The declaration’s passing example is a single point at the upper end of the CSD range (2.8%) versus a single point outside the range (3.5%), using only sitagliptin phosphate and dapagliflozin L-proline. There is no data at 0.7% CSD, no data across the full 2.0–3.5% water window at low CSD, and no data for other salts or hydrates. Instant claim 1 is broader than the examples. Arguments of counsel cannot take the place of evidence commensurate with the claims. In re Budnick, 537 F.2d 535, 190 USPQ 422 (CCPA 1976); In re Schulze, 346 F.2d 600, 145 USPQ 716 (CCPA 1965). The Declaration removes the earlier uncertainty about the Table 1 amounts. It does not establish unexpected results over the closest prior art or over the full scope of claim 1.
Applicant argues that the Examiner mischaracterized Abebe: Abebe’s bilayer is metformin + SGLT2 only; sitagliptin is mentioned only as a separately administered agent for combination therapy; saxagliptin is only in a coating over the core (Abebe claim 27; p. 30, lines 17–21); a POSA treats core and coating as distinct and would not read “saxagliptin in the coat” as “sitagliptin in the same dry granules as dapagliflozin.”
The above assertions are not found persuasive. A prior art reference must be considered in its entirety. W.L. Gore & Assoc., Inc. v. Garlock, Inc., 721 F.2d 1540, 220 USPQ 303 (Fed. Cir. 1983). Abebe teaches (1) a bilayer of metformin XR and an SGLT2 inhibitor, including dapagliflozin (claims 1–8; Examples 4, 7, 13); (2) use of that bilayer in combination with DPP-4 inhibitors, expressly including sitagliptin (pp. 32–33); and (3) a coated bilayer in which at least one coating comprises a DPP-4 inhibitor (saxagliptin) (claim 27; p. 30, lines 17–21). Sitagliptin and saxagliptin are both DPP-4 inhibitors. Substituting one for the other is prima facie obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982).
Applicant’s core-versus-coat distinction does not remove Abebe’s teaching that a DPP-4 inhibitor may be present in the same finished dosage form as the metformin/dapagliflozin bilayer. Once a POSA is taught to include a DPP-4 inhibitor in that product, placing the second, low-dose IR API into the already dry-granulated SGLT2 layer (Abebe Example 4) is an ordinary formulation choice. Claim 1 as amended itself requires a film coating on the bilayer. Abebe already has that coating. The remaining difference—sitagliptin inside the first-layer dry granules rather than in the coat—is the difference Kweon (dapagliflozin L-proline) and Preskar (sitagliptin phosphate) are cited to address, together with ordinary skill in bilayer tableting.Applicant argues that even a saxagliptin-to-sitagliptin substitution would leave sitagliptin in the coating, and that reaching claim 1 would require five untaught steps (swap the DPP-4 inhibitor, remove it from the coat, put it in the core, put it in the dapagliflozin layer, and co-dry-granulate it with dapagliflozin), which is hindsight. Applicant further argues that Abebe does not recognize the problem of sitagliptin and dapagliflozin related substances in a three-drug FDC or any role of metformin-layer CSD in that problem.
The above assertions are not found persuasive because obviousness does not require the prior art to recognize the same problem. Applicant solved or to provide an express invitation to make every intermediate change. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418–22 (2007); In re Kahn, 441 F.3d 977, 988 (Fed. Cir. 2006). Abebe already dry-granulates the SGLT2 layer and already puts a DPP-4 inhibitor in the same product. Combining those teachings with the known salts of Kweon and Preskar and the known residual-moisture guidance of Chawla does not require hindsight. That Abebe does not discuss three-drug related substances does not negate the structural obviousness of the combination. Newly observed properties of an obvious structure do not confer patentability. In re Oelrich, 666 F.2d 578, 581 (CCPA 1981); PAR Pharm., Inc. v. TWI Pharm., Inc., 773 F.3d 1186, 1194–95 (Fed. Cir. 2014).
Applicant argues, citing specification paragraph [0098] and the Declaration, that Examples 5–7 versus 17–19 isolate CSD and therefore support nonobviousness of the 0.7–2.8 wt% range. Paragraph [0098] and the Declaration are consistent with each other.
The above assertions are not found persuasive because for the reasons already stated—closest-art comparison, difference of degree rather than kind, and lack of commensurateness with claim 1—the showing does not rebut the prima facie case. Regarding claim 2 and claim 16 Applicant’s remarks as provided do not separately traverse the rejection of claim 2 over Raveendra Babu or the applicability of the same combination to new claim 16. Raveendra Babu teaches that bilayer-tablet mechanical integrity is a recognized concern and that a 1% weight-loss limit is an accepted standard. Controlling interlayer shrinkage to within about 1% is an obvious quality target for the Abebe bilayer. Claim 16 recites conventional coating materials (HPC, HPMC, PVA, PEG, titanium dioxide, iron oxide) already within the scope of Abebe’s Opadry II/PVA-based coats (claims 5–6, 27). Claim 16 stands or falls with claim 1.
In light of the foregoing, the subject matter of claims 1, 2, 4, 6–10, and 16 would have been obvious under 35 U.S.C. § 103. No claim is allowed.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. 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.
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/TIGABU KASSA/Primary Examiner, Art Unit 1619
