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 . 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 (i.e., changing from AIA to pre-AIA ) 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.
Priority
The instant application is a 371 of PCT/CN2020/119547 filed on 09/30/2020.
Status of the Claims
The claim amendments and remarks filed on 11/19/2025 is acknowledged. Claims 42-43, 49, and 52 are amended.
Accordingly, claims 39-52 are pending and being examined on the merits herein.
Withdrawn Objections/Rejections
The objection to the specification and drawings are withdrawn in view of the newly filed figures and structures in the specification having sufficient resolution as well as the figures being properly labeled as “FIG.”.
The 35 USC 112(b) rejection over claims 42-43 are withdrawn in view of these amended claims now recited a conjunction “and” for the recited list of diffraction peaks.
The 35 USC 112(a) rejection over claims 49 and 52 are withdrawn in view of the removal of the term “preventing”.
Specification
The disclosure is objected to because of the following informalities:
Several of the structures shown on Table 1 (pages 4-6) appear to be cut off on the right-hand side. For example, the structure for Dapaglifozin (first row on Table 1) is missing a methyl group on the right side, and the structure of Canagliflozin (third row on Table 1) is missing a fluorine on the right side.
Appropriate correction is required.
The following grounds of rejection are maintained from the previous Office Action dated 08/19/2025.
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.
Claim(s) 39-41, 44, and 46 are rejected under 35 U.S.C. 103 as being unpatentable over CN’372 (CN110922372A in IDS filed on 03/28/2023, an English translation is provided in the IDS filed on 03/28/2023 and used as the basis of this rejection herein) in view of Yuan et al. (Crystal Growth and Design, 2019 in IDS filed on 10/10/24).
CN’372 discloses an amino acid co-crystal of dapagliflozin and a preparation method thereof (see paragraph 0009). CN’372 demonstrates in Example 1 the preparation of a dapagliflozin – L-proline cocrystal, in which 4.08 grams of dapagliflozin and 1.15 grams of L-proline (dissolved in 20 ml and 10 ml ethanol solution, respectively) was mixed at 20 degree Celsius, heated to 40 degree Celsius and stirred for 48 hours, separate the resulting suspension, and after drying at 20 degrees Celsius for 24 hours, the obtained solid is a crystal of dapagliflozin and L-proline (see paragraph 0043). Here, the stirring for 48 hours at 40 degrees Celsius, separating the resulting suspension, and drying at 20 degrees Celsius for 24 hours meets the limitation of “crystallizing by standing or cooling, and solid-liquid separating” as recited in claim 44. CN’372 discloses that their preparation method uses a molar ratio of amorphous dapagliflozin to L-proline as 1:1 (see paragraph 0017).
The difference between CN’372 and the claimed invention is that CN’372 does not disclose a SGLT-2 inhibitor-sarcosine cocrystal.
Yuan et al. discloses two novel pharmaceutical cocrystals, Sulfamethizole (SMZ) – sarcosine (SAR) and SMZ – saccharin (SAC) as well as a previously obtained SMZ – L-proline cocrystal (see Abstract). Yuan et al. discloses that all cocrystals demonstrate lower equilibrium solubility and intrinsic dissolution rates compared to SMZ alone and therefore are suitable crystal forms for possible improvement in therapeutic performance of SMZ (see Abstract). Yuan et al. discloses a structural resemblance strategy was employed to guide the design of new pharmaceutical cocrystals of SMZ, since molecules having similar chemical structures are likely to form cocrystals with the same cocrystal former (co-former) (see left and right column, page 7185). Yuan et al. discloses that sarcosine, a structural analogue of L-proline, was used to form cocrystals with SMZ (see right column, page 7185). Yuan et al. demonstrates the similarity of the cocrystal structures of SMZ-SAR and SMZ-L-proline in Figure 3(a) on page 7188. Yuan et al. discloses that isostructural structures of the two cocrystals are due to the similar intermolecular hydrogen bonding interactions and molecular packing arrangements (see left column page 7189). Yuan et al. discloses that such similar structural and energy features are expected to lead to similar physicochemical properties, such as density, melting point, and dissolution properties (see left column page 7189).
It would have been prima facie obvious to combine CN’372 and Yuan et al. before the effective filing date of the claimed invention by substituting the L-proline of CN’372 with the sarcosine of Yuan et al. to form the cocrystal. One of ordinary skill in the art would have made a simple substitution of one known element (L-proline co-former) for another (sarcosine co-former) to obtain predictable results because Yuan et al. provides guidance of selecting sarcosine as an alternative crystal co-former based on its structural similarity to L-proline as well as its similar hydrogen bonding interaction and molecular packing arrangements.
Claim(s) 42-43 and 45 are rejected under 35 U.S.C. 103 as being unpatentable over CN’372 (CN110922372A in IDS filed on 03/28/2023, an English translation is provided in the IDS filed on 03/28/2023 and used as the basis of this rejection herein) in view of Yuan et al. (Crystal Growth and Design, 2019 in IDS filed on 10/10/24), as applied to claims 39 and 44 above, and further in view of CN’230 (CN103694230A in IDS filed on 03/28/2023, an English translation is provided in the IDS filed on 03/28/2023 and used as the basis of this rejection herein).
CN’372 modified by Yuan et al. teaches the SGLT-2 inhibitor-sarcosine cocrystal recited in claim 39 and the method of preparing an SGLT-2 inhibitor-sarcosine cocrystal recited in claim 44 as described above.
The difference between the combination of CN’372 and Yuan and the claimed invention is that the combination of CN’372 and Yuan do not disclose the SGLT-2 is canagliflozin or using a water solvent for the solution of sarcosine.
CN’230 discloses the process of improving the purity of canagliflozin compounds by forming cocrystals of canagliflozin and amino acids in solvents, separating the co-crystals, and then decomposing the co-crystal to obtain pure canagliflozin compound (see paragraph 0022). CN’230 disclose the solvent to dissolve canagliflozin and amino acid can be selected from methanol, ethanol, isopropanol, water, … , as well as a mixed solvent of water and ethanol, methanol, … (see paragraph 0026). CN’230 discloses the amino acid can be preferably proline or phenylalanine and preferably the L-type (see paragraph 0028-0029).
It would have been prima facie obvious to combine CN’372 and Yuan with CN’230 before the effective filing date of the claimed invention by substituting the dapagliflozin in the modified cocrystal of CN’372 in view of Yuan as described above and selecting water as the solvent for a solution of sarcosine to form the co-crystal and arrive at the claimed invention. One of ordinary skill in the art would have made these modifications with a reasonable expectation of success because both CN’372 and CN’230 disclose the formation of SGLT-2 cocrystals using the same L-proline co-former. Furthermore, CN’230 provides guidance of using water as a solvent to dissolve amino acids in solution to form co-crystals.
The recited X-ray powder diffraction powder peaks of claims 42-43 would be necessarily present in the modified cocrystal structures of CN’372 in view of Yuan et al. and CN’230 because Yuan et al. provides guidance of substituting the L-proline with sarcosine to form the same dapagliflozin-sarcosine cocrystal or canagliflozin-sarcosine cocrystal as described above. Furthermore, the combined teachings of CN’372 and CN’230 disclose the same process of making steps for the recited SGLT-2-sarcosine co-crystals because as evidenced in Examples 1-7 of the instant specification (pages 25-29), the process of making the recited cocrystals is performed by first dissolving the SGLT-2 compound in an organic solvent such as ethanol and dissolving the sarcosine in water and subsequently mixing the solutions together. Then, the combined solution is stirred for crystallization in a temperature range of -20 C to 40 C for a time period of 4 to 48 hours and subsequently dried for 6-7 hours in a temperature range of 20-70 C to obtain the recited cocrystals. As described above, CN’372 recites the same steps of dissolving the compounds in solvents, mixing the two solutions together, stirring the mixed solution within the same temperature and time range for crystallization, and drying the co-crystal within the same temperature and time range. The only differences in the process of CN’372 and the instant process is the added step of heating the mixed solution before stirring and using water as a solvent for the sarcosine.
However, heating is an added step that can also be added to form the recited co-crystal as disclosed in the instant specification, which recites “after mixing the solution of the SGLT-2 inhibitor with the solution of sarcosine, heating can be carried out if the solution is not clarified” (see paragraph 0045 on page 12 in specification), and the instant specification also discloses stirring at 40 C (Example 4), which further indicates a heating step. Additionally, CN’230 provides guidance of using water as a solvent for the amino acid in forming SGLT2 cocrystal compounds as described above.
Therefore, the combined teachings of CN’372, Yuan, and CN’230 disclose all of the same steps and conditions of making the recited SGLT2-sarcosine co-crystals in claim 42-43, and would necessarily have the recited X-ray powder diffraction powder peaks in claims 42-43. MPEP 2112 section I recite "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable”. Furthermore, MPEP 2112.01 section II recites “Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.”
Therefore, claims 42-43 and 45 are prima facie obvious.
Claim(s) 47 is rejected under 35 U.S.C. 103 as being unpatentable over CN’372 (CN110922372A in IDS filed on 03/28/2023, an English translation is provided in the IDS filed on 03/28/2023 and used as the basis of this rejection herein) in view of Yuan et al. (Crystal Growth and Design, 2019 in IDS filed on 10/10/24). as applied to claims 39 and 44 above, and further in view of CN’230 (CN103694230A in IDS filed on 03/28/2023, an English translation is provided in the IDS filed on 03/28/2023 and used as the basis of this rejection herein).
The independent teachings of CN’372 and Yuan et al. are as discussed above.
CN’372 modified by the teachings of Yuan et al. disclose the steps of mixing SGLT-2 inhibitor with a sarcosine, stirring at room temperature, and solid-liquid separating to obtain an SGLT-2 inhibitor-sarcosine complex.
The difference between the combined teachings of CN’372 and Yuan is that the combined teachings of CN’372 and Yuan do not disclose a method of purifying a crude of SGLT-2 inhibitor.
CN’230 discloses the process of improving the purity of canagliflozin compounds by forming cocrystals of canagliflozin and amino acids in solvents, separating the co-crystals, and then decomposing the co-crystal to obtain pure canagliflozin compound (see paragraph 0022). CN’230 disclose the solvent to dissolve canagliflozin and amino acid can be selected from methanol, ethanol, isopropanol, water, … , as well as a mixed solvent of water and ethanol, methanol, … (see paragraph 0026). CN’230 discloses the amino acid can be preferably proline or phenylalanine and preferably the L-type (see paragraph 0028-0029). CN’230 demonstrates in Example 1 that after forming the canagliflozin-L-proline cocrystal, it underwent a series of steps described in paragraph 0086 to purify and obtain the canagliflozin product with a yield of 89% (see paragraph 0085-0086). Here, the steps of purifying the canagliflozin from the cocrystal meets the limitation of “dissociating the sarcosine complex of SGLT-2 inhibitor to obtain a pure product of SGLT-2 inhibitor in free state” as recited in claim 47.
It would have been prima facie obvious to combine CN’372 and Yuan with CN’230 before the effective filing date of the claimed invention by further applying the SGLT-2-sarcosine co-crystal as suggested by the combined teachings of CN’372 and Yuan described above in a process of purifying an SGLT-2 inhibitor as described in CN’230. One of ordinary skill in the art would have made this modification with a reasonable expectation of success because CN’230 demonstrates a process of purifying out an SGLT-2 inhibitor compound (canagliflozin) starting from the same SGLT-2 - L-proline cocrystal compound.
Claim(s) 48 is rejected under 35 U.S.C. 103 as being unpatentable over CN’372 (CN110922372A in IDS filed on 03/28/2023, an English translation is provided in the IDS filed on 03/28/2023 and used as the basis of this rejection herein) in view of Yuan et al. (Crystal Growth and Design, 2019 in IDS filed on 10/10/24) and Desai et al. (US20170247356A1 in IDS filed on 03/28/2023).
The independent teachings of CN’372 and Yuan et al. are as discussed above.
CN’372 modified by Yuan et al. teaches an SGLT-2 inhibitor-sarcosine cocrystal that is prepared by a mixing a solution of SGLT-2 inhibitor with a solution of sarcosine, crystallizing by standing or cooling, and solid-liquid separating to obtain the SGLT-2 inhibitor-sarcosine co-crystal as described above.
The difference between the combination of CN’372 and Yuan and the claimed invention is that the combination of CN’372 and Yuan do not disclose a pharmaceutical composition comprising the SGLT2-sarcosine cocrystal and a pharmaceutically acceptable carrier.
Desai et al. discloses a co-crystal of empagliflozin and an amino acid (see Abstract). Desai et al. demonstrates in Examples 12-14 the preparation of a co-crystal of empagliflozin and L-proline (see paragraphs 0199-0201). Desai et al. discloses a pharmaceutical composition comprising therapeutically effective amount of co-crystal of empagliflozin and amino acid and one or more pharmaceutically acceptable carriers, excipients or diluents (see paragraph 0046).
It would have been prima facie obvious before the effective filing date of the claimed invention that the modified SGLT2 cocrystal of CN’372 in view of Yuan as described above can also be in a form of a pharmaceutical composition with one or more one or more pharmaceutically acceptable carriers, excipients or diluents. One of ordinary skill in the art would have made this modification with a reasonable expectation of success because Desai et al. provides guidance of a pharmaceutical composition comprising a similar structured SGLT-2 – amino acid cocrystal and one or more pharmaceutically acceptable carriers, excipients or diluents.
Claim(s) 49-52 are rejected under 35 U.S.C. 103 as being unpatentable over Sonesson et al. (Cardiovascular Diabetology, 2016 in PTO-892 dated 08/19/2025) in view of CN’372 (CN110922372A in IDS filed on 03/28/2023, an English translation is provided in the IDS filed on 03/28/2023 and used as the basis of this rejection herein) and Yuan et al. (Crystal Growth and Design, 2019 in IDS filed on 10/10/24).
Sonesson et al. discloses the cardiovascular effects of dapagliflozin in patients with type 2 diabetes (see Abstract). Sonesson et al. discloses that dapagliflozin is a SGLT2 inhibitor lowers blood glucose levels by reducing glucose reabsorption in the kidney independently of insulin secretion or action, resulting in increased urinary glucose excretion with associated osmotic diuresis and caloric loss (see page 2 left column). Sonesson et al. discloses that the efficacy and safety of dapagliflozin has been studied in a wide range of populations as monotherapy or in combination with a variety of other glucose-lowering therapies, and that the mechanism of action of dapagliflozin influences a number of CVD risk factors, in particular, decreasing blood pressure, reducing body weight (predominantly through reductions in total body fat mass, including visceral adipose tissue), reducing waist circumference, and lowering albuminuria and serum uric acid levels, with a low intrinsic risk of hypoglycemia (see left column page 2). Sonesson et al. discloses that their results show a beneficial CV effect for patients receiving dapagliflozin and is consistent with multifactorial benefits on CV risk factors associated with SGLT2 inhibitors (see “Conclusions” in Abstract). Sonesson et al. also discloses that significantly lower rates of hospitalization for heart failure and death from any cause were also observed for patients receiving empagliflozin and is consistent with their beneficial CV effect seen with dapagliflozin (see left and right column page 7).
The difference between Sonesson et al. and the claimed invention is that Sonesson et al. does not disclose an SGLT-2 inhibitor-sarcosine cocrystal.
The independent teachings of CN’372 and Yuan et al. are as discussed above. Furthermore, CN’372 discloses that a co-crystal drug can improve the physical and chemical properties of the drug, effectively improve the thermal stability, solubility, dissolution, and bioavailability of the drug, and improve the hygroscopicity of the drug (see paragraph 0008).
CN’372 modified by Yuan et al. teaches an SGLT-2 inhibitor-sarcosine cocrystal that is prepared by a mixing a solution of SGLT-2 inhibitor with a solution of sarcosine, crystallizing by standing or cooling, and solid-liquid separating to obtain the SGLT-2 inhibitor-sarcosine co-crystal as described above.
It would have been prima facie obvious to combine Sonesson with CN’372 and Yuan before the effective filing date of the claimed invention by substituting the dapagliflozin SGLT2 inhibitor of Sonesson with the SGLT-2 inhibitor-sarcosine cocrystal as disclosed in the combined teachings of CN’372 and Yuan for treating diabetes, cardiovascular disease, and/or lowering blood pressure. One of ordinary skill in the art would have been motivated to make this modification with a reasonable expectation of success because Sonesson et al. establishes that SGLT2 inhibitors are useful for treating diabetes as well as providing potential CV benefits such as reducing blood pressure, and further suggests SGLT2 inhibitors may help in reducing hospitalization of heart failure. Furthermore, CN’372 discloses several advantages of using the co-crystal form of an active drug such as improving the thermal stability, solubility, dissolution, and bioavailability, and hygroscopicity of the drug. Therefore, an ordinary skill artisan would have predictably considered substituting the dapagliflozin of Sonesson with a dapagliflozin-sarcosine co-crystal to improve the efficacy of the dapagliflozin.
Response to Arguments
Applicant' s arguments filed on 11/19/2025 have been fully considered but were not persuasive.
Applicant states that an ordinary skilled artisan would have no motivation to replace the L-proline in CN’372 with the sarcosine disclosed in Yuan to arrive at the claimed invention. Applicant states that the amine-carboxylate synthon in Yuan plays an important role in the intermolecular hydrogen bonding interactions of both SMZ-sarcosine and SMZ-L-proline cocrystals. Applicant states that both sarcosine and L-proline provide a carboxylate group and reduce the SMZ solubility compared to SMZ alone (Figure 7 in Yuan). Applicant states that CN’372 discloses dapagliflozin-L-proline cocrystals with improved solubility and bioavailability. Furthermore, Applicant states that SGLT2 inhibitors usually do not have amine groups. Therefore, Applicant states that there is no motivation to substitute the L-proline of CN’372 with sarcosine since dapagliflozin lacks an amine group and thus cannot form the same type of interaction with sarcosine.
Applicant’s arguments above were not found persuasive because the rationale described above is not based on a motivation but based on the KSR(B) rationale in MPEP 2141 III, which states “(B) Simple substitution of one known element for another to obtain predictable results”. Furthermore, even though SGLT2 inhibitors may lack an amine group, it is recognized that the amine-carboxylate interaction is specific to the interaction with SMZ and either sarcosine and L-proline, and that the basis of the substitution described above does not rely on the presence of this amine group. Rather, the basis of the substitution is from Yuan providing guidance of sarcosine being an alternative crystal co-former to L-proline based on its structural similarity to L-proline as well as its similar hydrogen bonding interaction and molecular packing arrangements. Therefore, an ordinary skilled artisan, when forming SGLT2 – L-proline cocrystals such as disclosed in CN’372, could have reasonably considered using sarcosine as an alternative crystal co-former based on these similarities described above.
Applicant states that their SGLT2-sarcosine cocrystal achieves the technical effects of lowering impurity content and stable solubility across different pH media. Applicant presents several arguments and comparative data as to why neither the SMZ-sarcosine cocrystal of Yuan nor the dapagliflozin-L-proline cocrystal of CN’372 achieve the described technical effects as discussed below.
Applicant states that the SMZ of Yuan is antibiotic drug with good solubility but short in vivo half life. Applicant states that thus, reducing the dissolution rate is expected to improve bioavailability and therapeutic activity. Applicant points to the teachings of Yuan that the feasibility of this strategy is based on the intermolecular interactions between SMZ and sarcosine and that the this cocrystal exhibited significantly different equilibrium solubility across various pH media. Applicant states that their SGLT-2 inhibitor – cocrystal does not change the solubility of the drug. Applicant states that the SMZ-sarcosine cocrystal of Yuan had a 70% reduction going from a pH 6.8 PBS solution to 1.2 pH HCl solution, whereas their dapagliflozin-sarcosine cocrystal only resulted in a 0.1% increase going from 6.8 pH PBS to 1.0 pH HCl. Thus, Applicant states that Yuan teaches completely different technical effects, and that the combined teachings of CN’372 and Yuan teach away from the claimed invention.
Applicant’s arguments above were not found persuasive because while Yuan may teach different technical effects of their SMZ co-crystals, these technical effects disclosed in Yuan are in relation to SMZ and not SGLT-2 inhibitors. Therefore, the data disclosed in Yuan does not teach away from the technical effects described above because the instant claims are directed toward the SGLT-2 inhibitor and not the SMZ drug. Furthermore, CN’372 discloses a dapagliflozin-L-proline cocrystal, which is the closest prior art to the claimed invention and is used as the comparative cocrystal set forth below.
Applicant demonstrates in Table 6 (page 31) that dapagliflozin-sarcosine cocrystal (example 9) shows only one impurity exceeding 0.1%, whereas dapagliflozin-L-proline (comparative example 3) had six impurities exceeding 0.1%. Applicant states that the levels of ring-opened impurity, five-membered ring impurity, and diastereomer impurity are also all significantly lower in comparison to the dapagliflozin-L-proline cocrystal.
In response to Applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., impurity content) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Furthermore, even if Applicant were to add in the impurity content feature into the instant claims, this feature would not be commensurate in scope with the instant claims. While Applicant has demonstrated a lower impurity content for dapagliflozin-sarcosine cocrystal in comparison to the closest prior art cocrystal (dapagliflozin-L-proline as disclosed in CN’372), Applicant has not demonstrated that this technical effect would be commensurate for the full scope of SGLT2 inhibitors encompassed by claim 39. As shown in Table 1 on pages 4-6 of the instant specification, SGLT2 inhibitor compounds have different chemical structures and substituents, which will influence the intermolecular hydrogen bonding interactions / molecular packing arrangements and could result in significantly changing the properties of the co-crystal formation with sarcosine. For example, in Table 1, Tofogliflozin, Remoglifozin, and Alligliflozin have the following structures, respectively:
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Here, these SGLT2 inhibitor compounds have signficantly different structures, ring groups, and substituents such that the intermoelcular interaction / molecule packing arrangment will be signficitanly different and result in different properties of the formed co-crystal.
Applicant demonstrates in Table 25 on page 52 of the instant specification that both the dapagliflozin-sarcosine and canagliflozin-sarcosine cocrystals exhibit stable solubility across different pH media. Here, Applicant states that dapagliflozin -sarcosine cocrystal had a solubility of 1.64 mg/mL in citrate buffer at pH 4.0 and 1.58 mg/mL in phosphate buffer at approximately pH 6.8, resulting in a 3.7% decrease in solubility. In contrast, Applicant states that CN’372 discloses that dapagliflozin -L-proline cocrystal exhibited 0.4 mg/mL solubility in a phosphate buffer at pH 4.0 and 0.3 mg/mL solubility in a phosphate buffer at pH ~7.0, resulting in a 25% decrease in solubility.
Here, Applicant has not provided a proper comparison to the closest prior art (the dapagliflozin-L-proline cocrystal of CN’372). Applicant has presented solubility tests across different types of buffer solutions (citrate buffer vs phosphate buffer) and simultaneously across different pH ranges, whereas CN’372 discloses solubility tests with the same phosphate buffer solution across different pH ranges. Therefore, Applicant’s described technical effect of a more stable solubility across different pH media cannot be determined over the closest prior art, since a proper comparison (keeping the solution type the same as disclosed in CN’372) was not provided.
Applicant also presents arguments against the rejection over instant claim 47, which recites a purification process of a SGLT-2 inhibitor using the recited SGLT2-sarcosine cocrystal. Applicant states that the purification process disclosed in CN’230, which discloses purification using a canagliflozin-proline cocrystal, only provides a canagliflozin containing less than 1% alpha-anomer impurities, whereas their SGLT2-sarcosine cocrystal can effectively remove multiple types of impurities including diastereomer, five-member ring, ring-opening, and dimer impurities.
Applicant’s argument described above was not found persuasive because this feature of removing more types of impurities would not be commensurate in scope with the instant claims. While Applicant has demonstrated more impurity types can be removed from their claimed purification process using dapagliflozin-sarcosine cocrystal in comparison to the closest prior art cocrystal (dapagliflozin-L-proline as disclosed in CN’372), Applicant has not demonstrated that this technical effect would be commensurate for the full scope of SGLT2 inhibitors encompassed by claim 47. As shown in Table 1 on pages 4-6 of the instant specification, SGLT2 inhibitor compounds have different chemical structures and substituents, which will influence the intermolecular hydrogen bonding interactions / molecular packing arrangements and could result in significantly changing the properties of the co-crystal formation with sarcosine and differences in the purification content when using these co-crystals. For example, in Table 1, Tofogliflozin, Remoglifozin, and Alligliflozin have the following structures, respectively:
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Here, these SGLT2 inhibitor compounds have signficantly different structures, ring groups, and substituents such that the intermoelcular interaction / molecule packing arrangment will be signficitanly different and result in different properties of the formed co-crystal.
Furthermore, Applicant’s technical feature of removing more types of impurities is also not commensurate in scope with claim 47 because while claim 47 specifies stirring at room temperature, claim 47 does not recite the solvent types for dissolving the SGLT-2 inhibitor and the sarcosine and mixing to form the SGLT-2-sarcosine complex before dissociation. The instant specification states that the similar polarity and structure of impurities makes it difficult to achieve the purpose of purification by simple liquid-liquid extraction or solvent recrystallization, and that by forming a SGLT2-sarcosine complex, the purity of the crude SGLT2 inhibitor can be increased with lower number / amount of impurties detected (see paragraph 0065 pages 15-16). Furthermore, Applicant has only demonstrated in Example 8 (page 29) of purifying crude dapaglifozin from first forming a complex with sarcosine by dissolving dapaglizoin in an organic-based solvent (ethanol) and sarcosine in water and mixing at 20-30 C. Therefore, Applicant has not demonstrated that the step of forming the SGLT2-sarcosine complex can be performed with any solvent and will result in the same feature of removing more types of impurities. Furthermore, it is noted that the present invention does not use an unsafe solvent during the preparation process; and a crude product or intermediate of the SGLT-2 inhibitor can be simultaneously purified (Abstract).
Lastly, Applicant has not provided comparison data between purifying canagliflozin using either the canagliflozin-sarcosine cocrystal of the instant invention or the canagliflozin-proline cocrystal of CN’230. MPEP 716.02(e) states that “Showing unexpected results over one of two equally close prior art references will not rebut prima facie obviousness unless the teachings of the prior art references are sufficiently similar to each other that the testing of one showing unexpected results would provide the same information as to the other.”
Here, the comparative data over the purity content of dapagliflozin from using dapagliflozin-L-proline described above would not be sufficiently similar to the purification method using canagliflozin-proline cocrystal disclosed in CN’230 because dapagliflozin and canagliflozin contain different chemical structures and substituents, which will influence the intermolecular hydrogen bonding interactions / molecular packing arrangements and could result in significantly changing the properties of the co-crystal formation with sarcosine and differences in the purification content when using these two co-crystals. Therefore, a comparison of the impurity content of canagliflozin using either canagliflozin-sarcosine or canagliflozin-proline cocrystals must also be provided in order to determine if the reduced impurity content is also seen from using this cocrystal as well.
In conclusion, the instant claims directed toward the co-crystal product and the method of making thereof (claims 39-46 and 48) do not recite features upon which applicant relies (i.e., impurity content) as described above. Furthermore, even if Applicant were to add in the impurity content feature into these claims, the results presented by Applicant would not be commensurate in scope with the instant claims as described above.
Additionally, the feature of removing more types of impurities is applicable to claim 47, which is directed toward a method of purifying a crude SGLT2 inhibitor (claim 47). However, as described above, the results presented by Applicant are also not commensurate in scope with claim 47.
Conclusion
No claim is found allowable.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
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/D.H.C./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693