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 .
DETAILED ACTION
Claims 1 and 3-30 are pending in the application. Claims 1 and 3-15 are rejected. Claims 16-30 are withdrawn.
Response to Amendments
Objections and rejections made in the Office Action mailed May 11, 2026 that do not appear below have been overcome by Applicant’s amendments to the claims and have been withdrawn.
Response to Arguments - 35 USC § 112(b)
In reply, Applicant traverses the claim rejections under 35 U.S.C. § 112(b) as presented in the Nonfinal Rejection mailed May 11, 2026. The claims rejections under 35 U.S.C. § 112(b) are withdrawn as a result of Applicant’s amendment filed on July 7, 2026.
Response to Arguments - 35 USC § 103
In reply, Applicant traverses the 35 U.S.C. § 103 rejection of claims 1-15 as presented* in the Nonfinal Rejection mailed May 11, 2026. *Note Examiner improperly identified claims rejected under 35 U.S.C. § 103 as “Claims 1-6, 9-12 and 15” in the Nonfinal Rejection mailed May 11, 2026. The newly applied 35 U.S.C. § 103 rejection of claims 1 and 3-15 has been necessitated by Applicant’s amendment filed on July 7, 2026. The previously presented rejection under 35 U.S.C. § 103 in the Office Action mailed May 11, 2026 has been withdrawn and replaced with the rejection(s) below. Applicant’s remarks, dated July 7, 2026, relevant to the newly applied 35 U.S.C. § 103 are addressed below.
Applicant argues that “Zhong does not disclose and would not have suggested a diluted formulation having a ‘glyburide solubility of at least 15 μg/mL’ that is ‘free of cyclodextrins,” as recited in amended claim 1.” See page 10 of Applicant’s Remarks dated July 7, 2026 (hereinafter “Response”). While, Zhong et al. (i.e., U.S. PGPub. No. 2020/0022993 A1) state that “the pharmaceutical composition of the present disclosure comprising an additive and a cyclodextrin can significantly inhibit the adsorption of the PVC infusion bag to the drugs” (see e.g., paragraph [0154]), Zhong et al. also teach aqueous solutions comprising glyburide (i.e., glibenclamide) and meglumine (i.e., sugar alcohol) with no added cyclodextrin (see e.g., pages 9-11) having solubilities of 0.96 mg/ml to 19.05 mg/ml (i.e., at least 15 μg/mL) (see e.g., paragraph [0135]). Although Applicant argues that because the instant claims “omit the cyclodextrins that Zhong taught were necessary for solubility and stability of glibenclamide” (see page 11 of Response), the fact that Zhong et al. disclose certain benefits of cyclodextrin does not detract from the fact that Zhong et al. explicitly teach glyburide formulations having no cyclodextrin present. Therefore, the instant claims are prima facie obvious over the prior art for the reason(s) discussed below in the rejection under 35 U.S.C. § 103 which is incorporated here by reference.
Applicant further argues that Zhong et al. “does not disclose and would not have suggested ‘a pH outside of the buffering capacity of the buffering agent[]’.” See page 13 of Response. As indicated below in the newly applied claim rejections under 35 U.S.C. § 103, Zhong et al. teach various formulation pH ranges and buffering agents such that a skilled artisan would be expected to arrive at the most appropriate formulation pH through a process of routine optimization. Therefore, while Applicant may have discovered a pH “that is critical to achieving the claimed solubility” (see page 12 of Response), the claimed invention is in line with and obviated by the teachings of the prior art.
Applicant argues that “Figueora-Valverde does not disclose or suggest the method of claim 1.” See page 13 of Response. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). Applicant also argues that “Figueora-Valverde does not disclose or suggest combining glibenclamide-OH with glibenclamide.” See page 13 of Response. However, there is no requirement that an “express, written motivation to combine must appear in prior art references before a finding of obviousness.” See Ruiz v. A.B. Chance Co., 357 F.3d 1270, 1276, 69 USPQ2d 1686, 1690 (Fed. Cir. 2004). See MPEP § 2145(X)(A). As discussed below in the rejection under 35 U.S.C. § 103, the prior art teaches that both glibenclamide-OH and glibenclamide share a common utility. Therefore, “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose.” In re Kerkhoven, 205 USPQ 1069 (CCPA 1980).
Applicant further argues that the Tris base/Tris HCl weight ratio limitation of dependent claim 8 would not be obvious based on Zhong et al. which discloses Tris buffer in e.g., paragraph [0023]. See page 14 of Response. Applicant asserts that “[c]reating formulations across the entire range would result in highly varied formulations with unpredictable characteristics” but does not indicate what, if any, “unpredictable characteristics” are present in this situation that would dissuade a skilled artisan from optimizing the teachings of the prior art. It has long been established law that “where 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). In the instant situation, Applicant has not demonstrated the criticality, if any, of the claimed Tris-HCl and Tris-base weight ratio which would provide evidence that the claimed Tris buffer interacts in an unpredictable or unexpected way with the other components of the claimed formulation(s). Notwithstanding, the “dissimilar characteristics of the members of the range” as indicated in Genetics Inst., LLC v. Novartis Vaccines & Diagnostics, Inc., 655 F.3d 1291, 1306, 99 USPQ2d 1713, 1725 (Fed. Cir. 2011) do not even correlate to the fact patterns presented in the instant situation. For instance, the relevant discussion provided in Genetics Inst., LLC v. Novartis Vaccines & Diagnostics, Inc. is drawn towards protein variants having structurally significant differences whereas the instant situation concerns a low MW compound base and its conjugate acid (i.e., single proton difference). Therefore, as discussed below in the rejection under 35 U.S.C. § 103, a skilled artisan would be expected to possess the general ability to determine and provide the appropriate Tris buffer for a particular experimental condition or application.
Applicant also argues that the “combination of the cited references and the Office Action ‘does not take into account the interdependence of the claimed [] components or how the adjustments would affect the [formulation] as a whole” and that “the Office Action fails to establish an evidentiary basis that the component amounts are result-effective variables ...[and] the need to optimize the amounts of...the formulations used in the claimed method.” See page 16. However, “[i]t is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions." In re Williams, 36 F.2d 436, 438 (CCPA 1929). Moreover, the fact patterns of Modernatx, Inc. v. Arbutus Biopharma Corp., 18 F.4th 1364, 2021 U.S.P.Q.2d 1177 (Fed. Cir. 2021) do not even correlate to the instant situation as the instantly claimed formulation of independent claim 1 is drawn towards generic components of which only one is further limited to a specific amount(s). Therefore, as stated before, “where 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).
For the reasons discussed above, claims 1 and 3-15 are prima facie obvious over the prior art.
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.
Claims 1 and 3-15 are rejected under 35 U.S.C. § 103 as being unpatentable over Zhong et al. (U.S. PGPub. No. 2020/0022993 A1; January 23, 2020) in view of Figueroa-Valverde et al. (Biomedical Papers, 2012, 156:122-127).
Determining the scope and contents of the prior art (See MPEP § 2141.01)
Zhong et al. teach “Example 2” (i.e., a preparation of glibenclamide injectable composition) in e.g., paragraph [0103] which is reproduced below:
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Note that glibenclamide (i.e., prior art Formula 1 as shown below) is also known as glyburide (see e.g., paragraphs [0002], [0003] and [0016]):
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Zhong et al. further teach a “corresponding injectable composition without hydroxypropyl-ß-cyclodextrin...diluted with 0.9% solution of sodium chloride until the concentration of glibenclamide was 5 μg/ml” (emphasis added). See e.g., paragraph [0148]. Zhong et al. also teach an aqueous glibenclamide solution with meglumine (i.e., sugar alcohol) but with zero concentration of cyclodextrin having solubilities of 0.96 mg/mL to 19.05 mg/mL (i.e., at least 15 μg/mL). See e.g., paragraph [0135]. Zhong et al. further teach an “additive [] selected from [inter alia] tris(hydroxylmethyl)aminomethane (i.e., Tris or Tris base buffer). See e.g., paragraph [0023]. It is noted that Tris buffer has a buffering capacity range of pH 7.0 to 9.0 and a pKa of 8.08 at 25°C. See e.g., paragraph [00120] of the instant specification. Zhong et al. further teach “preferably, the additive is sodium hydroxide.” See e.g., paragraph [0028]. Zhong et al. further teach the pharmaceutical composition further comprises a lyophilization additive e.g., “mannitol.” See e.g., paragraphs [0030] and [0118]. In addition, Zhong et al. teach that “in addition to the above active agents and additives, other excipients, buffering agents or pH regulator...may also be comprised in the composition.” See e.g., paragraph [0076]. Zhong et al. further teach the pharmaceutical composition has a pH of preferably 6-10 and also adjusting the solution formulation to pH 8.0. See e.g., paragraphs [0047], [0103] and [0104]. In addition, Zhong et al. teach a method for preparing the prior art pharmaceutical composition, wherein the method comprises combining the sulfonylurea drug with a solution (e.g., wherein solvent is physiological saline) followed by addition of the lyophilization additive to eventually form a freeze-dried product. See e.g., paragraphs [0048]-[0053]. Moreover, Zhong et al. teach the prior art pharmaceutical composition “may be dissolved in physiological saline to produce an injection” or otherwise “diluted by 500 times with 0.9% solution of sodium chloride.” See e.g., paragraphs [0079] and [0153]. Zhong et al. also teach a 1:1-50 “weight ratio of the sulfonylurea drug to the additive” which encompasses the required weight ratio limitation of instant claim 10 (i.e., wherein the additive is, for instance, the disclosed lyophilization additive mannitol). See e.g., paragraphs [0011] and [0030]. Lastly, Zhong et al. teach the following with respect to therapeutic treatments (see paragraph 0054):
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Note that the expression “for reducing an infusion rate of a glyburide formulation diluted in a saline infusion solution over the course of a 24 hour infusion,” as recited in the preamble of instant claim 1, is drawn towards characteristics that would necessarily be present from employing the instantly claimed method and is, therefore, considered to be non-limiting. In addition, note that instant claim 1 is directed to product-by-process limitations nested within a method claim. However, the nesting of a product-by-process limitation within a method claim does not change the proper construction of the product-by-process limitation itself. MPEP 2113 states the following:
"[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985)
"[T]he lack of physical description in a product-by-process claim makes determination of the patentability of the claim more difficult, since in spite of the fact that the claim may recite only process limitations, it is the patentability of the product claimed and not of the recited process steps which must be established. We are therefore of the opinion that when the prior art discloses a product which reasonably appears to be either identical with or only slightly different than a product claimed in a product-by-process claim, a rejection based alternatively on either section 102 or section 103 of the statute is eminently fair and acceptable. As a practical matter, the Patent Office is not equipped to manufacture products by the myriad of processes put before it and then obtain prior art products and make physical comparisons therewith." In re Brown, 459 F.2d 531, 535, 173 USPQ 685, 688 (CCPA 1972). Office personnel should note that reliance on the alternative grounds of 35 U.S.C. 102 or 35 U.S.C. 103 does not eliminate the need to explain both the anticipation and obviousness aspects of the rejections.
In this situation, the product-by-process limitations are drawn towards “a stabilized and soluble glyburide formulation” and “a diluted formulation.” Additionally, note that the expression “wherein the diluted formulation is configured to be infused into a human at a rate of less than 16 mL/hour for 24 hours” is considered to be non-limiting due to being drawn towards characteristics necessarily present in the “diluted formulation” product obtained as a result of employing the instantly claimed method. Similarly, the expression “wherein the pH of the diluted formulation does not change by more than 0.2 pH units over the course of the 24 hour infusion,” as recited in instant claim 3, is also drawn towards characteristics that would necessarily be present in the “diluted formulation” of parent claim 1 and is, therefore, considered to be non-limiting. Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). In addition, “[p]roducts 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. See MPEP § 2112.01(II).
Ascertainment of the differences between the prior art and the claims (See MPEP § 2141.02)
Regarding instant claim 1, Zhong et al. does not explicitly teach a buffered formulation which has a pH outside of the buffering agent buffering capacity and also having a pH of 7.8 to 9. However, Zhong et al. teach various buffering agents including tris(hydroxylmethyl)aminomethane (i.e., Tris or Tris base) (see e.g., paragraph [0023]) which has a buffering capacity range of pH 7.0 to 9.0 and a pKa of 8.08 at 25°C. Zhong et al. also teach various pH regulators and formulation pH ranges (i.e., “5~11, preferably 6~10, preferably 7~9, more preferably 7~8”). See e.g., paragraphs [0032]-[0048].
Regarding instant claims 7 and 8, although Zhong et al. teach tris(hydroxylmethyl)aminomethane (i.e., Tris base) as an additive. While Zhong et al. does teach Tris buffer, Zhong et al. does not explicitly teach a combination of Tris base and its conjugate acid Tris-HCl having the instantly claimed weight ratios ranges. However, Zhong et al. does teach pharmaceutical compositions further comprising “a pH regulator (e.g., hydrochloric acid).” See e.g., paragraphs [0030], [0032] and [0104].
Regarding instant claim 12, Zhong et al. does not teach a molar ratio between a base and glyburide. Zhong et al. does, however, teach a 1:1-10 “weight ratio of the sulfonylurea drug to the additive” (i.e., wherein the additive is, for instance, sodium hydroxide). See e.g., paragraphs [0011] and [0028].
Regarding instant claim 13, Zhong et al. does not teach that the pharmaceutical composition further comprises one of the chemical compounds recited in the claim. However, Figueroa-Valverde et al., in the same field of endeavor, teach glibenclamide-OH [i.e., a glyburide/glibenclamide derivative originally referenced in Asian J Chem 2011, 23(9):3999-4002; see e.g., page 4000] having the chemical structure below and which corresponds to the second compound as recited in instant claim 13 (see e.g., page 123):
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Regarding instant claim 14, Zhong et al. does not teach the instantly claimed 26 to 34 mg/mL concentration of sugar alcohol. However, Zhong et al. teach a pharmaceutical composition comprising 5 g of mannitol in 100 mL solution (i.e., 50 mg/mL concentration). See e.g., paragraph [0118].
Finding of prima facie obviousness --- rationale and motivation (See MPEP § 2142-2143)
Regarding instant claims 7 and 8, considering that Zhong et al. teach both Tris base as an additive and the addition of hydrochloric acid, it would have been obvious to a person of ordinary skill in the art to form the instantly claimed Tris base and Tris-HCl conjugate acid buffer solution. It is within the ability of a skilled artisan to determine the appropriate buffer formulation (e.g., Tris, Tris-HCl, Tris/Tris-HCl, etc.) for a given experimental workflow or application. Tris buffer has a buffering capacity range of pH 7.0 to 9.0 and a pKa of 8.08 at 25°C and is, therefore, generally known to be effective at maintaining a physiological pH range. Therefore, a skilled artisan looking to further improve properties such as stability, solubility, bioavailability, etc., would be motivated to determine the appropriate weight ratio of Tris base and its acid addition salt (e.g., Tris-HCl) through a process of routine optimization. Furthermore, the skilled artisan would have a reasonable expectation that the resulting Tris-HCl/Tris buffer would not alter the utility of the pharmaceutical composition taught by Zhong et al- especially in view of the fact that Zhong et al. provide support for formulations comprising both Tris and HCl. See e.g., paragraphs [0023], [0030], [0032] and [0104]. “It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.” In re Williams, 36 F.2d 436, 438 (CCPA 1929).
Regarding instant claim 13, it would, therefore, have been obvious to further comprise glibenclamide-OH, as taught by Figueroa-Valverde et al., in the pharmaceutical composition of Zhong et al. Figueroa-Valverde et al. teach glibenclamide-OH as having the same utility (and hypoglycemic effect) as glyburide. Therefore, one skilled in the art would have had a reasonable expectation that a combination of compounds known individually to treat diabetes mellitus would be effective in treating diabetes mellitus collectively. It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose. In re Kerkhoven, 205 USPQ 1069 (CCPA 1980). The idea of combining them flows logically from their having been individually taught in the prior art. At least in the interest of determining various combinations that may result in greater treatment efficacy, a skilled artisan would have been motivated to include an additional active ingredient in the prior art composition with a reasonable expectation of success in treating, for instance, diabetes mellitus.
Regarding instant claims 1, 12 and 14, it would have been obvious for a person of ordinary skill in the art to arrive at the instantly claimed formulation pH (as recited in instant claim 1), molar ratio (as recited in instant claim 12) and concentration range (as recited in instant claim 14) based on the teaching of Zhong et al. The optimization of result-effective variables, i.e., variables that achieve a recognized result, such as pH and concentration, are considered to be within the ability of the skilled artisan. “[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). Therefore, a skilled artisan would be motivated to optimize the formulation pH and/or molar ratio/concentration range taught by Zhong et al. as part of the routine optimization process.
Conclusion
No claims are allowed.
Applicant’s amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/D.M.S./Examiner, Art Unit 1626
/REBECCA L ANDERSON/Primary Examiner, Art Unit 1626
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