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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-25, 27, 28 in the reply filed on 9/2/2025 is acknowledged.
Applicant’s election without traverse of:
(i) the sodium addition salt of glyburide, encompassed by claims 1-25, 27, 28;
(ii) an additional agent is present, encompassed by claim 28; and the compound:
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(iii) the buffering agent is a combination of Tris-HCl and Tris base, encompassed by claims 1-25, 27, 28;
(iv) NaOH as the base, encompassed by claims 1-25, 27, and 28;
(v) mannitol as the sugar alcohol, encompassed by claims 1-25, 27, 28,
in the reply filed on 9/2/2025 is acknowledged.
Claims 26-27 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 9/2/2025.
Claims 9, 23-24 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 9/2/2025.
Newly submitted claims 17-18, 31-34 are directed to an invention that is independent or distinct from the invention originally claimed for the following reasons: claims 17-18 & 34 are drawn to a liquid solution, which is no longer the subject matter of amended claim 1. Claim 31-33 are construed to be drawn to liquid solutions with certain materials part of containers, which were not originally presented; this construct differs from a lyophilized formulation, which has no details of the materials in the container.
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, claims 17-18, 31-34 are withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
The terminal disclaimer filed on 1/15/2026 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of any patent issued on U.S. Application No. 17/686,538 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (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.
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.
Claim(s) 1-8, 11-13, 15, 17-22, 25, 35 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jacobson et al. (WO 2009/073711 A1; 2009; cited in a prior Office action).
Jacobson teaches compositions (formulations) with therapeutic agents that have low solubility at low pH and medium pH values; steps include preparing aqueous solutions of a compound of interest in the absence of buffer, and adjusting the pH to high values of pH in order to increase the solubility of the compound of interest; aqueous solutions including buffer are also disclosed (abstract).
Compounds that are weak acids are often poorly soluble at low (pH 4 or 5) and medium pH values (about pH 6 or 7). Such compounds are often difficult to use as pharmaceuticals due to, for example, poor solubility in pharmaceutically acceptable solutions. Pages 3-6 discuss characteristics of Glibenclamide [according to the instant specification at [0003], glyburide is also known as glibenclamide].
Solutions and lyophilized formulations having features of the invention may include compounds which are substantially pharmaceutically inert; these include sugars such as, inter alia, Applicant elected mannitol (7:17-20).
Methods for lyophilizing compounds in liquid solutions may include steps of preparing aqueous solutions in one embodiment in the presence of a weak buffer (8:15-17; 9:18-20); adjusting to high values of pH in order to increase the solubility of the glibenclamide. Methods for lyophilizing compounds in liquid solutions including preparing aqueous solutions of glibenclamide and mannitol, adjusting the pH to high values of pH in order to increase the solubility of the glibenclamide and mannitol compounds; adjustment of pH to high values, which include pH values of 10, 11, in order to increase the solubility of the compound of interest. Adjusting the pH of the solution to high pH may be achieved using, inter alia, Applicant elected base, sodium hydroxide. Once the compound of interest is dissolved the pH may optionally be lowered, e.g., by addition of acid such as hydrochloric acid (10:19 to 11:1).
Solutions of glibenclamide solutions, formulations, and lyophilates may be prepared; can include a sugar (e.g., mannitol included; instant claim 25), and may include a salt, such as sodium chloride; and may also include a buffer, e.g., including, inter alia, Applicant elected Tris buffer; solutions include combinations of the above (23:9-20).
pH values of 11.4 and 9.4 are explicitly named (24:17-20); these pH values are close to the recited pH range when reconstituted in WFI of amended claim 1 (lines 10-11), rendering the pH criteria upon dilution in WFI prima facie obvious (MPEP 2144.05 (I), 2nd paragraph: Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985)).
The claimed criteria of pH values upon dilution with WFI or saline infusion solution of claim 1 are construed to be characteristic. Note also the similar ingredients, pH ranges, reconstitution in WFI, dilution with saline named in Table 3, rendering claimed characteristics as obvious.
In Example 7, 4.7-5.0 mg glibenclamide powder, 180 mg mannitol and sodium hydroxide as needed to adjust the pH to 11.3 prior to lyophilization; removal of 6 mL of water per vial occurred during lyophilization. After reconstitution pH was in the range 10.4-11.4 (pp. 47-49; overlapping with claim 1 line 11, rendering the claimed range prima facie obvious; MPEP 2144.05 (I)).
Using NaOH to adjust to pH 11.3, would have been indistinguishable from dissolution of Applicant elected sodium salt of glibenclamide, giving a formulation indistinguishable from claim 2. While the specific amount of NaOH is not stated, presuming solid amount similar to that of glibenclamide and water, the solid materials contain 180 mg mannitol relative to about 195 mg total components, renders obvious about 92% mannitol, within or at least close to the content of claim 4, a ratio of 180:4.7-5.0, or 36-38:1 ratio, within the claim 5 ranges. Glibenclamide content would be about 4.7-5.0/195, or 2.4-2.5, within the claim 3 range.
Regarding buffer, amounts in the range of between 1 mM and 100 mM are taught (47:18-19). Concentrations of Tris base are about 1.21% or for Tris-HCl 1.58% for the 100 mM concentration, or 5-fold lower for 20 mM, 0.242 or 0.316%, respectively. For mannitol, 2-3% or 3-4% concentrations of mannitol are taught in Table 9; relative to 20 mM, the weight ratios are 2-4% /0.242% or 0.316%, mannitol/Tris ratios include 2/.242 or 4/.316; i.e., 8.2:1 or 12:1, within the claim 11 sugar alcohol/buffer ratio ranges
Regarding claim 12, mannitol concentrations include 3% (which corresponds to about 30 mg/mL), within the claim 12 range.
Examiner notes the base/glyburide molar ratios utilize similar amounts to achieve nearly the same pH values as claim 14; thus amounts of base and glyburide ratios are presumed to overlap with claim 13, or to be close, rendering the molar ratios prima facie obvious.
Regarding claim 14, the pH value of 11.3 is close to 11.2, and the range of this claim is within a range encompassed by exemplary pH levels taught, including pH 11, rendering this range obvious.
Regarding amended claim 1, the elected buffer is disclosed to have a pKa of 8.07, within the claimed range, and the pH greater than 9.0 of claim 17 or the pH range 9.8-11.2 of amended claim 1) correspond to pH is outside of buffering capacity of Tris, disclosed to be up to pH 9.0; i.e., 9.01, obvious from ranges taught, is outside buffering capacity of 7-9), rendering claim 17 obvious. The range 9.3-11 of claim 18 is obvious from pH 10 and 11 taught.
Regarding claim 19, the pKb of sodium hydroxide (claim 20) is 1.0, reading on the elected NaOH pH adjusting agent.
Regarding the elected combination of Tris-HCl and Tris-base, absent evidence to the contrary, the combination of Tris (either HCl or base), and adjustment to pH 9.01, 10 or 11, or 11.4, each taught or obvious over Jacobson, would have given a formulation indistinguishable from the elected combination of Tris-HCl and Tris base.
Thus, the elected combinations of the instant claims 1-8, 11-13, 15, 17-22, 25 would have been obvious to combine and adjust to the claimed pH characteristics, based on the individual components and reasons taught by Jacobson.
Regarding the pH range 10-11 in 20 mL WFI, absent evidence to the contrary, the obvious ranges of pH taught would include this pH range, if reconstituted to 20 ml volume. Or, alternatively, based on pH considerations, this range would have been obvious to adjust for, as a result of routine optimization.
Regarding claims 34-35, the requirements of claim 34 are construed as characteristic of the elected components. As discussed above, amounts overlapping or close to claim 35 are taught by Jacobsen, rendering this claim obvious.
Applicant argues that the claimed amendments to claim 1 require a lyophilized formulation, and specific characteristics of pH when reconstituted in WFI and when diluted in a saline infusion solution. Applicant argues that Jacobson does not specify the pH under these conditions.
This is not persuasive. Jacobson clearly teaches lyophilized formulations. Very similar, if not identical, dilutions and pH ranges are stated by Jacobson. In some cases, the pH values are close, rendering the claimed pH values characteristic or close enough to render the claims prima facie obvious.
Applicant further argues about absence of buffer. While the Examiner acknowledges such teachings, the presence of buffer, including Tris buffer are alternately taught, and are clearly obvious constructions within the teachings of this reference.
Regarding solubility, Jacobson clearly teaches solubility increases at higher pH values. Regarding sorption, the claims under examination do not require any components that give rise to sorption characteristics argued.
Regarding buffer effects, the presence of Tris buffers is clearly taught, and dilutions giving the same or close pH values are taught by Jacobson. Thus, there is nothing that achieves unexpected results over what is taught by Jacobson.
High glyburide solubility is explicitly taught at pH conditions corresponding to Jacobson formulations, and claim 1 pH characteristics.
Claim(s) 1-8, 11-13, 15, 17-22, 25, 28, 35 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jacobson et al. (WO 2009/073711 A1; 2009; cited in a prior Office action), as applied to claims 1-8, 11-13, 15, 17-22, 25, 35 above, and further in view of Wei et L. (WO 2016/138473 A1; 2016; cited in a prior Office action).
As set forth above, Jacobson renders obvious the elected combination of claim 1: a) glyburide (glibenclamide; or the sodium addition salt of glyburide, rendered obvious, when sodium hydroxide is added in excess of a 1:1 molar ratio, to dissolve the glyburide);
b) Tris buffer
c) NaOH;
d) mannitol;
and pH characteristics of amended claim 1, under various dilution conditions; for Tris, according to the specification at [0121], the buffering capacity is pH 7.0-9.0; Jacobson teaches pH values higher than pH 9.0, rendering obvious this pH range of claim 1, pH levels that more effectively solubilize glyburide.
Regarding dependent claim 28, this claim requires a second active compound, in addition to glyburide. The elected second compound of claim 28 is:
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5-chloro-2-methoxy-N-[2-(4-sulfamoylphenyl)ethyl]benzamide
This second compound is not taught by Jacobson.
Wei teaches methods for treating a myelodysplastic syndrome (MDS) in a subject that involves administering to the subject a therapeutically effective amount of an inflammasome inhibitor (abstract); claim 1.
Claim 2 recited the inflammasome inhibitor compreses a NLRP3 inflammasome inhibitor; Claim 4, dependent from claim 2 limit the inflammasome inhibitor to one of three alternative compounds, glybenclamide (glyburide), and 5-chloro-2-methoxy-N-[2-(4-sulfamoylphenyl)ethyl]benzamide are two of the claimed compounds.
Because 5-chloro-2-methoxy-N-[2-(4-sulfamoylphenyl)ethyl]benzamide is clearly claimed to be an alternative compound for treating MDS, to glyburide, the skilled artisan would have found it obvious to add this compound to the formulation obvious over Jacobson, the formulation of claim 1, rendering obvious the elected formulation of claim 28. The motivation would have been that both active compounds are art-recognized to have the same activity in treating MDS, rendering obvious their combination.
MPEP 2144.06 establishes: "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 order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Conclusion
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 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TIMOTHY P THOMAS whose telephone number is (571)272-8994. The examiner can normally be reached M-Th 6:30-5:00.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ali Soroush can be reached at (571)272-9925. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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TIMOTHY P. THOMAS
Primary Examiner
Art Unit 1614
/TIMOTHY P THOMAS/Primary Examiner, Art Unit 1614
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