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In view of the amendment, previous 112(b) rejection on claims 32, 34, 43 and 45 is hereby withdrawn.
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.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 35 and 46 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. The amended claims 31 and 42, from which instant claims 35 and 46 depend, respectively, now require that the aqueous solution composition for oral administration does not include a surfactant. Yet, claims 35 and 46 recite that the second component does not include a surfactant. Since the independent claims 31 and 42 already require that the aqueous solution composition for oral administration does not include a surfactant, dependent claims 35 and 46, which recite that the second component does not include a surfactant, fail to further limit the subject matter of the independent claims 31 and 42. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 31-35, 40, 42-46 and 51 are rejected under 35 U.S.C. 103 as being unpatentable over Van Moorleghem (GB 912,894) in view of Javaid et al (“Dissolution of Aspirin from Tablets Containing Various Buffering Agents”, Journal of Pharmaceutical Sciences, Vol.61(9), October 1972, pg.1370-1373), Galat (5,776,431) and ONDQA Biopharmaceutics Review (“Clinical Pharmacology and Biopharmaceutics Review(s)”, Center for Drug Evaluation and Research, (December 2, 2012) - a review paper obtained from the website: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/203697Orig1s000ClinpharmR.pdf. ).
Van Moorleghem teaches (pg.1, lines 15-20) a novel method for preparing an injectable solution of acetylsalicylic acid (aspirin) in a solution of sodium citrate in pyrogen-free distilled water (an aqueous solution of sodium citrate): In this method (see pg.1, lines 30-40, lines 50-76), 0.50 grams (500 mg) of pulverulent (powdery) aspirin is filled into a sterilized phial, which is then closed by a rubber stopper. The phial is then sterilized again by electron beam radiation. A solution of sodium citrate is prepared in pyrogen-free distilled water and filled into a separate phial and then sterilized. The injectable solution of aspirin is prepared at the moment of use by withdrawing 10 mL of sterile aqueous sodium citrate solution by using an injection needle and injecting this solution through the rubber stopper into the phial containing the pulverulent aspirin after which the phial is shaken so as to provide for dissolution of the aspirin within a few seconds (pg.1, lines 79-86, pg.2, lines 1-7). Van Moorleghem’s injectable solution of aspirin does not contain any other pharmaceutically active agent with analgesic, anti-inflammatory and anti-cardiovascular disorder activity. Thus, Van Moorleghem teaches instant two component composition, which provides an aqueous solution composition, comprising a first and second component where the first component is in dry powder form and comprises 100-600 mgs of acetylsalicylic acid and the second component comprises an aqueous solution comprising sodium citrate and having a volume of 8-15 ml, wherein acetylsalicylic acid is the only pharmaceutically active agent with analgesic, anti-inflammatory and anti-cardiovascular disorder activity in the two-component composition, wherein the first and second components form an aqueous solution composition within one minute of mixing.
Van Moorleghem does not teach instant carbonate which is contained in instant aqueous solution of the second component. However, as evidenced by Javaid (see abstract), it is known in the art that carbon dioxide-producing buffering agent (such as sodium bicarbonate, magnesium carbonate and calcium carbonate) gives more rapid dissolution of aspirin than the readily water-soluble buffering agents (such as sodium ascorbate or sodium citrate). Since Van Moorleghem desires a rapid dissolving aspirin composition (see pg.2, lines 3-5), it would have been obvious to one skilled in the art to include a sodium bicarbonate, magnesium carbonate or calcium carbonate in Van Moorleghem’s injectable aspirin solution with a reasonable expectation of achieving a rapid dissolving aspirin composition. As to the limitation of instant carbonate being contained in instant aqueous solution of the second component, it is known in the art, as evidenced by Galat (col.2, lines 29-35, lines 47-50), that powders containing aspirin together with an alkali salt (such as sodium bicarbonate) become gummy in the air (hydrolysis occurs in admixtures (of aspirin) with salts containing water of crystallization). Even though the phial containing the pulverulent aspirin is sealed with a rubber stopper and thus air-tight, it would be common-sensical for one skilled in the art to avoid the risk of hydrolysis of the pulverulent aspirin by placing the carbonate in the phial with sodium citrate (and not in the phial containing the aspirin). Thus, Van Moorleghem in view of Javaid and Galat renders obvious instant limitation of the second component comprising an aqueous solution comprising at least one pharmaceutically acceptable salt of citric acid and a carbonate.
Van Moorleghem in view of Javaid and Galat does not teach instant pH limitations of claims 31 and 42. As evidenced by ONDQA Biopharmaceutics Review (“ONDQA” hereinafter) (see pg.6, Figure 1 and Table 2), it is known in the art that both the solubility and stability of aspirin in aqueous solution are pH dependent. ONDQA teaches that aspirin shows poor solubility but high stability at acidic pH and significantly increased solubility but more rapid degradation at alkaline pH. Under such guidelines known in the art, and in view of the fact that applicant also want to achieve optimal solubility and stability of aspirin in aqueous solution by adjusting pH (see [0083] and [0126] of US-PGPUB of present specification), instant pH limitations (about 8-11.5 for the aqueous solution comprising the salt of citric acid and carbonate and 5-8 for the aqueous solution composition for oral administration) would have been obvious to one skilled in the art before the effective filing date of the claimed invention since it has been held that discovering an optimum value of a result effective variable involves only routine skill in the art. In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980). Thus, Van Moorleghem in view of Javaid and Galat and ONDQA renders obvious instant pH limitations of claims 31, 33, 34, 42, 44 and 45.
With respect to instant limitation “for oral administration” (which is merely a limitation of intended use), since Van Moorleghem in view of Javaid, Galat and ONDQA teaches all elements of instant two-component composition (as explained above), such two-component composition would inherently be capable of being used for oral administration.
With respect to the newly added limitation “wherein the aqueous solution composition for oral administration does not include a surfactant, and wherein water is the only solvent”, Van Moorleghem’s injectable solution of aspirin (as modified by the teachings of Javaid, Galat and ONDQA) does not contain a surfactant or any other solvent than water. Thus, Van Moorleghem in view of Javaid, Galat and ONDQA teaches instant limitation.
Thus, Van Moorleghem in view of Javaid, Galat and ONDQA renders obvious instant claims 31, 33, 35, 42, 44, 46 and 51.
With respect to instant claims 32, 34, 43 and 45, it was established above that instant pH range for the aqueous solution composition for oral administration (i.e., the aqueous solution obtained by mixing the first component comprising the powdery aspirin (acetylsalicylic acid) and the second component comprising an aqueous solution comprising the salt of citric acid (sodium citrate) and carbonate) would have been obvious, and this would accordingly mean that instant concentration of sodium citrate would also have been obvious because the pH of the final aqueous solution depends on both the concentration of the dissolved aspirin and the concentration of sodium citrate, and if there is not enough sodium citrate, the pH of the final aqueous solution would become too acidic. Thus, Van Moorleghem in view of Javaid, Galat and ONDQA renders obvious instant claims 32, 34, 43 and 45.
With respect to instant claim 40, although Van Moorleghem uses 500 mg of aspirin in its specific example (shown in pg.1, lines 31-38), it does not give a general teaching as to a range for the amount of aspirin that can be used in its injectable aspirin solution. However, as shown by Galat (col.1, lines 50-52), 325-500 mg dosage of aspirin is known to be sufficient for pain alleviation. It would be obvious to one skilled in the art to use aspirin in the amount of 325-500 mg in Van Moorleghem’s injectable solution of aspirin with a reasonable expectation of success in pain alleviation. The range 325-500 mg overlaps with instant range 300-325 mg of claim 40, thus rendering instant range prima facie obvious. In the case “where the [claimed] ranges overlap or lie inside ranges disclosed by the prior art,” a prima facie case of obviousness would exist which may be overcome by a showing of unexpected results, In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976). Thus, Van Moorleghem in view of Javaid, Galat and ONDQA renders obvious instant claim 40.
Claim(s) 36-39, 41 and 47-50 are rejected under 35 U.S.C. 103 as being unpatentable over Van Moorleghem (GB 912,894) in view of Javaid et al (“Dissolution of Aspirin from Tablets Containing Various Buffering Agents”, Journal of Pharmaceutical Sciences, Vol.61(9), October 1972, pg.1370-1373), Galat (5,776,431) and ONDQA Biopharmaceutics Review (“Clinical Pharmacology and Biopharmaceutics Review(s)”, Center for Drug Evaluation and Research, (December 2, 2012) - a review paper obtained from the website: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/203697Orig1s000ClinpharmR.pdf. ) as applied to claims 31 and 42 above, and further in view of Zabrzewska et al (“Development Studies on Determination of Preservatives Decomposition Products”, Acta Poloniae Pharmaceutica – Drug Research, Vol.71(4), (2014), pg.563-573).
Van Moorleghem’s injectable solution of acetylsalicylic acid does not contain a preservative. As evidenced by Zabrzewska et al (abstract), it is well known in the art that preservatives protect medicinal products against harmful changes caused by microorganisms. They are known to be added to sterile medicinal products such as solutions for injections as well as to non-sterile products, such as water oral solutions. Since Van Moorleghem’s sodium citrate solution prepared in pyrogen-free distilled water may still contain bacteria (pyrogen-free does not mean sterile), it would have been obvious to one skilled in the art to add preservatives to the sodium citrate solution with a reasonable expectation of ensuring that microorganism growth does not occur thereby protecting the solidum citrate solution prepared in pyrogen-free distilled water. Zabrzewska further teaches (abstract) that the most commonly used preservatives include ethyl, methyl and propyl p-hydroxybenzoates (another name for paraben) and their sodium salts. Thus, Van Moorleghem in view of Javaid, Galat and ONDQA, and further in view of Zabrzewska renders obvious instant claims 36-39 and 47-50.
With respect to instant claim 41, it was already established above that it would be obvious (under Galat’s teaching) to one skilled in the art to use 325-500 mg of aspirin (acetylsalicylic acid) in Van Moorleghem’s injectable solution, which range overlaps with instant range of 300-325 mg, thus rendering instant range prima facie obvious. In re Wertheim, supra. As already discussed above, Van Moorleghem’s injectable solution of aspirin is prepared using 10 mL of sterile aqueous sodium citrate solution. It was established above that the range of 10-150 mg/ml for the concentration of sodium citrate would have been obvious (see Paragraph 7 above in relation to the discussion of claim 32). It was also established above that it would have been obvious (under Javaid’s teaching) to one skilled in the art to include a sodium bicarbonate, magnesium carbonate or calcium carbonate in Van Moorleghem’s injectable aspirin solution with a reasonable expectation of achieving a rapid dissolving aspirin composition. As discussed above, it would have been obvious (under Zabrzewska’s teaching) to one skilled in the art to add preservatives (such as sodium salt of methyl paraben, ethyl paraben or propyl paraben) to Van Moorleghem’s sodium citrate solution with a reasonable expectation of ensuring that microorganism growth does not occur thereby protecting the solidum citrate solution prepared in pyrogen-free distilled water. Therefore, Van Moorleghem in view of Javaid, Galat and ONDQA, and further in view of Zabrzewska renders obvious 41.
Response to Arguments
Applicant first argue that Javaid does not teach combining sodium citrate and carbonate and that Javid only shows the dissolution rates of ASA in either a salt of citric acid or a carbonate, not both. Applicant thus argue that one skilled in the art would not be drawn to dissolving ASA in both the salt of citric acid and carbonate. Applicant argue that Javaid provides no expectation of what would result when an acid is combined with a carbonate and argue that combining an acid source and a carbonate is known to provide effervescence. The Examiner disagrees. "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). In instant case, both sodium citrate and carbonate (such as sodium bicarbonate, magnesium carbonate and calcium carbonate) are being individually taught as being used for dissolution of ASA. Thus, it would be prima facie obvious to combine both sodium citrate and carbonate to be used in Van Moorleghem for enhanced dissolution of ASA. The Examiner also would like to point out that sodium citrate is not an acid but a weak base. Thus, since both sodium citrate and carbonate are basic, there would be no reaction to produce effervescence when combined.
Applicant argue that Javaid uses much more water as its dissolution medium (250 mL) while current claims are drawn to 8-15 ml (claim 31) and to 6-50 ml (claim 42). Applicant argue that Javaid thus does not address the issue of effervescence in small volume of water. However, the Examiner does not understand the point of applicant’s argument since Javaid is a secondary reference that is being used merely to show that is known in the art that carbon dioxide-producing buffering agent (such as sodium bicarbonate, magnesium carbonate and calcium carbonate) gives a rapid dissolution of aspirin and Van Moorleghem (instant primary reference) already teaches using a small volume (10 ml) of sterile aqueous sodium citrate solution to dissolve the aspirin within a few seconds (the dissolution of aspirin will be even more rapid once the carbonate is added). Also, even though applicant argue that Javaid does not address the issue of excess effervescence in dissolving ASA in small volumes, such argument is not persuasive because present claims do not include any limitation concerning effervescence.
Applicant argue that Javaid’s ASA tablet formulation include a starch which is a disintegrant and argue that Javaid does not provide any expectation of success in combining carbonate and the salt of citric acid to dissolve ASA without using starch. However, first of all, as evidenced by Van Moorleghem, it is already known that ASA can be rapidly dissolved in aqueous sodium citrate solution without using starch. Secondly, starch will only affect how fast the ASA will dissolve, not whether the ASA will dissolve in a solution.
Applicant next point to WO2017001468 (WO’468) and argue that combining acid with carbonate provides effervescence and in order to reduce the foaming and gas, a surfactant (polysorbate 80) and a co-solvent (ethanol) were needed. On the contrary, applicant that their Example 2 of present specification shows that the 300 mg of ASA dissolved in 10 minutes in 15 ml of a solution containing sodium citrate dihydrate, sodium carbonate anhydride and water with trisodium citrate and sodium carbonate and no problems with foaming/effervescence were reported. However, again, applicant’s argument is unpersuasive because present claims do not include any limitation concerning effervescence. The Examiner also notes that present Example 2 is actually is silent as to whether forming or effervescence was observed or not.
Applicant argue that Galat (which was cited by the Examiner for the teaching that ASA powders become “gummy” in air in admixture with carbonate salts) does not teach the issues of dissolving ASA at high concentration in a mixture of acid and carbonate. Applicant also argue that in view of Galat’s teaching that “[i]t was unexpected and surprising to discover that sodium citrate (tri)dihydrate and potassium citrate (tri)monohydrate are two compounds which in combination with aspirin exhibit both solubility in water and outstanding stability.” And in view of its Examples 1-3 in which ASA degraded in citric acid and carbonates separately, one would not be motivated to combine citric acid and carbonates. Applicant also notes that Galat teaches adding a surfactant to its composition. However, first of all, Galat was cited (as a secondary (evidentiary) reference) merely to show that it is known in the art that powders containing aspirin together with an alkali salt (such as sodium bicarbonate) become gummy (i.e., unstable) in the air. Thus, the reference provides motivation for placing the carbonate in the phial with sodium citrate (and not in the phial containing the aspirin) in Van Moorleghem. Secondly, even though applicant argue that one would not be motivated to combine citric acid and carbonate based on Galat’s teaching (including its Examples 1-3), as already pointed out, Van Moorleghem is not using citric acid but sodium citrate. Thirdly, although applicant states that Galat adds a surfactant to its composition, Van Moorleghem’s injectable solution of ASA containing sodium citrate and carbonate (as modified by the teachings of Javaid) does not contain any surfactant (the ASA already shows excellent solubility without having to use a surfactant).
Applicant disagrees with the Examiner’s assertion that presently claimed pH range is simply routine optimization and argue that in present invention, the pH of the citric acid/carbonate solution was carefully selected to optimize dissolution of ASA in that specific combination of agents. Applicant argue that Figure 1 and Table 2 of ONDQA are directed to dissolution of small amounts of ASA in an unspecified amount of phosphate-citrate buffer and argue that these results are irrelevant to present claims which specify a large amount of ASA to be dissolved in a small amount of a component containing citric acid and a carbonate. Applicant argue that the specified pH of the second component solution and the specified pH of the final pharmaceutical formulation could not have been predicted on ONDQA’s disclosure. The Examiner disagrees. ONDQA is describing fundamental physical and chemical properties of ASA. ASA’s solubility and stability dependence on pH would still apply no matter how much or how little water is used. As discussed above, ONDQA clearly teaches that both the solubility and stability of aspirin in aqueous solution are pH dependent. ONDQA teaches that aspirin shows poor solubility but high stability at acidic pH and significantly increased solubility but more rapid degradation at alkaline pH. Under such guidelines already known in the art, and in view of the fact that applicant also want to achieve optimal solubility and stability of aspirin in aqueous solution by adjusting pH, instant pH limitations (about 8-11.5 for the aqueous solution comprising the salt of citric acid and carbonate and 5-8 for the aqueous solution composition for oral administration) would have been obvious to one skilled in the art before the effective filing date of the claimed invention since it has been held that discovering an optimum value of a result effective variable involves only routine skill in the art. In re Boesch, supra.
For the reasons stated above, instant 103 rejections over Van Moorleghem in view of Javaid, Galat and ONDQA still stand.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SIN J. LEE whose telephone number is (571)272-1333. The examiner can normally be reached on M-F 9 am-5:30pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Brian Kwon can be reached on 571-272-0581. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SIN J LEE/
Primary Examiner, Art Unit 1613
May 26, 2026
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