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 .
The response filed 20 May 2026 has been received, entered and considered. The following information has been made of record in the instant amendment:
1. No Claims have been canceled.
2. No new Claims have been added.
3. No Claims have been amended.
4. Remarks drawn to rejections under double patenting and 35 USC 103.
Claims 1-20 are pending in the case.
The Terminal Disclaimer filed on 20 May 2026, disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of U.S. Patent No. 11,801,310 has been reviewed and is accepted. The Terminal Disclaimer has been recorded.
Therefore, the obviousness-type double patenting rejections of Claims 1-20 as being unpatentable over claims 1-5 of U.S. Patent No. 11.801,310, of record in the Office Action mailed 20 January 2026 is withdrawn.
Claim Rejections - 35 USC § 103
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.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 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 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over Loftsson et al (US 2007/0020336; of record) in view of Park et al (US 2003/0031715; of record) and Han et al (US 4,559,343; of record).
Loftsson teaches the preparation of a composition comprising a poorly soluble drug and a cyclodextrin suspended in an aqueous phase. The suspension may be in the form of an eye drop (abstract, Tables and paragraphs 0064-0071; limitation of claims 1, 7, 13-regarding cyclodextrin; and limitation of claim 20-eye drop; water-solvent as in claim 13). Suitable cyclodextrins include a-, b- and g-cyclodextrins, including derivatives like hydroxypropylcyclodextrin, wherein the cyclodextrin is present in the suspension up to about 40% w/v (paragraph 0083; limitation of claims 2-3, 10-11and 16-17). The reference further teaches the addition of a water-soluble polymer, such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, polyvinylpyrrolidone, wherein the polymer is present up to about 5% w/v (paragraph 0084; as in claims 1, 7 and 13, and claims 4, 12 and 18). The reference further suggests that the product may be a binary, ternary or quaternary complex with the addition of other agents, including salts, in an amount up to about 5% used to enhance the solubilization of the drug (paragraphs 0079, 0085, and 0086).
Loftsson does not teach caffeine as a stabilizer and the amounts by weight as in claims 1, 7 and 13, and does not teach the limitations of claims 5-6, 8-9, 14-15 and 19.
Park, drawn to increasing water solubility of poorly soluble drugs, teaches that the purine derivative, caffeine, is useful in complexation solubilization, categorizing it along with cyclodextrins (paragraphs 0009-0016 and 0029; water-soluble stabilizer as in claims 1, 7 and 13).
Han teaches that xanthine derivatives, such as caffeine, decrease the stinging associated with anti-inflammatory ocular agents (col 2, lines 3-24 and examples).
MPEP 2141 states, "The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit. The Court quoting In re Kahn, 441 F.3d 977, 988, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006), stated that "[R]ejections on obviousness cannot be sustained by mere conclusatory statements; instead, there must be some articulated reasoning with some rational underpinning to support the legal conclusion of obviousness.'" KSR, 550 U.S. at, 82 USPQ2d at 1396. Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) " Obvious to try " choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention."
According to the rationale discussed in KSR above, the rationale in (G) above is seen to be applicable here since based on the prior art teachings, cyclodextrins and its derivatives, water-soluble polymers and a water-soluble stabilizer like caffeine are known in the art to be used for making compositions comprising poorly water-soluble substances. Thus, it is obvious to make compositions comprising cyclodextrins and its derivatives, water-soluble polymers and a water-soluble stabilizer like caffeine as in claim 1 and dependents thereof, and the compositions as in claims 7-20 for improving the solubility of poorly water-soluble substances like tyrosine kinase inhibitors as in the instant claims and those in claims 5-6, 8-9, 14-15, and also make the compositions as in claims 19 and 20 with a reasonable expectation of success.
Thus, the claimed invention as a whole would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention over the combined teachings of the prior art.
The artisan would be motivated to modify the composition of Loftsson because the art establishes that the addition of caffeine would have at least two advantages regarding increased solubility of the drug and decreased irritation in the administration of it. In the absence of unexpected results, it would be within the scope of the artisan to optimize the amounts of the components in the composition by weight through routine experimentation based on the ranges taught in the art.
Response to Applicant’s Remarks
Applicant has traversed the rejection of claims 1-20 under 35 USC 103 over the cited prior art arguing that in the present invention a combination of cyclodextrin and/or a derivative thereof, at least one water-soluble polymer, and at least one water-soluble stabilizer has to be included in the composition to improve the solubility of poorly soluble substances. Based on Tables 9 and 10 of Example 2, Table 11 of Example 3, Table 12 of Example 4, and Table 13 of Example 5 of the specification, using the claimed components in the recited percentage range can further significantly increase the solubilities of various drugs. In particular, Table 10 clearly shows that when axitinib/HPgCD formula is combined with HPMC and the stabilizer, caffeine at the same time, the amount of axitinib dissolved an be greatly increased to 1833.53 mg/mL, which is about 17.4 times that of axitinib/HPgCD formula.
Loftsson is directed to an ophthalmic aqueous suspension system and makes no mention of any water-soluble stabilizer such as caffeine. Loftsson provides no teaching or suggestion regarding selection of caffeine or the specific weight ratios as defined in claims 1, 7 and 13. Concentrations in Loftsson are expressed in % w/v, which is not equivalent to the wt% as recited in claims 1, 7 and 13. Based on Loftsson, one skilled in the art cannot infer the effect of a water-soluble stabilizer such as caffeine, and cannot infer the effect, which can be achieved by the combination of cyclodextrin/derivatives thereof, water-soluble polymer and at least one water-soluble stabilizer.
Park is directed to hydrotropic agents, polymers thereof, and hydrogels thereof. The Examiner relies on para 0029 of Park. However, at para 0065 Park discloses that if water solubility of the hydrotropic agent is low (e.g., less than 2M), the hydrotropic properties are not significant. The agents that did not show any appreciable hydrotropic properties also have poor water-solubilities. For caffeine water solubility is 0.1M. The general teaching in para 0029 creates a clear contradiction with the experimental facts in para 0065, which identifies caffeine has almost no hydrotropic effect due to its water solubility being below the 2M threshold.
Han is directed to nonirritating aqueous ophthalmic compositions comfort formulations for ocular therapeutic agents. However, it is clear that decreasing stinging associated with anti-inflammatory ocular agents has nothing to do with improving the solubility of poorly soluble substances. Han does not teach the relationship between caffeine and improving the solubility of poorly soluble substances. Han does not mention cyclodextrin and/or derivatives thereof, or water-soluble polymers and does not provide effective amount of caffeine to be used.
Therefore, a prima facie case of obviousness has not been established. (Remarks-pages 7-21).
Applicant’s arguments have been considered but are not found to be persuasive.
Loftsson teaches the preparation of a composition comprising a poorly soluble drug and a cyclodextrin suspended in an aqueous phase. The suspension may be in the form of an eye drop. Suitable cyclodextrins include a-, b- and g-cyclodextrins, including derivatives like hydroxypropylcyclodextrin, wherein the cyclodextrin is present in the suspension up to about 40% w/v. The reference further teaches the addition of a water-soluble polymer, such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, polyvinylpyrrolidone, wherein the polymer is present up to about 5% w/v. The reference further suggests that the product may be a binary, ternary or quaternary complex with the addition of other agents, including salts, in an amount up to about 5% used to enhance the solubilization of the drug. It has been acknowledged in the rejection that Loftsson provides no teaching or suggestion regarding selection of caffeine or the specific weight ratios as defined in claims 1, 7 and 13. It is true that concentrations in Loftsson are expressed in % w/v, which is not equivalent to the wt%. However, one of ordinary skill in the art can get approximate wt% equivalent from concentrations expressed in %wt/v by conversion.
Park, drawn to increasing water solubility of poorly soluble drugs, teaches that the purine derivative, caffeine, is useful in complexation solubilization/stabilizer, categorizing it along with cyclodextrins. This means that caffeine can also be used as an agent to increase water solubility of poorly soluble drugs. At para 0065 Park discloses that if water solubility of the hydrotropic agent is low (e.g., less than 2M), the hydrotropic properties are not significant. This teaching of Park indicates that agents that have low water solubility can still increase the water solubility of low water-soluble drugs even though the increase may not be significant. Claims 1, 7 and 13 are drawn to improving water solubility of poorly soluble substances. So, any improvement provided by caffeine, even though not significant, is still an improvement.
Perusal of Table 2 of Park shows that some hydrotropic agents having water solubility greater than 2M significantly improved water solubility of paclitaxel, and some others even at 3.5M did not show a significant improvement. In view of the disclosure in Table 2, one of ordinary skill in the art will not assume that only those agents that have water solubility of at least 2M will work. Even though Park teaches that caffeine has water solubility of 0.1M, it does not disclose any examples using caffeine. Loftsson further suggests that the product may be a binary, ternary or quaternary complex with the addition of other agents, including salts, in an amount up to about 5% used to enhance the solubilization of the drug. Therefore, one of ordinary skill in the art, in view of the teachings of Park and Loftsson will use caffeine as a stabilizer/solubilizer along with cyclodextrin and a water-soluble polymer as taught by Loftsson to improve solubility of water-soluble drugs. The artisan can adjust the percentage of the components including caffeine via routine experimentation for optimal solubility increase of the poorly water-soluble drug.
Applicant has argued that the solubility of caffeine is low according to Park, but still show the use of a high amount of caffeine in the Tables. What is done different in the instant examples that the low water-soluble caffeine is able to improve the solubility of the drugs used.
The combined teachings of the cited prior art do render the instant claims obvious. The rejection is maintained.
Conclusion
Pending claims 1-20 are rejected
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/GANAPATHY KRISHNAN/Primary Examiner, Art Unit 1693
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