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 .
Applicants' arguments, filed October 10, 2025, have been fully considered but they are not deemed to be fully persuasive. The following rejections and/or objections constitute the complete set presently being applied to the instant application.
Response to Amendment
The declaration under 37 CFR 1.132 filed October 10, 2025 is insufficient to overcome the rejection of claims 5 – 14, 25 and 26 based upon Hwang et al., Napoli et al., Zidan et al. and Luschmann et al. because: the evidence in the declaration the evidence of record is not clear and does establish a clear nexus with the claimed invention and present evidence of unexpected results that are reasonably commensurate in scope with the claims.
The declaration filed October 10, 2025 tries to address various issue with the declaration filed March 18, 2025 that were detailed in the Office Action mailed June 10, 2025. The data presented in the declaration remains almost identical to the previous declaration except for the correction of an error as to the one material used (see section 12) to that in the previous declaration and the data in Table 1.
The conclusion of the declaration is that it was not found to be possible to successfully dissolve high concentrations of CsA (cyclosporin A), consistent with the experimental results of Hwang (the primary reference used in the art rejections of record) and Ran (a reference not used in the rejections of record but that deals with the solubilization of cyclosporin A) but is contrary to Hwang teaching that ethanol is optional for high concentrations of CsA. The declaration in section 18 indicates unexpected success in removing ethanol except as a “residual amount” while maintaining CsA dissolution and also obtaining stability of the dissolution at least in some embodiments. While ethanol must be added to increase the concentration of CsA, the ethanol can unexpectedly be removed without affecting the dissolution leaving only a residual amount of ethanol (section 11). A “residual amount of ethanol” is not defined and/or correlated with the claim language of “ethanol in a concentration of more than 0 mg/mL and less than 12 mg/mL”.
The discussion in the declaration and data in the table of the declaration focuses in the ratio of Kolliphor® [polyoxyethylene castor oil (POE castor oil) material] to CsA and was intended to show that the stability of the resulting solution is dependent at least in part on this ratio (section 16 of the declaration). However, the ratio of these ingredients is not claimed. The claims require a micellar composition (so an aqueous and hydrophobic phase must be present) with at least 10 mg/mL CsA and a content of the oily phase, which includes at least the CsA and POE castor oil, of 11.25% to 27.5%. The second column in Tables A and B are labeled “CsA concentration (mg/l)” with values given being 1, 10 and 20. This contradicts the labels given at section 11 of the declaration of 10 or 20 mg/mL that are a factor of 1,000 higher than those given in the table. Section 12 of the declaration indicates that the CsA was mixed with the Kolliphor® and if the dissolution was complete, then the oily phase was diluted with an aqueous phase to the total volume indicated. The concentration in the initial solution cannot be used to meet the claim limitations as the at least 10 mg/mL CsA concentration is for the micellar solution, which requires the presence of an aqueous solution. While there are no units for the total volume column in either table of the declaration, dilution would further lower the CsA concentration and the value reported in the tables of 1, 10 or 20 mg/l is already much lower than the claims require. Given the uncertainty of the final volume, the content of the oily phase in the micellar solution cannot be determined to determine if this limitation is met. The process referenced in the declaration indicated removal of ethanol at some point but the claims are drawn to a product and not even the process by which the product is prepared. Dilution of a CsA, Kolliphor® and ethanol containing material with an aqueous phase reduces the concentration of the ethanol although the same total amount of ethanol would be present in the solution. Only samples 2.1., 2.2 and 2.3 in Table A indicate the presence of any ethanol, appearing to be the only possible formulations studied that might fall within the scope of the claims. The samples in table B contained 0.278 g/mL ethanol or 278 mg/mL, which greatly exceeds the claimed upper limit of 12 mg/mL, and is identical to the concentration of ethanol in the commercial SANDIMMUNE® product (see ¶ bridging p 7 and 8 of the Remarks filed October 10, 2025). The total volume column has “n/a” which would indicate that there was no further dilution of these samples that could reduce the ethanol concentration to a level that might fall within the scope of the claims. The data is stated to come from Tables 1 and 2 in the patent application which provides ranges in mg/mL that would fall within the scope of the claims, but it is not clear which units are the correct units. The units mg/mL, g/mL and mg/l results in different values for the same amounts of material as compared to g/l and mg/ml that have the same numeric value for the same amounts of material.
For evidence of unexcepted results to be persuasive, comparative data for formulations clearly falling within the scope of the claims and at least one composition falling outside the scope of the claims is required and what is or is not within the scope of the claims. Despite the additional explanation given in the most recent declaration, the evidence remains unpersuasive as the ratio of the CsA and POE castor oil is not claimed. The scope of POE castor oil claimed also encompasses any length of the POE portion (with the exception of claims 6 and 7) and only two of the many possibilities were tested. How the data for the material tested is reasonably commensurate in scope with the broad genus of POE castor oil has not been addressed. Therefore the evidence of record in support of unexpected results is not sufficient to outweigh the prima facie case of obviousness and the obviousness rejections are maintained.
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.
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) 5, 8 – 14, 25 and 26 were rejected under 35 U.S.C. 103 as being unpatentable over Hwang et al. (WO 2013/165047; all citations from EP 2845602 that is in the same family and published in English) in view of Napoli et al. (US 2001/0041671), Zidan et al. (Int J Pharm, 2007) and Luschmann et al. (Cornea, Jan 2014). This rejection is MAINTAINED for the reasons of record set forth in the Office Action mailed June 10, 2025 and those set forth herein.
The remarks reference the contents of the concurrently filed Supplemental Declaration which was discussed in detail above.
The remarks reference the claimed concentration of ethanol and the process by which the product is repaired as recited in currently withdrawn claim 15 in which at least 99% of the ethanol is removed prior to dilution with the aqueous solution (see actual claim language that specifies this step order that is not reflected in the language set forth in the remarks). The maintenance of CsA solubilization obtention of the micellar solution during this process and the claimed eye drop formulation is an unexpected result over Hwang properly interpreted by the person of the art in view of the experimental testing of Ran regarding the solubilization limits of CsA in Cremophor EL. The other cited references fail to remedy the deficiencies of Hwang. The formulations of Napoli comprise about 2 mg/mL CsA, about 6 to 8 mg/mL CsA was obtained in Zidan and 0.1 mg/mL as the final CsA concentration in Luschmann. The present inventors discovered the ability to provide a micellar solution with at least 10 mg/mL CsA, at least 11.25% being oily phase with residually present ethanol (at more than 0% but less than 12 mg/mL). A formulation with highly increased concentration of active and simultaneously high reduced ethanol concentration as compared to the teachings and examples of Hwang would not have been predictable.
These arguments are unpersuasive. The declaration and arguments focus on the ratio of CsA to Kolliphor®, which is not claimed. The effect of addition such as how much, how much of the ethanol was removed to arrive at a final concentration is not described in detail in the declaration. Several of the cited references discuss a process by which one of ordinary skill in the art before the effective filing date of the claimed invention can optimize solubilization of poorly water soluble drugs and the system used by Applicants is that suggested by Hwang – a solubilizer of POE castor oil, POE hydrogenated castor oil that may further includes, such as 1 – 30 mg/mL (0.1 – 30 wt%) ethanol as a sub-solvent (¶ [0016]), a range with substantial overlap with the presently claimed ranges. Prior art is relevant for all that is taught and is not limited to the examples and the criticality of the ethanol concentration in the final product and/or the specific process used to prepare the product has not been clearly established. When the arguments and evidence of record are weighed, the weight of the evidence in support of non-obviousness and unexpected results does not outweigh the prima facie case of obviousness.
Regarding claim 12 and 23 – 26, Applicants argue that the references fail to teach or suggest the features recited in these claims. The declaration shows that stability of the filtered compositions a J+14 days at 25°C required a significantly higher ratio of Kolliphor® to CsA than the max of 97.9:1 proposed by Hwang at ¶ [0009] for 0.1% CsA. The declaration makes clear the solution stability is an additional surprising benefit of the compositions according to the present invention after removal of all but a residual amount of ethanol. The cited references alone or in combination fail to teach suggest or provide a reasonable expectation of success for the claimed stability.
These arguments are unpersuasive. “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.” MPEP 2113 Given the issue with the units in the data presented in the declaration and specification, the lack of nexus between the parameters stated to be critical (namely the ratio of Kolliphor® to CsA) and the claim language, and that one of ordinary skill in the art would optimize the solubilization formulations and can use the ranges set forth in the entirety of Hwang et al. as a starting point for such optimization, the criticality of the claimed formulations that result in the claimed stability has not been established.
Claim(s) 6 and 7 were rejected under 35 U.S.C. 103 as being unpatentable over Hwang et al., Napoli et al., Zidan et al. and Luschmann et al. as applied to claims 5, 8 – 14, 25 and 26 above, and further in view of Wang et al. (Int J Nanomed, 2014). This rejection is MAINTAINED for the reasons of record set forth in the Office Action mailed June 10, 2025 and those set forth herein.
No specific arguments regarding Wang et al. were set forth for the Examiner to address herein.
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Nissa M Westerberg whose telephone number is (571)270-3532. The examiner can normally be reached M - F 8 am - 4 pm.
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/Nissa M Westerberg/Primary Examiner, Art Unit 1618