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 .
Application Status
The amendment filed on 1/07/2026 in response to the Non-Final rejection of 10/10/2025 is acknowledged and has been entered.
Claims 1-9 and 11-20 are currently pending and under consideration.
Claims 16 and 20 are withdrawn from consideration as being drawn to a non-elected invention.
Claims 1-9, 11-15 and 17-19 are currently under consideration.
Applicants further elected the following species:
-Amphotericin B from claim 14; and
-Liposomes as the drug delivery vehicle of claim 12.
Rejections Withdrawn:
The rejection of Claim 14 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in view of Applicants amendment.
Rejections Maintained:
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) 1-9, 11, 13-14, and 17-18 remain rejected under 35 U.S.C. 103 as being unpatentable over Perrissoud et al. (US2007/0167408A1, 2007-07-19, IDS) in view of Calogeropoulou et al. (J. Med. Chem. 2008; 51: 897-908, IDS).
Perrissoud et al. teach alkyl phospholipid derivatives with reduced cytotoxicity that are useful for treating various diseases and/or pathophysiological conditions in mammals, preferable humans, that are caused by microorganisms, in particular bacteria, fungi, protozoa and/or viruses (Abstract). With regards to the disease, Perrissoud et al. teach that the preferred diseases in mammals that are caused by protozoa include, but are not limited to, American trypanosomiasis, leishmaniasis and visceral leishmaniasis(paragraph 0149). In addition to humans, Perrissoud et al. teach that mammals include, but are not limited to, domestic animals such as dogs (paragraph 00156). With regards to the administration, Perrissoud et al. teach that the compounds can be administered topically, transdermally, intravenously or by oral administration which can be in the form of a tablet, capsule, gel capsule or as a microparticulate, wherein the compound is combined with carriers, diluents, emulsifiers and/or lubricants (paragraph 0180 and 0182). With regards to the amount, Perrissoud et al. teach that the dosage may vary within a wide range depending on the type and/or severity of the disease, mode of administration, age, gender, bodyweight and sensitivity of the subject to be treated, but is within the ability of a skilled worker to determine a “pharmaceutically effective amount” (paragraph 0184). For example, Perrissoud et al. teach that a suitable unit dose is 0.001 mg to 100 mg active ingredient per kg of patients body weight (paragraph 0185). Moreover, Perrissoud et al. teach that the compounds of the invention can be used in combination with at least one additional pharmacologically active substance such as liposomal amphotericin B (paragraph 0157 and 159).
Perrissoud et al. does not specifically teach that the alkyl phospholipid derivative is 5-cyclopentadecylpentyl (2- (trimethylammonio)ethyl) phosphate.
Calogeropoulou et al. teach the design and synthesis of potent antileishmanial cycloalkylidene-substituted ether phospholipid derivatives (title). In particular, Calogeropoulou et al. teach a compound referred to as compound 38 having the structure
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36
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wherein R’ is
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and X is
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which reads on the instantly claimed compound. Moreover, Calogeropoulou et al. teach that compound 38 is the least cytotoxic analogue of the present study, why its antileishmanial activity is in the submicromolar range, being 9-fold more active than miltefosine, wherein these findings make compound 38 an interesting and suitable candidate for further studies in vivo as well as against trypanosmatidae (page 903, 2nd column, 1st full paragraph and page 904, 1st column, Conclusion).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to substitute or modify the method taught by Perrissoud et al. to include compound 38 taught by Calogeropoulou et al.. One of ordinary skill in the art would have been motivated to make such a substitution or modification, with a reasonable expectation of success, because:
- Calogeropoulou et al. teach that compound 38 is the least cytotoxic analogue of the present study, why its antileishmanial activity is in the submicromolar range, being 9-fold more active than miltefosine, wherein these findings make compound 38 an interesting and suitable candidate for further studies in vivo as well as against trypanosmatidae.
Moreover, it would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the method taught by Perrissoud et al. to optimize the amount or dosing schedule of compound 38 taught by Calogeropoulou et al.. One of ordinary skill in the art would have been motivated to make such a substitution or modification, with a reasonable expectation of success, because:
- Perrissoud et al. teach that the dosage may vary with a wide range depending on the type and/or severity of the disease, mode of administration, age, gender, bodyweight and sensitivity of the subject to be treated, but is within the ability of a skilled worker to determine a “pharmaceutically effective amount”.
- Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[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). MPEP 2144.05.
In response to this rejection, Applicants contend that the presently claimed invention has demonstrated what is already known to the skilled person working in the field of protozoal disease, that the available assays do not reflect in vivo efficacy. For example, Applicants argue that several laboratories have shown that in vitro promastigotes or axenic amistigotes, which have been frequently used for in vitro evaluation, result in relatively high rate of false positives and have yet to yield a bona fide drug candidate. In contrast, Applicants point out that a better choice is the use of intracellular amastigotes, yet this is far from optimal. Indeed, Applicants point out that the inventors have demonstrated in the present application (e.g. in Example 7) that the above common knowledge is also true for the ring-substituted ether phospholipid derivatives studied therein, i.e., that in vitro efficacy is not sufficient to predict pharmacokinetic characteristics, let alone in vivo efficacy. Therefore, Applicants contend that the skilled person working in the field of protozoal diseases would be aware of the limited capacity of the existing in vitro tests to identify compounds suitable for use in the treatment of such diseases, thus of the low expectation of success.
These arguments have been carefully considered, but are not found persuasive.
The majority of Applicants arguments appear to be directed to the lack of an in vitro to in vivo efficacy correlation. However, Applicants have not provided any factual evidence to show this lack of correlation. There is a reference within the specification to “The in vitro assays used to evaluate potential compound activities do not reflect the complexity of the in vivo leishmania infection (a citation to Yardley and Koniordou). As a result, the efficacy in vitro does not guarantee activity in vivo, which depends on the complex drug pharmacokinetics, the site and nature of the infection, and the ability of the drug to reach the site(s) of invention at effective concentrations (pharmacodynamics), to name a few.” (starting at page 3, line 28). However, Applicants have not provided this document (Yardley and Koniodou) for consideration. Moreover, regarding Applicants statement that in vitro efficacy is not sufficient to predict pharmacokinetic characteristics, let alone in vivo efficacy. The examiner does not dispute Applicants contention that in vitro efficacy is not sufficient to predict pharmacokinetic characteristics. However, regarding Applicants statement about in vivo efficacy, it appears that Applicants are arguing clinical efficacy which seems to be an argument for the Food and Drug administration vs. the US Patent and Trademark office. In the instant case, the rejection is not based on picking or choosing compound 38 from all of the other compounds disclosed. As noted in the rejection above, Calogeropoulou et al. provides strong motivation for in vivo administration by specifically singling out compound 38 because it was the least cytotoxic analogue of the present study, its antileishmanial activity is in the submicromolar range, being 9-fold more active than miltefosine, suggesting that compound 38 an interesting and suitable candidate for further studies in vivo as well as against trypanosmatidae (page 903, 2nd column, 1st full paragraph and page 904, 1st column, Conclusion). As such, while the predictability of clinical efficacy of the compound may be low, there would be reasonable expectation that the compound would show some type of in vivo activity. As note by Perrissoud et al. the determination of a “pharmaceutically effective amount” is within the ability of a skilled worker (paragraph 0184). Note: Calogeropoulou et al., in its in vitro model, uses the better choice of intracellular amistigotes (see for example, page 901, 2nd column, last full paragraph).
Therefore, the rejection is maintained.
Claim(s) 12 and 19 remain rejected under 35 U.S.C. 103 as being unpatentable over Perrissoud et al. (US2007/0167408A1, 2007-07-19, IDS) in view of Calogeropoulou et al. (J. Med. Chem. 2008; 51: 897-908, IDS), as applied above to claims 1-11, 13-14, and 17-18, in further view of Kavian et al. (Acta Troica (2019); 196: 142-149) as evidenced by Mistry and Notman (J. Phys. Chem. B (2024); 128: 3885-3897).
The teachings of the combination of Perrissoud et al. and Calogeropoulou et al. have been described above and incorporated herein. In short, the combination of Perrissoud et al. and Calogeropoulou et al. teach a method of treating American trypanosomiasis, leishmaniasis and visceral leishmaniasis in a mammal comprising administering a composition comprising 5-cyclopentadecylpentyl (2- (trimethylammonio)ethyl) phosphate either alone or in combination with another therapeutic agent.
The combination of Perrissoud et al. and Calogeropoulou et al. do not specifically teach that the composition comprise a liposome or a penetration enhancer.
Kavian et al. teach the development of topical liposomes containing miltefosine for the treatment of Leishmania major infection in susceptible BALB/c mice (title). In particular, Kavian et al. teach that topical formulation offer several advantages over systemic therapies due to their ease of administration, better compliance and reduced systemic exposure (page 143, 1st column, 2nd full paragraph). For example, Kavian et al. teach liposomes containing miltefosine comprising the following components PC, cholesterol, propylene glycol, vitamin E, MP and PP (page 143, 2nd column, section 2.2). Moreover, Kavian et al. teach that topical administration of miltefosine in the liposomal formulation caused a marked reduction in lesion size (page 147, 1st column, 2nd full paragraph). Thus, while Kavian et al. does not specifically teach that propylene glycol is a penetration enhancer, as evidenced by Mistry and Notman propylene glycol is a chemical penetration enhancer that could be included in topical formulation to in order to overcome the barrier properties of the skin and facilitated the transport of drugs across it (abstract).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to formulate the composition as taught by the combination Perrissoud et al. and Calogeropoulou et al. for topical application via a liposome in view of the teachings of Kavian et al.. One of ordinary skill in the art would have been motivated to make such a substitution, with a reasonable expectation of success, because:
- Kavian et al. teaches the benefits of topical administration vs. systemic administration and further teaches that the liposomes comprising miltefosine reduced lesion size.
Claim(s) 15 remain rejected under 35 U.S.C. 103 as being unpatentable over Perrissoud et al. (US2007/0167408A1, 2007-07-19, IDS) in view of Calogeropoulou et al. (J. Med. Chem. 2008; 51: 897-908, IDS), as applied above to claims 1-11, 13-14, and 17-18, in further view of MacLaughlan, Todd (US20200093842A1, 2020-03-26).
The teachings of the combination of Perrissoud et al. and Calogeropoulou et al. have been described above and incorporated herein. In short, the combination of Perrissoud et al. and Calogeropoulou et al. teach a method of treating American trypanosomiasis, leishmaniasis and visceral leishmaniasis in a mammal comprising administering a composition comprising 5-cyclopentadecylpentyl (2- (trimethylammonio)ethyl) phosphate either alone or in combination with another therapeutic agent.
The combination of Perrissoud et al. and Calogeropoulou et al. do not specifically teach that the composition comprise saline as the pharmaceutically acceptable carrier.
MacLaughlan, Todd teaches methods of treating infection caused by free-living amoeba comprising systemic administration of an effective amount of miltefosine in an oral or intravenous formulation (abstract). In particular, MacLaughlan, Todd teaches that miltefosine is formulated in a sterile saline solution for intravenous administration (paragraph 0065).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to formulate the composition as taught by the combination Perrissoud et al. and Calogeropoulou et al. for intravenous administration in a saline solution in view of the teachings of MacLaughlan, Todd.. One of ordinary skill in the art would have been motivated to make such a substitution, with a reasonable expectation of success, because:
- MacLaughlan, Todd teaches formulating a structurally similar compound to 5-cyclopentadecylpentyl (2- (trimethylammonio)ethyl) phosphate in a saline solution for intravenous administration.
Conclusion
Therefore, No claim is allowed.
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 BRANDON J FETTEROLF whose telephone number is (571)272-2919. The examiner can normally be reached M-F 6AM-4PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey S Lundgren can be reached at 571-272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/BRANDON J FETTEROLF/ Primary Examiner, Art Unit 1626