--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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant’s submission filed on June 12, 2026 has been entered.
Priority
This application is a 371 of PCT/US2020/048358 filed on 08/28/2020, which claims
benefit in provisional application 62/992,699 filed on 03/20/2020, and in provisional application
62/894, 187 filed on 08/30/2019.
Claim Status
Claims 1, 10, 12, 19, 21, 95-100, and 104-110 are pending and examined. Claims 2-9, 11, 13-18, 20, 22-94, and 101-103 were canceled. Newly added claims 104-110 read on the elected invention of Group I and encompass the elected species of a troponoid.
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 CPR 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.
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.
Claims 1, 10, 12, 19, 21, and 95-103 are rejected under 35 U.S.C. 103 as being
unpatentable over Donlin (WO 2017 /184752 Al Published October 26, 2017 - of record in PTO-
892 dated 12/04/2024), Woodle (US 5,843,473 Date of Patent December 1, 1998 - of record in
PTO-892 dated 12/04/2024), Ahmad (WO 02/32400 Published April 25, 2002), and Abra (WO
87/01933 Published April 9, 1987).
The claims encompass a liposome formulation comprising:
a troponoid of structure represented by a formula
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(b) a lipid, (c) cholesterol, and (d) vitamin E as defined by the claims.
The teachings of Donlin are related to compounds of formula I, II, and III for use in the
treatment of a fungal infection by Cryptococcus neojormans fungus (Abstract). In some
embodiments, the compound is defined as
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(pages 13-14). In some embodiments, the compound is formulated as a
pharmaceutical composition comprising the compound and an excipient (page 20 lines 2-8). One
embodiment teaches a pharmaceutical composition comprising (A) a compound of formula I and
(B) a second anti-fungal compound (pages 26-30). The second anti-fungal compound is
fluconazole (33 lines 17-19). In some embodiments, the compositions are formulated for
administration liposomally, by injection, topically, and in lipid compositions, among others
(page 33 lines 17-28). Under ordinary conditions of storage and use, these preparations contain a
preservative to prevent the growth of microorganisms (page 70 lines 23-27). Preservatives
include anti-oxidants (page 71 line 7). The topical composition may be administered to the skin
and the mucous membranes, in particular to the cornea (page 71 lines 10-17). Combination
therapy is contemplated where drugs suitable for combination therapy include amphotericin B in
combination with the compound (paragraph bridging pages 71-72).
The teachings of Donlin are relied upon as summarized above, however Donlin does not
teach concentration of troponoid and components (b), (c), and (d).
The teachings of Woodle are related to a method of treating a systemic infection which
includes administering a therapeutic compound entrapped in liposomes. Also included is a
liposomal composition and a method of preparing a liposomal composition for use in
concentrating a therapeutic compound to an infected region via the bloodstream. The liposomes,
which contain the agent in entrapped form, are composed of vesicle forming lipids (Abstract).
Liposome entrapped therapeutic compounds are preferably antimicrobial including antifungal
(column 4 lines 16-19). Vesicle forming lipids include phospholipids such as
phosphatidylcholine (PC). Another vesicle forming lipid which may be employed is cholesterol
(column 7 lines 19-30). Liposomes were characterized by apparent homogeneity of the initial
dispersion and ease of extrusion. Incorporation of drug ranges from 6 to 24 % prior to removal of
free drug from the samples (column 13 lines 26-33). Examples of infections and liposome
entrapped drugs suitable for treatment include Cryptococcus treatment by amphotericin or
fluconazole (column 21 lines 55-57).
The teachings of Ahmad are related to liposomal formulations comprising an antifungal
agent and liposome-forming materials (Abstract). Preferred liposome-forming compounds
include cardiolipin, phosphatidyl choline, cholesterol, dipalmitoyl phosphatidyl choline,
phosphatidyl serine, and alpha-tocopherol (page 4 lines 26-28). Preferred liposomal formulations
contain suitable amounts of antioxidants such as alpha-tocopherol. Suitable amounts range from
about 0.001 or more to about 5 wt.% or less (page 5 lines 19-21).
The teachings of Abra are related to liposome compositions of amphotericin B (Abstract). The compositions comprise cholesterol in a ratio of 20-50 mole% of the liposome membrane components and amphotericin B at a mole ratio of 3-7% (paragraph bridging pages 4-5). The liposomes are prepared from phospholipid and sterol components. Preferred lipid components include phosphatidylcholine (PC) and phosphatidylglycerol (PG), and cholesterol. The concentration of phospholipid components is preferably 55-80 mole%. The sterol component is preferably present at a concentration of 20-45 mole%. It was observed in Example VI that increasing amounts of cholesterol, up to at least about 20 mole %, reduced the toxicity of
AMB liposomes in mice. The lipids may also contain a lipophilic antioxidant such as alpha-tocopherol. One preferred lipid composition, described in Example I, includes PC, PG,
cholesterol, and alpha-tocopherol at a mole ratio of 49.7:5.5:44.2:0.6 (paragraph bridging pages
5-6). AMB is included in the liposomes at a mole ratio of at least about 1 mole percent, and
preferably between about 3-7 mole percent, of the lipid components forming the liposomes (page
7 lines 3-6).
The teachings of Donlin, Woodle, and Abra are related to liposomal compositions
comprising an anti-fungal agent selected from amphotericin B, where the composition is
intended for treatment of fungal infections such as Cryptococcus, and it would have been
obvious to have combined them because they are in the same field of endeavor.
It would have been prima facie obvious to a person of ordinary skill in the art before the
effective filing date of the claimed invention to have formed a liposome formulation comprising
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, amphotericin B, a lipid, and an antioxidant, with a reasonable expectation of success because Donlin teaches a pharmaceutical composition for treatment of fungal infections, the composition comprising a compound of formula
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and an excipient comprising an anti-oxidant wherein the composition is formulated for administration liposomally. Donlin teaches a combination therapy wherein the compound is
combined with another antifungal drug such as amphotericin B. One of skill in the art would
have recognized that a liposomal composition comprises a lipid. Furthermore, it would have
been further obvious to have formulated the liposomal composition as a lipid composition with a
reasonable expectation of success because Donlin teaches formulating the compound in a lipid
composition.
Donlin does not teach suitable lipids for making liposomes and it would have been
obvious to the skilled artisan to look to the teachings of Abra because Abra is concerned with
liposomal formulation comprising amphotericin B and teaches specific components and amounts
suitable for making liposomal formulations of amphotericin B. It would have been obvious to a
person of ordinary skill it the art before the effective filing date of the claimed invention to have
formed Donlin's liposome composition using lipids and antioxidant disclosed in Abra, with a
reasonable expectation of success because Abra teaches a method of making liposome
formulations comprising amphotericin B where the formulations are intended for treatment of
fungal infections. It would have been obvious to have formed Donlin's liposome formulation
with a mixture of lipids comprising PC, PG, and cholesterol and lipophilic antioxidant alphatocopherol, with a reasonable expectation of success because Abra teaches teaches said mixture of lipids and antioxidant as suitable for making liposomes intended for making a formulation of antifungal agents such as amphotericin B.
The teachings of Woodle are relied upon for suitable wt. % concentrations of antifungal
drugs in liposome compositions. It would have been obvious to have added the antifungal agents
comprising troponoid compound and amphotericin Bin a concentration of 6-24 wt.% prior to
removal of free drug, with a reasonable expectation of success because Woodle teaches adding
6-24 % of drug during the process of making a liposome composition, prior to removing free
drug from the composition.
The claimed range of about 15 wt. % or less of troponoid is obvious because prior art
teaches adding 6-24 wt. % of drug to the composition prior to removing free drug. A person
skilled in the art would have recognized that the composition after removal of free drug would
have contained the troponoid and amphotericin in an amount of up to 24 wt. % of the
formulation. The method teaches encapsulating the drug in liposomes, and therefore some
amount of drug would have remained encapsulated in the composition after removal of free drug.
The claimed range of troponoid is obvious because it would have been obvious to have varied
the concentrations of the troponoid and amphotericin B from 0 and up to 24 wt. % as long as the
combined the concentration of the two does not exceed 24 wt. %, which overlaps with the
claimed range. Furthermore, it is within the skill of a person of ordinary skill in the art to
determine amounts of active agents in a pharmaceutical formulation through routine
experimentation.
While Abra teaches an amount of alpha-tocopherol as a mole ratio relative to PC, PG,
and cholesterol, Abra does not teach suitable wt. % concentrations of alpha-tocopherol in the
formulation. It would have been obvious to have varied the concentration of alpha-tocopherol in
the formulation in the range of 0.001-5 wt. %, with a reasonable expectation of success because
Ahamad teaches 0.001-5 wt. % as a suitable concentration range of antioxidant such as alpha-tocopherol in a liposomal formulation. The claimed concentration range of vitamin E is obvious
because it encompasses 0.001-5 wt.%.
Donlin' s formulation would have contained the combination of troponoid and
amphotericin B in a concentration of up to 24 wt. % and alpha-tocopherol in a concentration of
0.001-5 wt. %. Therefore, the remaining components PC, PG, and cholesterol would have been
present in a concentration of at least 71 wt.%. It would have been obvious to have varied the
concentration of cholesterol from 0 to 44 mole % in the composition because Abra teaches
varying cholesterol from 0 to 44 mole % while adjusting the amount of PC to compensate for
concentration changes in cholesterol (page 12 lines 9-24). Therefore, the skilled artisan starting
with the molar ratio of 49.7:5.5:44.2:0.6 (PC:PG:cholesterol:alpha-tocopherol) where cholesterol
is at the upper end of the range (about 44 mole) would have varied the concentration of cholesterol down to the smallest measurable amount (such as about 0.2) while increasing
concentration of PC, which would have resulted in the molar ratio of 93.7:5.5:0.2:0.6. The range
between the two molar ratio extremes of cholesterol would have encompassed embodiments
where wt. % concentration of PC overlaps with the claimed range, and wt. % concentration of
cholesterol overlaps with the claimed range.
The claimed concentration ranges are obvious because they overlap with their respective
concentration ranges in the prior art composition. The specification was reviewed and there is no
evidence that claimed concentration ranges are critical. Furthermore, it was known from Donlin
that troponoids have antifungal properties and a person skilled in the art would have been
capable of determining a concentration of the troponoid in the liposome composition in order to
form a composition suitable for treating a fungal infection. A person skilled in the art would have
arrived at a concentration range that either overlaps with or is close enough in number to the
claimed concentration range through routine experimentation.
The claimed liposome formulation is obvious because Donlin's liposome formulation
modified by Woodle, Abra, and Ahmad comprises all of the components of claimed liposome
formulation where each prior art component is present in a concentration range that overlaps
with the claimed concentration range.
Regarding claims 21 and 99, it would have been obvious to have used PC sourced from
an egg because Abra teaches egg phosphatidylcholine (page 12 lines 12-17).
Regarding claims 104 and 105, it would have been obvious to have formulated the composition without amphotericin B where the compound disclosed above is the only active agent because it is apparent from the teachings of Donlin that a composition comprising the compound without additional antifungal agent is sufficient for treating fungal infections. For example, Donlin’s claim 1 is a method of treating a fungal infection comprising administering to the patient a therapeutically effective amount of a compound of formula (I), and Donlin’s claim 32 requires any one of the methods of claims 1-26, wherein the method further comprises administering a second anti-fungal therapy. Thus, it is apparent that Donlin’s composition is not required to contain an antifungal in addition to the compound of formula (I).
Regarding claim 106, it would have been obvious to have formed the liposomes with a membrane-stabilizing agent because Abra teaches forming liposomes using a membrane-stabilizing agent (paragraph bridging pages 4-5 and page 5 lines 3-7). It would have been obvious to have selected mannitol as the membrane-stabilizing agent because Abra teaches that mannitol is suitable size stabilization in liposomes (page 7 lines 19-26).
Regarding claim 107, it would have been obvious to have formed the composition to comprise an antibacterial because Donlin teaches that the active compound is dispersed in a pharmaceutically acceptable carrier, where “pharmaceutically acceptable carrier” is defined as including antibacterial agents among others (page 70 lines 10-22).
Regarding claim 108, it would have been obvious to have formed the composition as a liquid, a lyophilized powder, a cream or an ointment because Donlin teaches that the compositions may be in the form of solutions, suspensions, powders, cream or ointment (page 71 lines 10-17).
Regarding claim 109, it would have been obvious to have formed the composition substantially free of DMSO, methanol, and/or chloroform because Donlin does not require the presence of these solvents in the composition.
Regarding claim 110, it would have been obvious to have formed the composition substantially free of organic solvent because Donlin does not require the comprising to comprise an organic solvent.
Combining prior art elements according to known methods to obtain predictable results
supports obviousness and the selection of a known material suitable for its intended purpose
supports obviousness.
Response to Arguments
Applicant’s arguments submitted in the remarks dated June 12, 2026 were fully considered but are not persuasive for the following reasons.
It would have been obvious to the skilled artisan to select compound 281 out of 47 exemplified compounds and use it to make the composition because Donlin teaches a pharmaceutical composition comprising a compound of formula (I) and exemplifies 47 compounds that fall within the genus of formula (I) where compound 281 is one of the 47 exemplified compounds. The fact that Donlin teaches alternatives from which the compound of formula (I) is selected does not render any one alternative less obvious than another alternative. The lesser effectiveness (MIC80) of compound 281 relative to other exemplified compounds does not render compound 281 non-obvious because compound 281 still has antifungal activity and would have been obvious to use in a composition that is intended for treating a fungal infection. The teaching is sufficient for an obviousness rejection. A reference is not required to teach express suggestion to select one active agent over another to render the selection obvious. Donlin does not criticize, discourage, discredit or otherwise discourage using compound 281 to make the composition.
Conclusion
No claims are allowed.
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/ALMA PIPIC/
Primary Examiner, Art Unit 1617
Prosecution Insights