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 .
Claim Status
Claims 1-13 were previously pending.
By virtue of the 27 February 2025 Preliminary Amendment, Applicant cancelled claims 2-4 and 9-13; amended claim 1; and did not add additional claims.
Therefore, claims 1 and 5-8 are now pending and currently under examination.
Information Disclosure Statement (IDS)
The IDS (1) filed on 27 February 2025 has been considered by the examiner. A signed copy is enclosed.
Applicant is reminded of their duty to disclose to the Office all information known to the person to be material to patentability as defined in 37 CFR 1.56. As stated therein, “[e]ach individual associated with the filing and prosecution of a patent application has a duty of candor and good faith in dealing with the Office, which includes a duty to disclose to the Office all information known to that individual to be material to patentability as defined in this section.”
Priority
Examiner acknowledges applicant’s claim to the following priority:
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Claim Objections
Claim 7 is objected to for the following grammatical defect:
Claim 7 recites, “…are maintained for 14 at least days after preparation.” This is assumed to be a typographical error. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1 and 5-8 are rejected 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.
Claim 1 recites a method for preparing a vitamin C-encapsulated liposome comprising the steps of mixing lecithin, vitamin C, and anhydrous citric acid in an aqueous solution “…wherein surfactants other than the anhydrous citric acid are not used in the mixing step…” It is unclear what applicant means by ‘surfactant’ and the specification fails to adequately redefine the term. With regards to the scope of claim 1, this is problematic because lecithin is an art-recognized surfactant while anhydrous citric acid is recognized as a pH regulator, preservative, and chelating agent, not as a surfactant. Therefore, claim 1 internally contradicts itself because it requires lecithin while prohibiting surfactants other than anhydrous citric acid.
If applicant intends the term ‘surfactant’ to exclude lecithin, it is unclear what definition of surfactant is being applied and applicant has failed to redefine the term as required when applicant uses a definition inconsistent with its widely accepted meaning. Therefore, one of ordinary skill could not determine the metes and bounds of claim 1 with reasonable certainty because it is impossible to determine what component constitutes a surfactant.
Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999).
Claims 5-8 are included in this rejection for depending on, requiring every limitation of, and failing to cure the defects of claim 1.
Claim 7 is also rejected under 35 USC 112(b) as indefinite for the following reason:
Claim 7 recites, “…wherein the average particle size and average zeta potential are maintained for 14 at least days after preparation.” This limitation is being interpreted as “…wherein the average particle size and average zeta potential are maintained for at least 14 days after preparation.” However, it is still unclear what constitutes ‘maintained’ when referencing a single liposome (claim 6), yet reciting a particle size and zeta potential range. For example, if the single liposome was initially measured at 160 nm, but dropped to 150 nm after 14 days, would this constitute ‘maintained’ since it’s still within the recited range? Or, as would be consistent with the accepted use of the term ‘maintained,’ does the particle size need to stay the same over the course of 14 days (e.g., day zero at 150 nm and day 14 at 150 nm)? The specification fails to define or set parameters on what would constitute ‘maintained’ and therefore, one of ordinary skill could not determine the metes and bounds of the claim with reasonable certainty.
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.
Claims 1 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Kim (KR102259975B1; published: 03 June 2021; machine translation relied upon) and Lin (US 2022/0125758 A1; published 28 April 2022), further in view of Mayer (US Pat. No. 5,795,589; patented 18 August 1998).
Kim teaches a method of mass-producing liposomes having a high encapsulation efficiency (p. 2).
Regarding claim 1 –
Kim specifically teaches preparation of a first liposome emulsion followed by a second rolling process using an impeller reactor (p. 4). Kim teaches the rolling process is performed by rotating the stirrer at 20 to 1,000 rpms for 0.5 to 2 hours at a temperature of 35 to 70° C (p. 1). Thus, Kim expressly teaches ranges encompassing the presently claimed stirring conditions of 30 to 90 rpm, 60 to 120 minutes, and 60 to 70° C. See MPEP 2144.05.
Kim further teaches that the rolling parameters are significant to liposome formation (p. 3). Kim explains rotational speeds outside the disclosed range provide unsuitable shear conditions, temperatures outside the disclosed range interfere with liposome formation or active agent stability, and rolling for less than 0.5 hours fail to provide the desired liposome-forming reaction while rolling for more than 2 hours decreases liposome production and encapsulation efficiency (p. 3). Accordingly, Kim recognizes rolling speed, temperature, and duration as result-effective variables in liposome manufacture.
Kim’s example 1 details preparation of a vitamin C-encapsulated liposome by: dissolving 60 kg of ascorbic acid and 6 kg of sodium ascorbate in 200 L of purified water, adding 60 kg of purified soybean lecithin, and stirred at 2,000 rpm for 30 minutes (p. 4). This resulting first liposome emulsion is then introduced into the disclosed rolling reactor and maintained at 50 to 100 rpm for 60 minutes (p. 4). Thus, Kim expressly teaches an aqueous vitamin C/soybean lecithin liposomal composition comprising approximately 18 wt% lecithin and 17.9 wt% vitamin C subjected to a low-speed rolling operation within the parameters recited by instant claim 1(iii).
Regarding the recitation that the liposomes are rolled using a paddle, Kim performs the rolling process using an impeller stirrer comprising multiple internal and external impeller members that mechanically move the liposome dispersion. Selection of a paddle-type impeller for carrying out the same low-speed stirring/rolling function would have constituted a predictable use of a known mechanical mixing element to perform the same known function of moving the dispersion through the reactor. No critical distinction between a paddle and the functionally equivalent impeller surface taught by Kim is apparent from claim 1.
Regarding the recitation that the mixture is cooled after step (iii), Kim expressly teaches the prepared liposome may be lyophilized for ease of storage (p. 3). Since the previous step (iii) was conducted at 60 to 70° C, the first step of lyophilization, which occurs at temperatures well below freezing, would constitute cooling of the mixture from step (iii).
Kim further teaches its inventive process avoids the organic solvents required by conventional Bangham film methods and specifically states these conventional methods are effective at producing liposomes at a small-scale laboratory production level, but are not effective at mass-producing liposomes due to the problem of removing the organic solvent for dissolving phospholipids and the size of the reactor for forming a lipid membrane (p. 2).
While Kim does not expressly teach inclusion of 5 wt% anhydrous citric acid in its vitamin C/lecithin composition and does not expressly teach the presently claimed 6,000 rpm homogenization for 20 minutes at 60 to 70° C, these limitations are made obvious by Lin.
Lin teaches an aqueous method of preparing liposomes capable of stably encapsulating vitamin C wherein the method includes a mixture of lecithin, citric acid, and vitamin C (abstract, [0086]). Lin teaches the mixture can comprise citric acid as an acidifier ([0034]). Lin further describes a process comprising: 10 mg lecithin, 30 mg citric acid, and 1000 mg vitamin C dissolved in 8393.25 mg water and stirred uniformly to form a mixture; followed by homogenizing the mixture to form a liposome suspension ([0087]). Lin teaches the active ingredient capable of liposome encapsulation is present in the initial mixture between 5 to 30 wt% ([0032]) and the active ingredient can be vitamin C ([0010]).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to include citric acid in Kim’s aqueous vitamin C/soybean lecithin as taught by Lin because Lin teaches the same type of active agent, vitamin C, in a lecithin liposome prepared in water and expressly identifies citric acid as an acidifying component suitable for that formulation. A person of ordinary skill seeking to formulate Kim’s vitamin C liposomes would therefore have had reason to employ Lin’s known citric acid formulation to control the acidic environment of the vitamin C liposome system.
Mayer further teaches that substantial concentrations of citric acid are conventional in liposomal preparation as an aqueous acidic buffer (col. 7, lines 54-65). Mayer identifies citric acid as a particularly desirable buffer for promoting liposomal uptake (col. 7, lines 61-63). Mayer further discloses an optimal formulation of 300 mM citric acid buffer at pH 4.0, which corresponds to 5-6 wt%, for optimal loading (col. 7, lines 57-60).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to optimize the amount of citric acid taught by Lin in view of the substantially higher citric acid concentrations known from Mayer to obtain an appropriate acidic environment for liposome formation and loading. Citric acid concentration was a known formulation variable affecting pH and liposome loading, and Mayer expressly teaches selecting the citric acid concentration for that purpose. Therefore, selection of approximately 5 wt% citric acid would have represented routine optimization of a known result-effective variable absent evidence that the claimed 5 wt% concentration produces a result unexpectedly different from similar concentrations.
The claimed use of anhydrous citric acid would likewise have been obvious because anhydrous citric acid is merely a physical form of citric acid conventionally used in pharmaceutical applications. Once a particular amount of citric acid was selected for aqueous formulation, selection of the anhydrous commercially available form, with appropriate adjustment of weight to obtain the desired concentration, would have been within the expertise of a skilled artisan.
Regarding homogenization, Kim itself recognizes homogenization as one of the conventional techniques used for liposome manufacture. Mayer further acknowledges homogenization or milling may be employed as size-reduction techniques (col. 14, lines 4-7). The first composition in Kim is mechanically mixed at 2,000 rpm for 30 minutes before being subjected to the second rolling process. The prior liposome art further establishes that homogenizer speed, homogenization time, and processing temperature are routinely selected to control vesicle formation and size.
It would have been obvious to increase the first mechanical mixing of Kim to a conventional high-shear homogenization condition such as 6,000 rpm and to operate at an elevated phospholipid processing temperature within approximately 60 to 70° C to facilitate formation of a uniform liposome dispersion just prior to the rolling technique expressly taught by Kim. Speed, time, and temperature are result-effective variables in homogenization, and optimization of such variables to achieve desired liposome size and uniformity would have required only routine experimentation. Selection of 20 minutes rather than Kim’s exemplified 30 minutes likewise would have been within the ordinary optimization of homogenization duration. Applicant has not established that precisely 20 minutes produces an unexpected result relative to other homogenization durations.
Regarding claim 5 –
Kim expressly teaches the secondary rolling process as disclosed and currently claimed increases the encapsulation efficiency from 10% (in conventional emulsion liposome compositions) to at least 40% (p. 3).
Thus, Kim teaches the performance of the very rolling process relied upon in the rejection of claim 1 produces encapsulation efficiency exceeding the claimed minimum of 30%.
Accordingly, one of ordinary skill the art would have found it obvious to modify Kim’s aqueous vitamin C/soy lecithin liposome process by (1) selecting concentrations of vitamin C wt% and lecithin wt% from Kim’s expressly disclosed formulation concentrations; (2) incorporating citric acid as taught by Lin and optimizing its concentration to approximately 5 wt% in view of the citric acid concentrations of Mayer; (3) employing conventional high-shear homogenization conditions before the rolling step; (4) selecting rolling speed, duration, and temperature from within Kim’s expressly disclosed overlapping ranges; (5) omitting optional auxiliary polysorbate surfactants; and (6) cooling the resulting dispersion after heated processing. The combined process would have yielded the claimed method by the predictable application and optimization of known liposome formulation and processing techniques as disclosed by the prior art.
Claims 6-8 are rejected under 35 U.S.C. 103 as being unpatentable over Kim (KR102259975B1; published: 03 June 2021; machine translation relied upon), Lin (US 2022/0125758 A1; published 28 April 2022), and Mayer (US Pat. No. 5,795,589; patented 18 August 1998) as applied to claims 1 and 5 above, and further in view of Maione-Silva (“Ascorbic acid encapsulated into negatively charged liposomes exhibits increased skin permeation, retention and enhances collagen synthesis by fibroblasts,” published 24 January 2019) and Serrano (“Phosphatidylcholine liposomes as carriers to improve topical ascorbic acid treatment of skin disorders,” published 17 December 2015).
While the combination of Kim, Lin, and Mayer make obvious the limitations of instant claims 1 and 5, neither Kim, Lin, nor Mayer expressly disclose what is claimed in instant claims 6-8. However, these limitations are made obvious in further view of Maione-Silva and Serrano.
Both Maione-Silva and Serrano teach ascorbic acid-loaded phosphatidylcholine liposomes.
Regarding claim 6 –
Maione-Silva teaches ascorbic acid loaded liposomes having mean diameters including 161 nm, 169 nm, 171 nm, 173 nm, and 190 nm (p. 2). Each of these values falls within the presently claimed 150-250 nm range.
Serrano teaches liposomes ranging from 80 to 120 nm in diameter (p. 594). This range overlaps with the instantly claimed range. Furthermore, Serrano teaches the liposomes having a zeta potential of -66.3±0.6 mV, -67.5±1.2 mV, and – 76.4±1.8 mV (p. 595), which fall within the instantly claimed -50 to -70 mV range.
The combination of Maione-Silva and Serrano teach particle size and zeta potential were known result-effective properties of vitamin C liposome formulations. A person of ordinary skill preparing the liposomes of Kim, as modified above, would have had reason to optimize lipid composition and homogenization/rolling conditions to provide the known and desirable particle sizes and surface charges previous disclosed for vitamin C liposomes.
Regarding claim 7 –
Maione-Silva teaches stability of the liposomes for at least 30 days, whereby the average particle size was within 3-5 nm of the initial particle size at day 0 (p. 10, Table 3).
Serrano further teaches absolute zeta potential is relevant to the physical stability of liposomal dispersions and correlates zeta potential characteristics with resistance to aggregation (p. 593). Serrano indicates stability generally improves when absolute zeta potential exceeds 30 mV (p. 593). Accordingly, a person of ordinary skill would have recognized zeta potential as a result-effective property to be optimized when formulating a physically stable vitamin C liposome dispersion.
Therefore, it would have been obvious to one of ordinary skill in the art to optimize the vitamin C liposomes of Kim, as modified above, so that the particle size and zeta potential ranges recited in claim 6 were maintained for at least 14 days. Such maintenance represents nothing more than achieving a known and desirable degree of colloidal stability over a storage period shorter than the 30-day period expressly evaluated in the prior art.
Regarding claim 8 –
Maione-Silva teaches liposomes having mean diameters within the claimed particle size range and reports a formulation having a polydispersity index (PDI) of 0.17±0.02 (p. 2, Table 1), which falls within the instantly claimed range of 0.15 to 0.30. Maione-Silva further explains that low PDI values (<0.18) indicate homogeneity in particle size distribution (p. 4). Therefore, PDI was a known and routinely optimized characteristic of liposome formulations.
It would have been obvious to optimize the homogenization and rolling technique of the combined references to provide a PDI within the presently claimed range because the prior art expressly demonstrates that a PDI of approximately 0.17 was achievable and desirable in ascorbic acid/phosphatidylcholine liposomes.
Conclusion
Claim 7 is objected to. Claims 1 and 5-8 are rejected. No claim is allowed.
Communication
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Julia A. Rossi whose telephone number is (571)272-0138. The examiner can normally be reached M-Th 7:30-5:30 (MST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert A. Wax can be reached at (571)272-0623. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JULIA A. ROSSI/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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