DETAILED ACTION
Applicants’ arguments, filed 21 November 2025, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Reopening of Prosecution
This office action contains a rejection for lack of enablement that is not necessitated by amendment. It is the examiner’s general position that, although various subject matter contained in applicant’s arguments submitted on 21 November 2025 support the examiner’s conclusion for lack of enablement (as set forth in the rejection below), the newly applied rejection for lack of enablement is not necessitated by a claim amendment. As such, this office action has been made NON-FINAL.
Claim Objections
Claim 10 is objected to because of the following informalities: Claim 10 recites the term “threhalose.” This appears to be a mis-spelling of “trehalose.” Appropriate correction is required.
Claim Interpretation
The examiner clarifies that the term “liposome” applies to a structure comprising a lipid bilayer and an aqueous core. As an example of a hypothetical liposome, the examiner cites Robson et al. (Frontiers in Pharmacology, Vol. 9, Article 80, February 2018, pages 1-8), which teaches the following as of page 3, figure 1, reproduced below.
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The examiner clarifies that a lipidic core structure is not a liposome because it does not have an aqueous core. Additionally, a micelle is understood by the examiner to comprise a lipid monolayer and a lipidic core, which differs from the lipid bilayer and an aqueous core as in a liposome.
As such, it is the examiner’s position that prior art teaching a micelle or other lipidic core structure is not understood to read on the claimed liposome, and will not be understood to anticipate the claimed invention or to render the claimed invention prima facie obvious.
Withdrawn Rejections
Previously in prosecution, the examiner rejected the instant claims as obvious over Ventosa Rull et al. (US 2015/0190530 A1). This rejection has been withdrawn for at least the following reasons:
Ventosa Rull et al. (hereafter referred to as Ventosa Rull) is drawn to a liposome, as of Ventosa Rull, title and abstract. Ventosa Rull teaches the following, as of Example 3, reproduced below.
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This example differs from the claimed composition at least because this example lacks a non-lipid cationic surfactant. While Ventosa Rull teaches an optional surfactant in paragraph 0029, the examiner notes that this surfactant is taught in the broad disclosure of Ventosa Rull and not in the examples of Ventosa Rull.
In applicant’s response on 21 November 2025 (hereafter referred to as applicant’s response), paragraph bridging pages 11-12, applicant makes the following argument:
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The examiner agrees with the position taken in the above-reproduced paragraph. In support of the position in the above-reproduced paragraph from applicant’s response, the examiner notes the following. First, supramolecular structures of amphiphilic molecules in water generally can take either of two forms: an aqueous core structure or a lipidic core structure. The examiner notes that the phrase “amphiphilic molecule” refers to a molecule with a polar headgroup and non-polar tail, and includes both surfactants and lipids. Aqueous core structures include liposomes and vesicles: these structures generally have a lipid bilayer which separates the aqueous interior from the aqueous exterior. Lipidic core structures include micelles, which comprise a lipid monolayer.
The issue of supramolecular structures of amphiphilic molecules is discussed by Israelachvili et al. (Quarterly Reviews of Biophysics, Vol. 13(2), 1980, pages 121-200). The issue of which types of amphiphilic molecules form which type of structure is discussed as of Israelachvili, page 158, figure 4.2, reproduced below.
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The above-reproduced figure appears to show that the lipids which form flexible bilayers, which are the structure found in liposomes, are generally double chained lipids with large headgroups. In contrast, single-chain lipids generally form lipidic core micelle structures, which are not liposomes.
While Israelachvili does not appear to specifically teach surfactants in the above-reproduced figure, the skilled artisan would have expected cationic surfactants to have formed lipidic-core micelles rather than liposomes. See e.g. Sharker et al. (Heliyon, Vol. 5, 2019, article e02425, pages 1-11). Sharker et al. (hereafter referred to as Sharker) teaches that micelles form the following structure, as of Sharker, page 2, relevant figure reproduced below.
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The above-reproduced figure shows that micelles have a core which lacks water; this is sufficiently different from the liposome required by the instant claims. See the section above entitled “Claim Interpretation.”
Consequently, and in agreement with the position taken in applicant’s arguments reproduced above, the skilled artisan would have expected that had a surfactant been added to a liposome, it would have been unpredictable that the liposome would have been able to have retained its liposomal structure. This is because surfactants thermodynamically disfavor the formation of a liposome with a bilayer and aqueous core and favor the formation of a micelle with a monolayer and a lipidic core. Therefore, the addition of surfactants to a liposome would have rendered it unpredictable that the liposome could have retained its liposomal structure because surfactants disfavor a liposomal structure.
Consequently, the examiner takes the position that there would have been no reasonable expectation that a liposome would have successfully remained in liposomal form upon addition of the surfactant required by part (d) of claim 1. Obviousness requires a reasonable expectation of success, and the examiner agrees with applicant’s argument on at least the paragraph bridging pages 11-12 of applicant’s response indicating a lack of a reasonable expectation of success.
The examiner has withdrawn the previously applied double patenting rejection over the claims of US Patent 9,744,247 for essentially the same reason as set forth above regarding the previously applied obviousness rejection.
Claim Rejections - 35 USC § 112(a) – Scope of Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-5, 7-11, and 15-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a liposome comprising components (a), (b), (c) and (e) of claim 1 (i.e. the composition in the absence of the surfactant), does not reasonably provide enablement for a liposome comprising all of components (a), (b), (c), (d), and (e) of claim 1 (i.e. the composition including the surfactant). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims.
To be enabling, the specification of the patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. See MPEP 2164.01(a). The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by MPEP 2164.01(a) and are set forth below.
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved; see MPEP 2164.03. Keeping that in mind, the factors set forth in MPEP 2164.01 are relevant to the instant fact situation for the following reasons:
1. The nature of the invention, state and predictability of the art, and relative skill level (B)-(E)
The invention relates to a liposomal composition. The relative skill of those in the art is high, that of an MD or PhD. That factor is outweighed, however, by the unpredictable nature of the art.
The examiner has reproduced claim 1 below with annotation by the examiner in order to explain which claimed features render the art to have an unpredictable nature.
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It is the examiner’s position that both liposomes and non-lipid cationic surfactants are well-known in the art. Nevertheless, it is also the examiner’s position that including these two features together in the same composition would have been unpredictable because the teachings of the prior art support the idea that the non-lipid cationic surfactant would have decreased the stability and structural integrity of the liposome. The examiner presents the following arguments in support of this position; various arguments presented here have been taken from the above section entitled “Withdrawn Rejections.”
As an initial matter, the skilled artisan would have understood a liposome to have comprised a lipid bilayer and an aqueous interior. The skilled artisan would not have understood a micelle or other lipidic core structure to have been a liposome.
As relevant prior art, the examiner cites Israelachvili et al. (Quarterly Reviews of Biophysics, Vol. 13(2), 1980, pages 121-200) and Sharker et al. (Heliyon, Vol. 5, 2019, article e02425, pages 1-11).
The issue of which types of amphiphilic molecules form which type of structure is discussed as of Israelachvili, page 158, figure 4.2, reproduced below.
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The above-reproduced figure appears to show that the lipids which form flexible bilayers, which are the structure found in liposomes, are generally double chained lipids with large headgroups. In contrast, single-chain lipids generally form lipidic core micelle structures, which are not liposomes.
While Israelachvili does not appear to specifically teach surfactants in the above-reproduced figure, the skilled artisan would have expected cationic surfactants to have formed lipidic-core micelles rather than liposomes. See e.g. Sharker et al. (Heliyon, Vol. 5, 2019, article e02425, pages 1-11). Sharker et al. (hereafter referred to as Sharker) teaches that micelles form the following structure, as of Sharker, page 2, relevant figure reproduced below.
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The above-reproduced figure shows that micelles have a core which lacks water; this is sufficiently different from the liposome required by the instant claims.
Consequently, the skilled artisan would have expected that had a surfactant been added to a liposome, it would have been unpredictable that the liposome would have been able to have retained its liposomal structure. This is because surfactants thermodynamically disfavor the formation of a liposome with a bilayer and aqueous core and favor the formation of a micelle with a monolayer and a lipidic core. Therefore, the addition of surfactants to a liposome would have rendered it unpredictable that the liposome could have retained its liposomal structure because surfactants disfavor a liposomal structure.
Consequently, the examiner takes the position that there would have been no reasonable expectation that a liposome would have successfully remained in liposomal form upon addition of the surfactant required by part (d) of claim 1 in the absence of undue experimentation.
The breadth of the claims (A)
Instant claim 1 is broad in that it recites a non-lipid cationic surfactant generically, and does not recite the specific chemical identity of the surfactant.
3. The amount of direction or guidance provided and the presence or absence of working examples (F)-(G)
The specification appears to provide examples of successful liposome formation in the case wherein the surfactant is myristalkonium chloride (abbreviated “MKC”) in amounts between 0.4% and 4.3%. See figures 2 and 4A, both of which are reproduced below.
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As such, applicant has provided data showing that myristalkonium chloride incorporated in the claimed amounts, along with the other claimed elements, successfully forms a liposome. This liposome appears to have superior properties as compared with a liposome lacking myristalkonium chloride.
The quantity of experimentation necessary (H)
The prior art indicates that the presence of surfactants destroys the liposomal character of liposomes because surfactants favor the formation of a non-liposomal structure. As such, incorporation of surfactants into liposomes is highly unpredictable. Applicant’s experiments have found that myristalkonium chloride incorporated into a liposome achieves stable liposomes that appear to have therapeutic properties superior to a liposome lacking surfactant entirely. However, the results obtained with myristalkonium chloride would not appear to be applicable to the full scope of surfactants because it would have been unpredictable that surfactants could have been incorporated into a liposome and that the liposome would have retained its structure as a liposome.
As such, because of the known unpredictability of the art, and in the absence of experimental evidence, no one skilled in the art would accept the assertion that the instantly claimed agents could be predictably used to form a liposome as inferred by the claim and contemplated by the specification. Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the claimed invention in its “full scope” a person of ordinary skill in the art would have to engage in undue experimentation, with no reasonable expectation of success.
The examiner has set forth proposed claim amendments at the end of the office action that would overcome the applied rejection and limit the claim to enabled subject matter.
Response to Arguments
Applicant has presented arguments in applicant’s response mailed on 21 November 2025 (hereafter referred to as applicant’s response). These arguments are drawn to previously applied obviousness rejections that have been withdrawn. As such, the examiner takes the position that applicant’s arguments are moot in view of the withdrawal of the obviousness and double patenting rejections, and will not be addressed substantively by the examiner other than the portions of applicant’s arguments already addressed in the above section entitled “Withdrawn Rejections.”
With that being said, the examiner notes that applicant has argued that the skilled artisan would have had no reasonable basis to conclude that Ventosa Rull enables or seriously suggests the stable incorporation of surfactants into the described liposomes, as of the paragraph bridging pages 11-12 of applicant’s response. The examiner agrees with this statement, and takes the position that this statement supports the examiner’s finding of lack of enablement as set forth in the rejection above.
Allowable Subject Matter – Proposed Amendment
The examiner suggests that the claims be amended in the following manner to place the claims in condition for allowance.
X) Claim 1 is proposed to be amended in the following manner:
Claim 1 (Proposed Amendment): A liposome comprising
a) a phospholipid which is dipalmitoylphosphatidylcholine (DPPC);
b) cholesterol (chol);
c) a conjugate comprising a cholesterol moiety, a polyethylene glycol (PEG) moiety and a peptide moiety comprising a RGD sequence, wherein the PEG moiety is covalently attached to the cholesterol moiety by one end via a bond of the type alkyl ether and is covalently attached to the peptide moiety comprising the RGD sequence by the other end:
d) [[ ]] myristalkonium chloride (MKC) present in a percentage of [[ ]] between 0.4 and 4.3 mol [[ ]] with respect to the total mol of the components of the liposome a), b), c) and d); and
e) alpha-galactosidase enzyme (GLA) present in a ratio of micrograms of GLA in respect to the total milligrams of the components of the liposome a), b), c) and d) of between and including 2 μg/mg to 35 µg/mg.
X) Claim 2 is proposed to be amended in the following manner:
Claim 2 (Proposed Amendment): The liposome according to claim 1 wherein, in the alpha-galactosidase enzyme, each of its monomers is either of sequence SEQ ID NO: 1, or of sequence with at least 85% of sequence identity with SEQ ID NO: 1.
X) Claim 3 is proposed to be allowed without further amendment.
X) Claims 4-5 are proposed to be cancelled without prejudice or disclaimer.
[The examiner notes that the cancellation of these claims is because, in view of the amendment to claim 1, claims 4-5 would be broader than claims and subject to a 112(d) rejection.]
X) Claim 6 has already been cancelled.
X) Claim 7 is proposed to be amended in the following manner:
Claim 7 (Amendment): The liposome according to claim 1, wherein the PEG moiety has [[ ]] a molecular weight from [[ ]] 50 to 600 Daltons.
X) Claim 8 is proposed to be amended in the following manner:
Claim 8 (Proposed Amendment): The liposome according to claim 1, wherein the PEG [[ ]] moiety has a molecular weight of 400 Daltons, the RGD sequence is SEQ ID NO: 2, [[ and the non-lipid cationic quaternary ammonium surfactant is MKC present in a percentage of less than or equal to 5% mol in respect to the total mol of the components of the liposome a), b), c) and d), ]] the ratio of micrograms of GLA to milligrams of the components of the liposome a), b), c), and d) is between 20-30 μg/mg, wherein, in the GLA, each of its monomers is either of sequence SEQ ID NO: 1, or of sequence with at least 85% of sequence identity with SEQ ID NO: 1, and the mol ratio DPPC:chol:chol-PEG-RGD is 10:6.5:0.5.
X) Claim 9 is proposed to be amended in the following manner:
Claim 9 (Proposed Amendment): A pharmaceutical composition comprising a therapeutically effective amount of liposomes as defined in claim 1, together with pharmaceutically acceptable excipient(s), carriers, or vehicles.
X) Claim 10 is proposed to be amended in the following manner:
Claim 10 (Proposed Amendment): The pharmaceutical composition according to claim 9 [[ ]] further comprising glucose, sucrose or [[ ]] trehalose in an amount from 2 to 10% in weight with respect to the total volume of the composition [[ ]] .
X) Claim 11 is proposed to be amended in the following manner:
Claim 11 (Proposed Amendment): The pharmaceutical composition according to claim 9, [[ ]] wherein GLA is present in an amount of at least 0.2 mg per mL of the pharmaceutical composition.
X) Claims 12-14 have already been cancelled.
X) Claim 15 has been amended in the following manner:
Claim 15 (Proposed Amendment): A process for the production of a liposome according to claim 1 comprising the following steps:
a) preparing an aqueous solution which comprises the GLA enzyme;
b) preparing a solution comprising the conjugate, cholesterol and a phospholipid dissolved in an organic solvent; [[ ]]
c) adding [[ ]] MKC, either to the solution of the step a), or to the solution of the step b); [[ ]]
d) expanding the solution of step b) with a compressed fluid, wherein, when the MKC is added to the solution of step b), the expanding step occurs after the MKC has been added;
[[ ]] e) depressurizing the expanded solution resulting from the step [[ ]] d) over the resulting solution of the step a); and
e) diafiltrating and concentrating, in any order, the resulting solution obtained in step [[ ]] e).
X) Claim 16 is proposed to be amended in the following manner:
Claim 16 (Proposed Amendment): The liposome according to claim 7, wherein the PEG moiety has [[ ]] a molecular weight from [[ ]] 200 to 400 Daltons.
X) Claim 17 is proposed to be amended in the following manner:
Claim 17 (Proposed Amendment): A method for the treatment of Fabry disease, which comprises administering the liposome according to claim 1 to a subject in need thereof.
X) Claim 18 is proposed to be allowed without further amendment.
X) Claim 19 is proposed to be amended in the following manner:
Claim 19 (Proposed Amendment): A method for the treatment of Fabry disease, which comprises administering the liposome according to claim 9 to a subject in need thereof.
X) Claim 20 is proposed to be allowed without further amendment.
Reasons Why Proposed Subject Matter is Allowable
The examiner presents the following rationale for indicating that the subject matter set forth above is in condition for allowance.
As relevant prior art, the examiner cites Ventosa Rull et al. (US 2015/0190530 A1). Ventosa Rull et al. (hereafter referred to as Ventosa Rull) is drawn to a liposome, as of Ventosa Rull, title and abstract. Ventosa Rull teaches the following, as of Example 3, reproduced below.
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This example differs from the claimed composition at least because this example lacks a non-lipid cationic surfactant, let alone MKC.
The examiner notes that Ventosa Rull teaches an optional surfactant in paragraph 0029. Nevertheless, it is the examiner’s position that there would have been no reasonable expectation that the optional surfactant could have been added to the liposome with the liposome maintaining its structural integrity.
Additionally, data shown in the instant application, especially in at least figures 2 4A would have enabled the skilled artisan to have made and used the liposome of the proposed allowable claims.
Conclusion
The instant claims are not currently in condition for allowance.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ISAAC SHOMER whose telephone number is (571)270-7671. The examiner can normally be reached 7:30 AM to 5:00 PM Monday Through Friday.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sahana Kaup can be reached at (571)272-6897. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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ISAAC . SHOMER
Primary Examiner
Art Unit 1612
/ISAAC SHOMER/ Primary Examiner, Art Unit 1612