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 5, 9-10, 12, 25, and 30-50 are cancelled.
Claims 1-4, 6-8, 11, 13-24, and 26-29 are pending and under current examination.
Priority
This application is a national stage entry of PCT/GB2023/051955, filed 07/25/2023. Foreign priority has been claimed to GB 2210829.4, filed 07/25/2022. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 01/28/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
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.
Claims 1-4, 6-8, 11, 13-24, and 26-29 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, regards as the invention.
Regarding claim 1, the phrase "e.g.” in the limitation “microscopic particles, e.g. nanoparticles or microparticles" renders the claim indefinite because it is unclear whether the limitation following the phrase “e.g.” are part of the claimed invention. See MPEP § 2173.05(d).
Claim 1 recites (emphasis added), “(i) controlling provision of a first liquid phase to a first membrane, the first membrane defining a first plurality of apertures; (ii) controlling provision of a second liquid phase to the first membrane via the first plurality of apertures to form a mixture” It is unclear how a second liquid can be provided to a membrane via apertures defined by said membrane. For purposes of examination and applying prior art, the Examiner interprets that the claim requires that a first and second liquid phase are provided to a first membrane to form a mixture. A similar issue arises in step (iv) “controlling provision of a pH buffer liquid phase to the second membrane via the second plurality of apertures” with “the second membrane defining a second plurality of apertures” and in step (vi) “controlling provision of a diafiltration buffering liquid phase to the third membrane via the third plurality of apertures” with “the third membrane defining a third plurality of apertures”.
In claim 1, it is unclear which limitations the term “optionally” applies to: a) step (iii), b) steps (iii)-(vii), c) all limitations following the term “optionally”, or d) some other requirement. For purposes of examination and applying prior art, the Examiner interprets that the claim does not require any of the limitations following the term “optionally”.
Claim 1 recites the limitation "controlling provision of the pH buffered mixture" in step (v). There is insufficient antecedent basis for “the pH buffered mixture” in the claim as the claim previously recites “a pH buffer liquid” forming “a stabilized suspension of particles”, but no “pH buffered mixture”. It is unclear what is required to be provided to a third membrane to satisfy the limitations of step (v).
Claim 1 recites the limitation "controlling provision of the stabilized mixture " in step (vii). There is insufficient antecedent basis for “the stabilized mixture” in the claim as the claim previously recites “a stabilized suspension of particles ” and a “pH buffered mixture”, but no “stabilized mixture”. It is unclear what is required to be provided to a fourth membrane to satisfy the limitations of step (vii).
Claims 2-4, 6-8, 11, 13-24, and 26-29 are rejected under 35 U.S.C. 112(b) by virtue of their dependency on indefinite claim 1 and failure to cure the deficiencies noted above.
Claim 4 recites “wherein steps (i) to (vii) are carried out sequentially”. As noted above, claim 1, from which claim 4 depends, recites that steps (iii)-(vii) are optional. It is unclear if claim 4 requires that all of steps (i) to (vii) must be carried out in order to satisfy the claim, or if steps satisfying claim 1 carried out in sequential order satisfy the claim. For purposes of examination and applying prior art, the Examiner interprets that steps satisfying claim 1 carried out in sequential order read on instant claim 4 (that is, that claim 4 does not require that optional steps (iii)-(vii) be carried out).
Claims 6, 8, and 28 contain the trademark/trade name AXF®. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a particular crossflow membrane apparatus and, accordingly, the identification/description is indefinite.
Claim 22 recites “wherein step (iv) comprises formation of a pH buffered mixture by controlling provision of the mixture to a second membrane”. There is insufficient antecedent basis for “the mixture” in the claim as the claim previously recites “a pH buffered mixture” and claim 1, from which claim 22 depends, recites “a mixture” formed in step (ii). It is unclear which of these “the mixture” in line 3 is intended to refer to.
Regarding claim 24, the phrase "e.g.” in the limitation “solidified particles, e.g. crystalline particles" renders the claim indefinite because it is unclear whether the limitation following the phrase “e.g.” are part of the claimed invention. See MPEP § 2173.05(d).
The term “towards the end” in claims 26 and 27, respectively, is a relative term which renders the claims indefinite. The term “towards” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear where an analytical characterization point needs to be positioned in order to satisfy being “towards the end” of a step, and the metes and bounds of the claims are uncertain.
Claim 28 recites the limitation "said crossflow emulsification apparatus" in line 2. There is insufficient antecedent basis for this limitation in the claim as the claim previously recites “at least one crossflow apparatus” and claim 8, from which claim 28 depends, recites “a crossflow apparatus”; no “crossflow emulsification apparatus” is previously recited . It is suggested that Applicant can recite in claim 28, “A continuous process according to claim 8 comprising at least one crossflow membrane apparatus wherein said at least one crossflow membrane apparatus comprises…”
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 7 is rejected under 35 U.S.C. 112(d) as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 7 recites the limitation, “the number of membranes used in the continuous process is from about 1 to about 4”. Absent a specific definition of the term “about” in the specification, the limitation “about 1” is interpreted as inclusive of values less than one. Claim 1, from which claim 7 depends, requires at least a “first membrane”, and thus claim 7 broadens the scope of the number of membranes required by claim 1.
Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
Claim Interpretation
The Examiner interprets that “(active loading)” in claim 20 provides a synonym for a method in which lipid vesicles are produced unloaded and loaded afterwards and is not a further limitation on the claim. Similarly, the Examiner interprets that “(passive loading)” in claim 21 provides a synonym for a method in which lipid vesicles are produced loaded and is not a further limitation on the claim.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-2, 4, 7, 11, 13-17, 19, 21-24, and 26-27 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Charcosset et al. (“Preparation of liposomes at large scale using the ethanol injection method: Effect of scale-up and injection devices” Chemical Engineering Research and Design 2015, 94, 508-515; included on IDS submitted 01/28/2025), hereafter “Charcosset”.
Regarding instant claim 1, Charcosset discloses the preparation of liposomes using the ethanol injection technique with an experimental set-up using two pumps for injecting both aqueous and organic phases (a first and second liquid phase) through a Shirasu Porous Glass (SPG) membrane and an experimental set-up using a pilot plant using two pumps for injection of both organic and aqueous phases through the SPG (see entire document, particularly Abstract, Fig. 1 at pg. 511, and Fig. 3 at pg. 512). Injection of the organic phase using a pump presents several advantages including continuous processing (pg. 513, column 1, paragraph 2). As the membrane of Charcosset comprises pores (see abstract and pg. 510, “2.1.2 SPG membranes”), it is interpreted to define a plurality of apertures. Charcosset exemplifies liposomes prepared via membrane injection methods with sizes of 123 ± 12 nm and 98 ± 2 nm (Table 3 at pg. 513), and thus the preparation of microscopic particles. As shown in Figs. 1 and 3 of Charcosset (reproduced below), an aqueous phase (a first liquid phase) and an organic phase (second liquid phase) are provided to a membrane, respectively, via a pump, resulting in a liposomal suspension (mixture).
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Regarding instant claim 2, Charcosset exemplifies liposomes prepared via membrane injection methods with sizes of 123 ± 12 nm and 98 ± 2 nm (Table 3 at pg. 513), and thus the preparation of nanoparticles.
Regarding instant claim 4, Charcosset discloses that a first pump circulated the aqueous phase from the inlet of the membrane to the outlet, and a second pump pushed the organic phase through the membrane pores; spontaneous formation of liposomes started as soon as the organic phase was brought into contact with the aqueous phase (pg. 510, “2.2.2. Injection of the organic phase using a membrane”). Thus, the aqueous phase (first liquid phase) is provided to the membrane sequentially followed by the organic phase being provided to the membrane (second liquid phase).
Regarding instant claim 7, as shown above in Figs. 1 and 3, Charcosset shows the use of one membrane module.
Regarding instant claim 11, the claim further limits the optional step (v) recited in instant claim 1. As set forth above, Charcosset anticipates the limitations of claim 1, which does not require the optional step (v) be performed.
Regarding instant claims 13-14, Charcosset discloses the preparation of liposomes (abstract), and also refers to the liposomes as lipid vesicles (pg. 512, “3.1 Unloaded liposomes” paragraph 2).
Regarding instant claim 15, Charcosset discloses the preparation of liposomes comprising lipids (see particularly pg. 512, “3.1 Unloaded liposomes” paragraphs 1-2). As noted above, Charcosset exemplifies liposomes prepared via membrane injection methods with sizes of 123 ± 12 nm and 98 ± 2 nm (Table 3 at pg. 513), and thus the preparation of lipid nanoparticles.
Regarding instant claims 16-17, Charcosset discloses the preparation of liposomes (abstract), and that liposomes have an inner aqueous core (pg. 508, “1. Introduction”, paragraph 1). Charcosset discloses α-Tocopherol-loaded liposomes, and that the drug is loaded within lipid bilayers (pg. 513, “3.2 α-Tocopherol-loaded liposomes”, paragraphs 1-2).
Regarding instant claim 19, Charcosset discloses that hydrophilic drugs can be entrapped in the internal aqueous compartment of liposomes (pg. 514, column 1, paragraph 1).
Regarding instant claim 21, Charcosset discloses the preparation of α-Tocopherol-loaded liposomes produced from Formulation 2 wherein α-Tocopherol is included in the organic phase (“3.2 α-Tocopherol-loaded liposomes” beginning at pg. 513 and Table 2 at pg. 510).
Regarding instant claim 22, the claim further limits the optional step (iv) recited in instant claim 1. As set forth above, Charcosset anticipates the limitations of claim 1, which does not require the optional step (iv) be performed.
Regarding instant claim 23, as set forth above, Charcosset discloses the preparation of nanoparticles loaded with α-Tocopherol (“3.2 α-Tocopherol-loaded liposomes”). Charcosset discloses that α-Tocopherol is a form of vitamin E that is preferentially absorbed and accumulated in humans; vitamin E has numerous functions, which include antioxidant, anti-inflammatory, antithrombolytic, and other therapeutic effects (pg. 513, ““3.2 α-Tocopherol-loaded liposomes”, paragraph 1), and is therefore a biologically active substance.
Regarding instant claim 24, Charcosset discloses that spontaneous formation of liposomes started as soon as the organic phase was brought in contact with the aqueous phase (pg. 510, “2.2.2. Injection of the organic phase using a membrane”, paragraph 1). As the liposomes are solid (see Fig. 4 at pg. 514) and formed from the process of Charcosset, it is interpreted that they are solidified.
Regarding instant claims 26-27, Charcosset discloses that liposomes are characterized following preparation (pg. 512, “2.2.5. Liposome characterization”), or at the end of step (ii), which is the end of the pair of steps (i) and (ii).
Claims 1-2, 4, 6-8, 11, 13-17, 19-24, and 26-29 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kerr et al. (WO 2022/018441 A1, published January 27th, 2022; included on IDS submitted 01/28/2025), hereafter “Kerr”.
Regarding instant claim 1, Kerr discloses a method of preparing lipid vesicles, comprising dispersing a first liquid phase in a second liquid phase; wherein said first liquid phase comprises a lipid phase and said second liquid phase comprises an aqueous phase; or said first liquid phase comprises an aqueous phase and said second liquid phase comprises a lipid phase; said method comprising controlling provision of the first liquid phase in a first flow direction to a membrane, said membrane defining a plurality of pores (apertures); and controlling provision of the second liquid phase to the membrane in a crossflow to the first flow direction, via the plurality of pores, to form a lipid vesicle suspension (see entire document, particularly Abstract and claims 1 and 7). The invention allows the continuous production of lipid vesicles (pg. 7, lines 15-16). The lipid vesicles are liposomes or lipid nanoparticles (claims 10-12 and 82-84), and are therefore microscopic particles.
Regarding instant claim 2, as noted above, Kerr discloses the preparation of lipid vesicles which are lipid nanoparticles (claims 10, 12, 34, 82 and 84).
Regarding instant claim 4, Kerr discloses that the first liquid phase is dispersed in a second liquid phase (claims 1 and 7), and thus the phases are provided sequentially.
Regarding instant claim 6, Kerr discloses preparing lipid vesicles using an AXF crossflow emulsification apparatus comprising a tubular membrane wherein the first and second liquid phases are provided to the tubular membrane (claim 7).
Regarding instant claim 7, Kerr claims the use of one membrane (claims 1 and 7).
Regarding instant claim 8, as set forth above, Kerr discloses preparing lipid vesicles using an AXF crossflow emulsification apparatus comprising a tubular membrane wherein the first and second liquid phases are provided to the tubular membrane (claim 7).
Regarding instant claim 11, the claim further limits the optional step (v) recited in instant claim 1. As set forth above, Kerr anticipates the limitations of claim 1, which does not require the optional step (v) be performed.
Regarding instant claims 13-15, as noted above, Kerr discloses the preparation of lipid vesicles which are liposomes or lipid nanoparticles (claims 10-12 and 82-84).
Regarding instant claim 16, Kerr discloses that the method produces lipid vesicles comprises a lipid bilayer encapsulating an aqueous core (claim 20).
Regarding instant claim 17, as noted above, Kerr discloses the preparation of lipid vesicles of lipid nanoparticles (claims 10, 12, 82, and 84) and that the lipid vesicles comprise a lipid bilayer encapsulating an aqueous core (claim 20).
Regarding instant claim 19, Kerr discloses the preparation of lipid vesicles encapsulating an aqueous core and wherein the aqueous core includes one or more active agents (claim 20).
Regarding instant claim 20, Kerr discloses that the lipid vesicles are produced unloaded and loaded afterwards (active loading) (claim 18).
Regarding instant claim 21, Kerr discloses that the lipid vesicles are produced loaded (passive loading) (claim 19).
Regarding instant claim 22, the claim further limits the optional step (iv) recited in instant claim 1. As set forth above, Kerr anticipates the limitations of claim 1, which does not require the optional step (iv) be performed.
Regarding instant claim 23, Kerr discloses the inclusion of one or more active agents (claims 13 and 20) including bioactive agents (claims 21-24).
Regarding instant claim 24, Kerr discloses that lipid vesicles are formed from a lipid solution (pg. 16, lines 20-25; pg. 35, lines 16-19). As the lipid vesicles (a solid) are formed from a lipid solution (liquid) it is interpreted that they are solidified.
Regarding instant claims 26-27, Kerr discloses that the suspension resulting from the process was analyzed via Dynamic Light Scattering/Quasi-Elastic Light Scattering (DLS/QELS) (see Examples beginning at pg. 35, such as at pg. 36, lines 11-13). Thus, Kerr discloses an analytical characterization point at the end of step (ii), which is the end of the pair of steps (i) and (ii).
Regarding instant claim 28, Kerr discloses the use of a crossflow emulsification apparatus (AXF) comprising an outer tubular sleeve provided with a first inlet at a first end; a lipid vesicle suspension outlet; and a second inlet, distal from and inclined relative to the first inlet; a tubular membrane provided with a plurality of pores and adapted to be positioned inside the tubular sleeve; and optionally an insert adapted to be located inside the tubular membrane, said insert comprising an inlet end and an outlet end, each of the inlet end and an outlet end being provided with chamfered region; the chamfered region is provided with a plurality of orifices and a furcation plate; and controlling provision of the first liquid phase to the tubular membrane; and controlling provision of a second liquid phase to the tubular membrane via the plurality of pores to form a lipid vesicle suspension (claim 7).
Regarding instant claim 29, Kerr discloses that the apparatus includes an insert (claim 40), that the first inlet is a continuous phase first inlet and the second inlet is a disperse phase inlet (claim 44), and that the disperse phase travels from outside the tubular membrane to inside (pg. 18, lines 4-7).
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.
Claims 1-2, 4, 6-8, 11, 13-17, 19, 21-24, and 26-27 are rejected under 35 U.S.C. 103 as being unpatentable over Charcosset et al. (“Preparation of liposomes at large scale using the ethanol injection method: Effect of scale-up and injection devices” Chemical Engineering Research and Design 2015, 94, 508-515; included on IDS submitted 01/28/2025), hereafter “Charcosset”.
Regarding instant claim 1, Charcosset teaches the preparation of liposomes using the ethanol injection technique with an experimental set-up using two pumps for injecting both aqueous and organic phases (a first and second liquid phase) through a Shirasu Porous Glass (SPG) membrane and an experimental set-up using a pilot plant using two pumps for injection of both organic and aqueous phases through the SPG (see entire document, particularly Abstract, Fig. 1 at pg. 511, and Fig. 3 at pg. 512). Injection of the organic phase using a pump presents several advantages including continuous processing (pg. 513, column 1, paragraph 2). As the membrane of Charcosset comprises pores (see abstract and pg. 510, “2.1.2 SPG membranes”), it is interpreted to define a plurality of apertures. Charcosset exemplifies liposomes prepared via membrane injection methods with sizes of 123 ± 12 nm and 98 ± 2 nm (Table 3 at pg. 513), and thus the preparation of microscopic particles. As shown in Figs. 1 and 3 of Charcosset (reproduced below), an aqueous phase (a first liquid phase) and an organic phase (second liquid phase) are provided to a membrane, respectively, via a pump, resulting in a liposomal suspension (mixture).
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Regarding instant claim 2, Charcosset exemplifies liposomes prepared via membrane injection methods with sizes of 123 ± 12 nm and 98 ± 2 nm (Table 3 at pg. 513), and thus the preparation of nanoparticles.
Regarding instant claim 4, Charcosset teaches that a first pump circulated the aqueous phase from the inlet of the membrane to the outlet, and a second pump pushed the organic phase through the membrane pores; spontaneous formation of liposomes started as soon as the organic phase was brought into contact with the aqueous phase (pg. 510, “2.2.2. Injection of the organic phase using a membrane”). Thus, the aqueous phase (first liquid phase) is provided to the membrane sequentially followed by the organic phase being provided to the membrane (second liquid phase).
Regarding instant claim 6, Charcosset teaches that a continuous system with a crossflow injection device has been used in preparation of large-scale quantities of liposomal suspensions; liposome size was controlled by the local lipid concentration at the injection point depending on process parameters such as injection pressure, lipid concentration and injection rate (pg. 509, column 1, paragraph 3-column 2, paragraph 3).
Regarding instant claim 7, as shown above in Figs. 1 and 3, Charcosset shows the use of one membrane module.
Regarding instant claim 8, as noted above, Charcosset teaches that a continuous system with a crossflow injection device has been used in preparation of large-scale quantities of liposomal suspensions; liposome size was controlled by the local lipid concentration at the injection point depending on process parameters such as injection pressure, lipid concentration and injection rate (pg. 509, column 1, paragraph 3-column 2, paragraph 3).
Regarding instant claim 11, the claim further limits the optional step (v) recited in instant claim 1. As set forth above, Charcosset teaches the limitations of claim 1, which does not require the optional step (v) be performed.
Regarding instant claims 13-14, Charcosset teaches the preparation of liposomes (abstract), and also refers to the liposomes as lipid vesicles (pg. 512, “3.1 Unloaded liposomes” paragraph 2).
Regarding instant claim 15, Charcosset teaches the preparation of liposomes comprising lipids (see particularly pg. 512, “3.1 Unloaded liposomes” paragraphs 1-2). As noted above, Charcosset exemplifies liposomes prepared via membrane injection methods with sizes of 123 ± 12 nm and 98 ± 2 nm (Table 3 at pg. 513), and thus the preparation of lipid nanoparticles.
Regarding instant claims 16-17, Charcosset teaches the preparation of liposomes (abstract), and that liposomes have an inner aqueous core (pg. 508, “1. Introduction”, paragraph 1). Charcosset discloses α-Tocopherol-loaded liposomes, and that the drug is loaded within lipid bilayers (pg. 513, “3.2 α-Tocopherol-loaded liposomes”, paragraphs 1-2).
Regarding instant claim 19, Charcosset teaches that hydrophilic drugs can be entrapped in the internal aqueous compartment of liposomes (pg. 514, column 1, paragraph 1).
Regarding instant claim 21, Charcosset teaches the preparation of α-Tocopherol-loaded liposomes produced from Formulation 2 wherein α-Tocopherol is included in the organic phase (“3.2 α-Tocopherol-loaded liposomes” beginning at pg. 513 and Table 2 at pg. 510).
Regarding instant claim 22, the claim further limits the optional step (iv) recited in instant claim 1. As set forth above, Charcosset teaches the limitations of claim 1, which does not require the optional step (iv) be performed.
Regarding instant claim 23, as set forth above, Charcosset teaches the preparation of nanoparticles loaded with α-Tocopherol (“3.2 α-Tocopherol-loaded liposomes” beginning at pg. 513). Charcosset teaches that α-Tocopherol is a form of vitamin E that is preferentially absorbed and accumulated in humans; vitamin E has numerous functions, which include antioxidant, anti-inflammatory, antithrombolytic, and other therapeutic effects (pg. 513, ““3.2 α-Tocopherol-loaded liposomes”, paragraph 1), and is therefore a biologically active substance.
Regarding instant claim 24, Charcosset teaches that spontaneous formation of liposomes started as soon as the organic phase was brought in contact with the aqueous phase (pg. 510, “2.2.2. Injection of the organic phase using a membrane”, paragraph 1). As the liposomes are solid (see Fig. 4 at pg. 514) and formed from the process of Charcosset, it is interpreted that they are solidified.
Regarding instant claims 26-27, Charcosset teaches that liposomes are characterized following preparation (pg. 512, “2.2.5. Liposome characterization”), or at the end of step (ii), which is the end of the pair of steps (i) and (ii).
Charcosset does not teach the inclusion of a crossflow apparatus (instant claims 6 and 8) with sufficient specificity to anticipate, but rather renders obvious the instant claims. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to modify the process of Charcosset to include a crossflow apparatus membrane. One of ordinary skill in the art would have been motivated to do so in order to include an apparatus that can control liposome size via process parameter such as injection pressure, lipid concentration, and injection rate, and which can be used to produce large volumes on an industrial scale (see Charcosset, pg. 509, column 1, paragraph 3-column 2, paragraph 3). There is a reasonable expectation of success as Charcosset exemplifies an ethanol injection method for liposome preparation, and teaches that such crossflow apparatuses are known in the art for use in ethanol injection methods (pg. 509, column 1, paragraph 3-column 2, paragraph 3).
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Charcosset as applied to claims 1-2, 4, 6-8, 11, 13-17, 19, 21-24, and 26-27 above, and further in view of Schutt et al. (US 2011/0250264 A1, published October 13, 2011), hereafter “Schutt”.
The teachings of Charcosset are described above. Charcosset further teaches that liposome size can be controlled in crossflow injection devices (pg. 509, column 1, paragraph 3).
Charcosset does not explicitly teach the limitation of instant claim 3 that particles are microparticles.
Schutt teaches the preparation of pharmaceutical formulations containing large diameter synthetic membrane vesicles, such as multivesicular liposomes (see entire document, particularly Abstract). The diameter of the vesicle is demonstrated to be on the micrometer scale (paragraphs [0056] and [0296] and Fig. 9). The vesicles can be used to incorporate many and varied therapeutic agents (paragraphs [0004] and [0115])), and the vesicles can be prepared via a continuous-flow diafiltration system wherein the pore size of cross-flow filtration modules can be chosen to retain large diameter vesicles (paragraphs [0288]-[0290]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to modify the process of Charcosset to produce micrometer-sized liposomes, as suggested by Schutt. One of ordinary skill in the art would have been motivated to do so in order to produce a liposome size that is suitable to encapsulate numerous and varied therapeutic agents, as suggested by Schutt. There is a reasonable expectation of success as Schutt teaches that large diameter liposomes can be produced with the use of cross-flow modules, and Charcosset similarly teaches that liposome size can be controlled in crossflow injection devices; Charcosset further teaches that the method can be used to prepare liposomes of varying compositions for pharmaceuticals (see “4. Conclusion” beginning at pg. 514).
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Charcosset as applied to claims 1-2, 4, 6-8, 11, 13-17, 19, 21-24, and 26-27 above, and further in view of Eun et al. (KR 20110104371 A, published September 22, 2011), hereafter “Eun”.
The teachings of Charcosset are described above. Charcosset does not teach the preparation of lipid nanoparticles comprising a non-aqueous solvent phase core.
Eun teaches a liposome comprising alcohol in the inner phase (core comprising a non-aqueous solvent) (see entire document, particularly abstract and claim 1). An inner alcoholic phase increases the encapsulation rate of drugs that are poorly soluble in water, but highly soluble in alcohol, enhancing the in vivo absorption rate (paragraphs [0001]-[0007]). Such liposomes can be used with a variety of drugs, including anticancer agents such as paclitaxel (paragraphs [0026] and [0066]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to modify the process of Charcosset to include an alcoholic solvent core in the liposomes, as suggested by Eun. One of ordinary skill in the art would have been motivated to do so in order to achieve increased encapsulation of poorly water-soluble drugs including anticancer agents, as suggested by Eun. There is a reasonable expectation of success as Charcosset teaches that the method can be used to prepare liposomes of varying compositions for pharmaceuticals (see “4. Conclusion” beginning at pg. 514).
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Charcosset as applied to claims 1-2, 4, 6-8, 11, 13-17, 19, 21-24, and 26-27 above, and further in view of Modi et al. (“Enhanced active liposomal loading of a poorly soluble ionizable drug using supersaturated drug solutions” Journal of Controlled Release 2012, 162, 330-339), hereafter “Modi”.
The teachings of Charcosset are described above. Regarding instant claim 20, Charcosset further teaches that unloaded liposomes without any active ingredient can be prepared (“3.1. Unloaded liposomes” beginning at pg. 512).
Charcosset does not teach the limitation of instant claim 20 that liposomes are loaded afterwards.
Modi teaches that liposomal drug loading can be achieved by either passive or active methods, and in active loading, drug internalization occurs into preformed liposomes (see entire document, particularly “1. Introduction”, paragraph 1). Active loading is the preferred method for optimizing loading of ionizable drugs in liposomes (Abstract) and has been proven to be more effective for achieving higher drug to lipid ratios compared to passive loading (“1. Introduction”, paragraph 1).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to modify the process of Charcosset to load the liposomes following formation, as suggested by Modi. One of ordinary skill in the art would have been motivated to do so in order to achieve a higher drug to lipid ratio and use a method preferred for loading ionizable drugs into liposomes, as suggested by Modi. There is a reasonable expectation of success as Charcosset teaches that liposomes can be produced unloaded, and the method can be used to prepare liposomes of varying compositions for pharmaceuticals (see “4. Conclusion” beginning at pg. 514).
Claims 28-29 are rejected under 35 U.S.C. 103 as being unpatentable over Charcosset as applied to claims 1-2, 4, 6-8, 11, 13-17, 19, 21-24, and 26-27 above, and further in view of Williams et al. (WO 2019/092461 A1, published May 16, 2019), hereafter “Williams”.
The teachings of Charcosset are described above. Charcosset does not teach the inclusion of a crossflow membrane apparatus with the specific structural limitations of instant claims 28 and 29.
Williams teaches a cross-flow apparatus for producing an emulsion or dispersion by dispersing a first phase in a second phase (see entire document, particularly abstract and claim 1). The cross-flow apparatus comprises an outer tubular sleeve provided with a first inlet at a first end; an emulsion outlet; and a second inlet, distal from and inclined relative to the first inlet; a tubular membrane provided with a plurality of pores and adapted to be positioned inside the tubular sleeve; and optionally an insert adapted to be located inside the tubular membrane, said insert comprising an inlet end and an outlet end, each of the inlet end and an outlet end being provided with chamfered region; the chamfered region is provided with a plurality of orifices and a furcation plate (abstract and claim 1). Williams further teaches that apparatus includes an insert (claim 2), that the first inlet is a continuous phase first inlet and the second inlet is a disperse phase inlet (claim 6), and that the disperse phase travels from outside the tubular membrane to inside (pg. 5, line 23-pg. 6, line 2). The apparatus is used in industries such as for generating pharmaceutical products (pg. 1, lines 14-20). The cross-flow assembly provides droplets with a good coefficient of variation at high throughput (pg. 1, lines 8-11).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to modify the process of Charcosset to include the crossflow apparatus of Williams. One of ordinary skill in the art would have been motivated to do so in order to include an apparatus that can provide a good coefficient of variation and high throughput when mixing phases, as suggested by Williams. There is a reasonable expectation of success as the apparatus of Williams can be used in the production of pharmaceutical products, and Charcosset teaches that cross-flow apparatuses are known in the art for use in ethanol injection methods to produce liposomes encapsulating pharmaceutical agents.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 4, 6-8, 11, 13-24, and 26-29 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 7, 10, 13, 18-19, 21, 26, 40, and 52 of copending Application No. 18/016,143 in view of Eun et al. (KR 20110104371 A, published September 22, 2011), hereafter “Eun” and Williams et al. (WO 2019/092461 A1, published May 16, 2019), hereafter “Williams”.
Both the instant claims and those of copending Application No. 18/016,143 recite the preparation of lipid vesicles of liposomes (known to have an aqueous core) or lipid nanoparticles (microscopic particles) by controlling provision of a first liquid phase to a membrane, the membrane defining a first plurality of apertures, and controlling provision of a second liquid phase to the membrane via the first plurality of apertures to form a mixture (lipid vesicle suspension). Both set of claims recite the same crossflow emulsification apparatus (compare copending claim 7 to instant claim 28). Both sets of claims recite that the lipid vesicles are produced by passive and active loading, and the inclusion of bioactive agents. The copending Application No. 18/016,143 recite a polydispersity index of <0.3, and thus it would be prima facie obvious to an ordinary skilled artisan to include an analytical characterization point at the end of step (ii) in order to measure the PDI.
The claims copending Application No. 18/016,143 do not recite lipid nanoparticles comprising a non-aqueous solvent phase core (instant claim 18). The claims copending Application No. 18/016,143 do not recite all of the structural limitations of the crossflow membrane recited in instant claim 29.
Eun teaches a liposome comprising alcohol in the inner phase (core comprising a non-aqueous solvent) (see entire document, particularly abstract and claim 1). An inner alcoholic phase increases the encapsulation rate of drugs that are poorly soluble in water, but highly soluble in alcohol, enhancing the in vivo absorption rate (paragraphs [0001]-[0007]). Such liposomes can be used with a variety of drugs, including anticancer agents such as paclitaxel (paragraphs [0026] and [0066]).
Williams teaches a cross-flow apparatus for producing an emulsion or dispersion by dispersing a first phase in a second phase (see entire document, particularly abstract and claim 1). The cross-flow apparatus comprises an outer tubular sleeve provided with a first inlet at a first end; an emulsion outlet; and a second inlet, distal from and inclined relative to the first inlet; a tubular membrane provided with a plurality of pores and adapted to be positioned inside the tubular sleeve; and optionally an insert adapted to be located inside the tubular membrane, said insert comprising an inlet end and an outlet end, each of the inlet end and an outlet end being provided with chamfered region; the chamfered region is provided with a plurality of orifices and a furcation plate (abstract and claim 1). Williams further teaches that apparatus includes an insert (claim 2), that the first inlet is a continuous phase first inlet and the second inlet is a disperse phase inlet (claim 6), and that the disperse phase travels from outside the tubular membrane to inside (pg. 5, line 23-pg. 6, line 2). The apparatus is used in industries such as for generating pharmaceutical products (pg. 1, lines 14-20). The cross-flow assembly provides droplets with a good coefficient of variation at high throughput (pg. 1, lines 8-11).
It would have been prima facie obvious to one of ordinary skill in the art to modify the process recited in copending Application No. 18/016,143 to include an alcoholic solvent core in the liposomes, as suggested by Eun. One of ordinary skill in the art would have been motivated to do so in order to achieve increased encapsulation of poorly water-soluble drugs including anticancer agents, as suggested by Eun. It would further have been prima facie obvious to one of ordinary skill in the art to modify the process recited in copending Application No. 18/016,143to include the crossflow apparatus of Williams. One of ordinary skill in the art would have been motivated to do so in order to include an apparatus that can provide a good coefficient of variation and high throughput in when mixing phases, as suggested by Williams.
Given the subject matter of the instant claims is obvious and substantially overlaps the subject matter of copending Application No. 18/016,143, the instant claims are rejected on the ground of nonstatutory double patenting. This is a provisional nonstatutory double patenting rejection.
Claims 1, 4, 6-8, 11, 22-24, and 28-29 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 5-6, 9, 12, 15, 18, 20, 22, 40, and 78 of copending Application No. 18/018,078 in view of Williams et al. (WO 2019/092461 A1, published May 16, 2019), hereafter “Williams”.
Both the instant claims and those of copending Application No. 18/018,078 recite a continuous process for the preparation of solid particles by controlling provision of a first liquid phase to a membrane, the membrane defining a first plurality of apertures (pores), and controlling provision of a second liquid phase to the membrane via crossflow. Both set of claims recite the same crossflow emulsification apparatus (compare copending claim 9 to instant claim 28) and inclusion of a bioactive agent.
The claims copending Application No. 18/018,078 do not recite all of the structural limitations of the crossflow membrane recited in instant claim 29.
Williams teaches a cross-flow apparatus for producing an emulsion or dispersion by dispersing a first phase in a second phase (see entire document, particularly abstract and claim 1). The cross-flow apparatus comprises an outer tubular sleeve provided with a first inlet at a first end; an emulsion outlet; and a second inlet, distal from and inclined relative to the first inlet; a tubular membrane provided with a plurality of pores and adapted to be positioned inside the tubular sleeve; and optionally an insert adapted to be located inside the tubular membrane, said insert comprising an inlet end and an outlet end, each of the inlet end and an outlet end being provided with chamfered region; the chamfered region is provided with a plurality of orifices and a furcation plate (abstract and claim 1). Williams further teaches that apparatus includes an insert (claim 2), that the first inlet is a continuous phase first inlet and the second inlet is a disperse phase inlet (claim 6), and that the disperse phase travels from outside the tubular membrane to inside (pg. 5, line 23-pg. 6, line 2). The apparatus is used in industries such as for generating pharmaceutical products (pg. 1, lines 14-20). The cross-flow assembly provides droplets with a good coefficient of variation at high throughput (pg. 1, lines 8-11).
It would have been prima facie obvious to one of ordinary skill in the art to modify the process recited in copending Application No. 18/018,078 to include the crossflow apparatus of Williams. One of ordinary skill in the art would have been motivated to do so in order to include an apparatus that can provide a good coefficient of variation and high throughput in when mixing phases, as suggested by Williams.
Given the subject matter of the instant claims is obvious and substantially overlaps the subject matter of copending Application No. 18/018,078, the instant claims are rejected on the ground of nonstatutory double patenting. This is a provisional nonstatutory double patenting rejection.
Claims 1, 4, 6-8, 11, 22-24, and 28-29 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6, 10-11, 15, 17, 24, 36, and 56 of copending Application No. 18/833,499 in view of Williams et al. (WO 2019/092461 A1, published May 16, 2019), hereafter “Williams”.
Both the instant claims and those of copending Application No. 18/833,499 recite the preparation of solid particles by controlling provision of a first liquid phase to a membrane, the membrane defining a first plurality of pores, and controlling provision of a second liquid phase to the membrane to produce a mixture. Both sets of claims recite a crossflow emulsification apparatus and inclusion of a bioactive agent.
The claims copending Application No. 18/833,499 do not recite all of the structural limitations of the crossflow membrane recited in instant claims 28 and 29.
Williams teaches a cross-flow apparatus for producing an emulsion or dispersion by dispersing a first phase in a second phase (see entire document, particularly abstract and claim 1). The cross-flow apparatus comprises an outer tubular sleeve provided with a first inlet at a first end; an emulsion outlet; and a second inlet, distal from and inclined relative to the first inlet; a tubular membrane provided with a plurality of pores and adapted to be positioned inside the tubular sleeve; and optionally an insert adapted to be located inside the tubular membrane, said insert comprising an inlet end and an outlet end, each of the inlet end and an outlet end being provided with chamfered region; the chamfered region is provided with a plurality of orifices and a furcation plate (abstract and claim 1). Williams further teaches that apparatus includes an insert (claim 2), that the first inlet is a continuous phase first inlet and the second inlet is a disperse phase inlet (claim 6), and that the disperse phase travels from outside the tubular membrane to inside (pg. 5, line 23-pg. 6, line 2). The apparatus is used in industries such as for generating pharmaceutical products (pg. 1, lines 14-20). The cross-flow assembly provides droplets with a good coefficient of variation at high throughput (pg. 1, lines 8-11).
It would have been prima facie obvious to one of ordinary skill in the art to modify the process recited in copending Application No. 18/833,499 to include the crossflow apparatus of Williams. One of ordinary skill in the art would have been motivated to do so in order to include an apparatus that can provide a good coefficient of variation and high throughput in when mixing phases, as suggested by Williams.
Given the subject matter of the instant claims is obvious and substantially overlaps the subject matter of copending Application No. 18/833,499, the instant claims are rejected on the ground of nonstatutory double patenting. This is a provisional nonstatutory double patenting rejection.
Conclusion
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/BETHANY P BARHAM/Supervisory Patent Examiner, Art Unit 1611
/J.M.K./Examiner, Art Unit 1611
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