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 .
Objections/Rejections Withdrawn
Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn.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, and constitute the complete set presently being applied to the instant application.
Response to Arguments
Applicant’s arguments, see Pg 6-8, filed 4/13/2026, with respect to the rejection(s) of claim(s) under 35 U.S.C. 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of the amended claims.
Applicant’s arguments, see Pg 8-9, filed 4/13/2026, with respect to the double patenting rejections have been fully considered and are persuasive. The rejections have been withdrawn.
Priority
The instant application is a 371 of PCT/IB2020/054346, which claims foreign priority to PT115500 with a filing date of 5/7/19. The priority date of 5/7/19 based on PT115500 is acknowledged.
Claim Status
Claims 1, 3, 7-9, 13, and 15-18 are pending. Claims 2, 4-6, 10-12, 14, and 19-23 are cancelled. Claim 1 is currently amended.
Maintained/Modified - Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3, 7-9, 13, and 15-18 are rejected under 35 U.S.C. 103 as being unpatentable Niyikiza et al. (US2016/0228573 A1, published 8/11/16, cited on IDS filed 11/5/21), Geldhof et al. (WO2017/223135 A1, published 12/28/17, cited on IDS filed 11/5/21), and Nogueira et al. (Peptide Anchor for Folate-Targeted Liposomal Delivery. Biomacromolecules. 2015 Sep 14;16(9):2904-10.).
Niyikiza teaches a liposomal antifolate composition comprising a medium comprising a liposome including an interior space; a bioactive antifolate agent (active ingredient) disposed within said interior space; a PEG attached to an exterior of the liposome; and a targeting moiety (targeting agent) comprising a protein with specific affinity for at least one folate receptor, said targeting moiety attached to at least one of the PEG and the exterior of the liposome ([0008]).
Niyikiza teaches that the liposomes may contain bioactive agents (active ingredients) that are anti-cancer (antineoplastic) agents ([0007]). In some embodiments, the liposomes may contain methotrexate as the bioactive agent (active ingredient [0016, 0098]).
Example 1 of Niyikiza describes a method of preparing liposomes and encapsulating active ingredient(s) in them. The lipid components of the liposome membrane are weighed out and combined as a concentrated solution in ethanol at a temperature of around 65°C; in this example, the lipids used are hydrogenated soy phosphatidyl choline, cholesterol, DSPE-PEG-2000 (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000]), PEG-DSPE-malemide and PEG-DSPE-FITC (mixing hydrophobic molecules of phospholipids and a steroid with ethanol). Pemetrexed (active ingredient) is dissolved in an aqueous buffer and heated to 65°C. The ethanolic lipid solution is injected into the Pemetrexed solution using a small-bore needle. During this step, the drug solution is well stirred using a magnetic stirrer. The mixing is performed at an elevated temperature (63-72°C) to ensure that the lipids are in the liquid crystalline state, as opposed to the gel state that they attain at temperatures below the lipid transition temperature Tm=51-54°C. As a result, the lipids are hydrated and form multiple bilayer (multilamellar) vesicles (MLV) containing pemetrexed in the aqueous core ([0152]).
Although Niyikiza does not explicitly teach evaporation of the ethanol after formation of the liposomes, one skilled in the art would recognize that by mixing and heating the ethanolic-aqueous solution post-injection would result in the evaporation of ethanol. Thus, Niyikiza implicitly teaches this step.
Niyikiza further indicates that extra-liposomal Pemetrexed is removed using dialysis or tangential flow filtration against a suitable buffer ([0155]).
Niyikiza does not explicitly teach that the ethanolic/aqueous phase volume ratio is 1:1 nor that the ethanol has a concentration between 40-60% relative to initial aqueous volume. Further, Niyikiza does not teach the targeting agent SEQ ID NO: 1 nor its inclusion in the aqueous phase. Niyikiza also does not teach a separate step wherein the liposomal dispersion is diluted 1-10-fold in a further diluted aqueous phase.
Geldhof teaches a method of producing lipid nanoparticles (liposomes; Pg 6, lines 1-9), including the steps of providing a lower alkanol solution (ethanol) including lipids, providing an aqueous solution (aqueous phase), and injecting the lower alkanol solution to the aqueous solution to produce lipid nanoparticles (Pg 1, lines 21-25).
Geldhof teaches that the term "lower alkanol" refers to an alcohol with 6 or fewer carbon atoms. Examples of lower alkanols include but are not limited to methanol, ethanol, propanol, pentanol, their isomers, and mixtures thereof (Pg 4, lines 17-19). The MPEP states that the selection of known materials based on their suitability for their intended uses is prima facie obvious. See MPEP § 2144.07. "Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).
Geldhof further teaches that the lipids can be phospholipids (Pg 12, lines 25-33). Geldhof notes that using phospholipids to make nanoparticles can produce limit size lipid nanoparticles that include a lipid bilayer surrounding an aqueous core or a hydrophobic core. The ability to generate an aqueous core or a hydrophobic core is advantageous in that it can accommodate a wider range of encapsulants depending on their solubility.
Geldhof teaches that in some embodiments the volume of the lower alkanol solution (ethanol) injected is between 10% and 100% of the volume of the aqueous solution (Pg 7, lines 16-20; a volume of 100% of the aqueous solution would necessarily result in a 1:1 volume ratio of the ethanolic to aqueous phase as well as constitute an ethanol concentration of 50% relative to the initial aqueous volume). Geldhof states that the greater the volume of the lower alkanol solution relative to the aqueous solution, the more concentrated the suspension of lipid nanoparticles will be upon completion of injection (Pg 7, lines 23-24).
Nogueira teaches peptide anchors for folate-targeted liposomal delivery (Title). Per Nogueira, folate receptors are abundantly overexpressed in chronically activated macrophages and in most cancer cells. To effectively target such cells without causing self-aggregation of folic acid at the liposome surface, Nogueira targeting peptides consisting of a hydrophobic fragment of surfactant protein D linked to folate (targeting agent; Abstract; Pg 2905, left column, second paragraph). Nogueira teaches one such folic acid linked peptide sequence consists of folic acid-DRDDQAAWFSQY or “SP-DS3” (Figure 1), which is identical to the elected SEQ ID NO: 1. Compared to other folic acid-linked peptides, SP-DS3 demonstrated a deeper insertion into the liposome bilayer (Pg 2907, left column, “Interaction of Peptide with Liposomes,” first paragraph; Figure 1C). In the process of making liposomes, SP-DS3 is added to the PBS buffer (aqueous phase; Pg 2905, “Liposome preparation,” left column).
Thus, regarding claims 1, 3, 7, and 8, Niyikiza teaches a method of preparing liposomes and encapsulating active ingredients in them that consists of generating an ethanolic solution comprising phospholipids and cholesterol, injecting the ethanolic solution into an aqueous solution comprising an active ingredient at a temperature of about 50-80°C while stirring, evaporating the ethanol, and removing excess active ingredient that is not encapsulated by tangential flow filtration. Geldhof teaches a method of making liposomes that consists of providing an aqueous solution, providing an ethanolic solution including lipids, and injecting it into the aqueous solution to produce nanoparticles that encapsulate therapeutics; moreover, Geldhof teaches the relative volumes of ethanol and aqueous phases to use in order to generate a more concentrated liposomal dispersion. Therefore, it would be prima facie obvious to use the ratios of Geldhof in the method taught by Niyikiza in order to generate a more concentrated dispersion of liposomes, which would allow for dilution of the dispersion to a desired concentration prior to downstream or subsequent applications. Practically, one skilled in the art would be motivated to use such a volumetric ratio in order to minimize the work required to accumulate a high amount of liposomes. One skilled in the art would have a reasonable expectation of success as Geldhof established the parameters needed to achieve a concentrated liposomal dispersion.
Further, Nogueira teaches a method of making liposomes designed to target cancer cells by incorporating the elected SEQ ID NO: 1 into the aqueous phase. Therefore, it would be prima facie obvious to add the elected SEQ ID NO: 1 into the aqueous phase of the method taught by Niyikiza and Geldhof. One skilled in the art would be motivated to do so and have a reasonable expectation of success as Nogueira demonstrated successful incorporation of SEQ ID NO: 1 into liposomes by performing this step.
Finally, Niyikiza, Geldhof, and Nogueira do not teach a step wherein the liposomal dispersion is diluted 1-10-fold in a further diluted aqueous phase. However, one skilled in the art would recognize that the concentration of the liposomal dispersion produced by the above method may not necessarily be the desired concentration and achieving the desired concentration would require dilution of the dispersion. In particular, Geldhof teaches administering liposomes formed from the method of making to individuals in need thereof (Formulations, starting Pg 32), which may require a certain concentration more dilute than what is produced. Moreover, as the method includes a step wherein the ethanol injected into the system is evaporated, meaning that the resulting liposomal dispersion exists in the aqueous phase/buffer, it would be obvious to dilute the dispersion in a further diluted aqueous phase.
Regarding claim 9, Niyikiza teaches that the liposomes may contain bioactive agents (active ingredients) that are anti-cancer (antineoplastic) agents ([0007]). In some embodiments, the liposomes may contain methotrexate as the bioactive agent (active ingredient [0016, 0098]). The instant specification discloses that methotrexate is negatively charged at about pH 4-7 (see [0041]).
Regarding claim 13, Geldhof also teaches that in some embodiments the aqueous solution further includes a buffer such as PBS (Pg 2, lines 11-13).
Regarding claim 15, Geldhof teaches that in some instances, the phospholipids in the ethanolic phase can be 1,2-Dioleoyl-sn-glycero-3-phosphatidylethanolamine (DOPE; Pg 13, lines 1-22).
Regarding claims 16-18, Geldhof teaches that in some embodiments, polyethylene glycol (PEG) is included as part of the lipid components in the lower alkanol solution (Pg 23 line 20 – Pg 24 line 11). PEG can be included in nanoparticles to enhance their delivery (stealth agent; Pg 24 line 39 – Pg 25 line 2). The instant specification teaches that PEG is a stealth agent (see [0045]). In some embodiments, PEG is a PEG-modified lipid (PEG bound to a phospholipid; Pg 14, line 1).
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/SARA E KONOPELSKI SNAVELY/Examiner, Art Unit 1658
/Melissa L Fisher/Supervisory Patent Examiner, Art Unit 1658
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