DETAILED ACTION
Previous Rejections
Applicant’s arguments, filed October 15, 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 Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.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.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on October 15, 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Status
Claims 40 – 44 are newly added.
Claims 18, 19, 21, 24, 25, 28, 29, 31-33, 35, and 36 are withdrawn.
Claims 1, 2, 4, 9, 12, 13, 15 – 17, and 40 – 44 are examined here-in.
Claim Rejections - 35 USC § 103 (New, Necessitated by Amendment)
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 non-obviousness.
Claims 1, 2, 4, 9, 12, 13, 15-17, and 40 – 44 are rejected under 35 U.S.C. 103 as being unpatentable over Abra (WO 01/05372 A2, of record) in view of Agnew (H. Agnew & M. Alviar-Agnew “Freezing point depression and boiling point elevation” Ch 13.9 LibreTexts, of record) and further in view of Cabral-Lilly (US 10,028,912 B2).
Abra teaches a composition with a liposome, an inner medium, and an external medium that has improved protection from damage associated with freezing and thawing (abstract). Abra emphasizes that liposome stability is an important parameter for liposomal formulations (page 1 lines 23 – 27).
Abra teaches that each liposome in the composition has an entrapped aqueous medium and is suspended in an external medium which contains a salt and a cryoprotectant (page 3 lines 7-11). Abra teaches that the external medium has a higher osmolarity than the inner medium (page 3 lines 11-12). Abra teaches the cryoprotectant can be a sugar, glycerol, or polyethylene glycol (page 3 lines 15 – 22, page 25 lines 14 – 17).
In Example 2, Abra shows a composition with liposomes, a solution with 5% w/v sucrose and 0.9% w/v NaCl as an external medium, and an internal aqueous medium of 0.9% w/v NaCl, without sucrose (page 7 lines 16-22).
Abra teaches phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, and phosphatidylserine as lipids suitable for a liposome (page 20 lines 22-23).
Abra does not teach the freezing points of the internal and external media, the relative amount of composition encapsulated in the liposomes, or that an excipient is 30 to 60% v/v of the external medium.
Agnew teaches a missing element of Abra.
Agnew teaches “A solution will have a lower freezing point than a pure solvent” because “the solute-solvent interactions prevent the solvent from going into the solid phase” (page 1).
Agnew’s teachings suggest that a medium with 5% w/v sucrose and 0.9% w/v NaCl will have a lower freezing point than a medium with 0.9% w/v NaCl because in the first case there is more solute in the solution, thus lowering the freezing temperature.
The combination of Abra and Agnew is prima facie obvious as combining prior art elements according to known methods to yield predictable results (MPEP 2143(i)(a)). Abra teaches a liposomal composition with aqueous internal and external media, where the external medium has increased osmolarity than the internal medium, i.e. Abra teaches each of the claimed components of the composition. A person of ordinary skill in the art would recognize that the increased osmolarity of the external medium relative to the internal medium would necessarily result in a depressed freezing temperature for the external medium relative to the internal medium, as taught generally by Agnew. The combination of Abra and Agnew is prima facie obvious as combining known ingredients according to known methods to yield predictable results (MPEP 2143(I)(a)).
The combination of Abra and Agnew does not teach an excipient in the amount of 30 to 60% v/v of the external medium.
Cabral-Lilly teaches the missing element of the combination of Abra and Agnew.
Cabral-Lilly teaches a composition which contains liposomes in an external medium, wherein the external medium includes a cryoprotectant (column 4 lines 18 – 25, column 8 lines 62 - 65). Cabral-Lilly suggests that including cryoprotectant in the external medium facilitates composition stability (column 4 lines 18 – 25).
Cabral-Lilly teaches the inclusion of a cryoprotectant in the amount of 100 to 500 mM (column 8 line 62 to column 9 line 12).
The combination of Abra, Agnew, and Cabral-Lilly is prima facie obvious as combining prior art elements according to known methods to yield predictable results (MPEP 2143(i)(a)). A person of ordinary skill in the art would be motivated to modify the combination of Abra and Agnew to include the amount of cryoprotectant as taught by Cabral-Lilly because an increased amount of solute will drive freezing point depression, as taught by Agnew. Furthermore, Cabral-Lilly teaches that higher concentration of cryoprotectant in the external medium as compared to the internal medium of the liposome is desirable, suggesting that this difference functions to stabilize the composition (column 2 lines 9 – 10, column 8 line 62 – column 9 line 14). Cabral-Lilly’s teachings for stabilizing liposomal compositions are in agreement with Abra’s teachings that liposome stability is paramount (page 1 lines 23 – 27).
The combination of Abra’s teachings of a liposomal solution with an external medium of which contains a higher osmolarity than the internal encapsulated medium (page 7 lines 16-22) with Agnew’s teachings about and increased amount of solute resulting in a lower freezing point (page 1), and further combined with Cabral-Lilly’s teaching to include cryoprotectant in the amount of 100 to 500 mM (column 8 line 62 to column 9 line 12) reads on instant claim 1. Cabral-Lilly’s teaching for cryoprotectant in the amount of 100 to 500 mM (column 8 line 62 to column 9 line 12) overlaps on the instantly claimed amount of 30 to 60% v/v for cases where the cryoprotectant has a molecular weight of 600 to 6,000 g/mol, as shown in the calculation below.
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For 30% v/v as recited in instant claim 1, with Cabral-Lilly’s molarity of 100 mM and an estimated density of solution of 1 g/cm3, the calculation becomes:
30
=
0.1
m
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Which calculates to a molar mass of solute of 3,000 g/mol.
For 30% v/v as recited in instant claim 1, with Cabral-Lilly’s molarity of 500 mM and an estimated density of solution of 1 g/cm3, the calculation becomes:
30
=
0.5
m
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Which calculates to a molar mass of solute of 600 g/mol.
For 60% v/v as recited in instant claim 1, with Cabral-Lilly’s molarity of 100 mM and an estimated density of solution of 1 g/cm3, the calculation becomes:
60
=
0.1
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Which calculates to a molar mass of solute of 6,000 g/mol.
For 60% v/v as recited in instant claim 1, with Cabral-Lilly’s molarity of 500 mM and an estimated density of solution of 1 g/cm3, the calculation becomes:
60
=
0.5
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Which calculates to a molar mass of solute of 1,200 g/mol.
Therefore, Cabral-Lilly’s teaching for cryoprotectant in the amount of 100 to 500 mM (column 8 line 62 to column 9 line 12) overlaps on the instantly claimed amount of 30 to 60% v/v for cases where the cryoprotectant has a molecular weight of 600 to 6,000 g/mol, as shown in the calculations above, reading on instant claim 1. Claimed ranges that overlap with teachings of the prior art are prima facie obvious according to MPEP 2144.05(i).
Abra’s teaching of phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, and phosphatidylserine as lipids suitable for a liposome (page 20 lines 22-23) reads on claim 2 of the instant application.
Abra’s teaching that the cryoprotectant can be a sugar, glycerol, or polyethylene glycol (page 3 lines 15 – 22, page 25 lines 14 – 17) and example of NaCl and sucrose in the external medium (page 7 lines 16-22) reads on claim 4 of the instant application.
In one example, Abra teaches that the volume of external medium is 85% of the total volume of the solution (page 30 line 8), therefore the liposomes and internal medium would necessarily make up the remaining 15% volume of the total solution. Although Abra does not explicitly teach that the encapsulated volume is a certain amount relative to the total volume of the composition, it would be within the expertise of a person of ordinary skill in the art to perform routine experimentation to arrive at the claimed range of 20 to 50% as recited in instant claim 9. Routine experimentation is prima facie obvious according to MPEP 2144.05(II)(a). Furthermore, changes in proportion do not render an invention patentably distinct from prior art according to MPEP 2144.04(IV)(a). In this case, Abra teaches the internal medium is less than 15% volume of the total composition which is not within the claimed range of 20 to 50% recited in instant claim 9 but is effectively merely a change in proportions.
Agnew teaches the following formula to calculate the freezing point decrease of a solution:
∆
T
=
k
f
*
m
*
i
Where
∆
T
is the change in temperature, kf is the freezing point depression constant (for water 1.86 °C/m), m is the molality of the solution, and i is the number of particles formed when the particle dissolves (page 3).
For Abra’s inner medium, 0.9% w/v NaCl aqueous solution the freezing point is -0.3 °C (NaCl MW 58.4 g/mol, density 2.16 g/mL, i = 2). For Abra’s external medium, 5% w/v sucrose and 0.9% w/v NaCl aqueous solution the freezing point is approximately - 0.5 °C (NaCl MW 58.4 g/mol, NaCl density 2.16 g/mL, NaCl i = 2, sucrose MW 342.3 g/mol, sucrose density 1.58 g/mL, sucrose i = 1). A freezing point of -0.3 °C for the internal medium overlaps on the claimed range of between – 2 °C and 0 °C recited in instant claim 12. Claimed ranges that overlap with the prior art are prima facie obvious according to MPEP 2144.05I(I).
Abra teaches that a preferred concentration of NaCl in the external medium is greater than 3% w/v (page 16 line 5) and explains that with higher NaCl concentrations, liposomes were more protected from freeze/thaw damage (page 11 lines 8-9). The Examiner has calculated that 7% w/v NaCl solution would have a freezing point of – 10 °C. Given Abra’s teaching that a preferred concentration of NaCl in the external medium is greater than 3% w/v (page 16 line 5) and teachings that higher NaCl concentrations lead to greater protection from freeze/thaw (page 11 lines 8-9) a person of ordinary skill in the art would have been motivated to optimize the amount of solute in external medium to reach a desired freezing point, such as that of – 20 °C to – 10 °C as recited in instant claim 13. Routine optimization and experimentation is prima facie obvious according to MPEP 2144.05(II)(a).
Instant claim 15 recites “The composition of claim 1, wherein the encapsulated first volume is configured to form a plurality of ice particles when the composition is cooled to a predetermined temperature”. The limitation of forming ice particles at a predetermined temperature is interpreted as a product-by-process limitation. Product-by-process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps, thus the determination of patentability is based on the product itself (MPEP 2113). The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process. In the instant case, Abra’s composition of liposomes encapsulating an internal medium and suspended in an external medium reads on the composition of claim 15 because freezing is an inherent property of solutions. Therefore, Abra’s composition of liposomes with an internal and external medium will necessarily form ice crystals at a freezing point specific to the solutions. As such, the patentability of the instant composition does not depend on its method of production, and the Applicant’s limitation regarding the process of forming ice particles at a predetermined temperature is not patentable, in view of Abra.
Instant claim 16 recites the ice particles comprise between about 30% and 50% by weight of the total composition. A person of ordinary skill in the art would have the expertise to formulate the claimed composition with the ice particles in the claimed range. Routine experimentation is prima facie obvious according to MPEP 2144.05(II)(a). Furthermore, changes in proportion do not render an invention patentably distinct from prior art according to MPEP 2144.04(IV)(a). In this instance, ice particles in the amount of 30 to 50% by weight of the total composition is a proportion that does not render the claimed invention patentably distinct from the prior art.
As discussed above with regards to claim 13, a person of ordinary skill in the art is able to perform routine calculations to determine the solute required for a given freezing point, therefore instant claim 17’s recitation of temperature between – 20 °C and – 5 °C is prima facie obvious (MPEP 2144.05(II)(a).
Abra’s teaching that the cryoprotectant can be a sugar, glycerol, or polyethylene glycol (page 3 lines 15 – 22, page 25 lines 14 – 17) reads on claims 40 and 41 of the instant application.
Cabral-Lilly’s teaching for cryoprotectant in the amount of 100 to 500 mM (column 8 line 62 to column 9 line 12) overlaps on the instantly claimed amount of 30 to 60% v/v for cases where the cryoprotectant has a molecular weight of 600 to 6,000 g/mol, as shown in the calculations above, reading on instant claim 1. With regards to the recitations of 30 to 50% v/v and 40 to 50% v/v as recited in instant claims 42 – 44, Cabral-Lilly’s teaching for cryoprotectant in the amount of 100 to 500 mM (column 8 line 62 to column 9 line 12) overlaps on the instantly claimed amount of 30 to 50% v/v for cases where the cryoprotectant has a molecular weight of 600 to 5,000 g/mol and 40 to 50% v/v for cases where the cryoprotectant has a molecular weight of 800 to 5,000 g/mol as recited in instant claims 42 – 44.
The combination of Abra’s teaching that the cryoprotectant can be polyethylene glycol (page 3 lines 15 – 22, page 25 lines 14 – 17) and Cabral-Lilly’s teaching for cryoprotectant in the amount of 100 to 500 mM reads on claims 44.
Examiner’s Reply to Attorney Arguments Dated October 15, 2025
Applicant argues that the combination of Abra and Agnew does not teach the limitations of the amended claim (Remarks page 9). This argument is moot because the new ground of rejection addresses the claims as amended.
Double Patenting
The judicially created doctrine for non-statutory double patenting rejections has been described in detail in the previous action.
Double Patenting over 18/569,188
Claims 1, 2, and 4 are provisionally rejected on the ground of non-statutory double patenting as being unpatentable over claims 1-4, 7-9, 12 of copending Application No. 18/569,188 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because: instant claim 1 is drawn to a composition comprising water, at least one liposome, and at least one excipient.
Conflicting claim 1 is drawn to a composition comprising water, a non-water-soluble substance, and an excipient.
The instant and conflicting claims differ because conflicting claim 1 a non-water-soluble substance rather than a liposome, as recited in instant claim 1. However, conflicting claims 2-4 and 7 recite the non-water-soluble substance is a liposome.
Conflicting claims 8 and 9 recite the lipids are phospholipids selected from the group of DSPC, DPSM, DPPC, DCP, soy PC, PE, PS, PG, and a combination thereof, reading on instant claim 2.
Conflicting claims 12 recites the excipient is selected from the group of a salt, an ion, Lactated Ringer’s solution, a sugar, a biocompatible surfactant, a polyol, and a combination thereof, reading on instant claim 4.
This is a provisional non-statutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Examiner’s Reply to Attorney Arguments Dated October 15, 2025
Applicant does not argue against the non-statutory double patenting rejection, rather requests the rejection be held in abeyance (Remarks page 12). According to MPEP 804(1), a complete response to a non-statutory double patenting rejection is either a showing that the claims subject to the rejection are patentably distinct from the reference claim or the filing of a terminal disclaimer. The Examiner notes that Applicant’s argument is not a showing that the claims are patentably distinct from the reference claims. As such, the non-statutory double patenting rejection is maintained.
Conclusion
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.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Toriana N. Vigil whose telephone number is (571)270-7549. The examiner can normally be reached Monday - Friday 9:00 a.m. - 5:00 p.m. EST.
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/TORIANA N. VIGIL/Examiner, Art Unit 1612
/FREDERICK F KRASS/Supervisory Patent Examiner, Art Unit 1612