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 .
Acknowledgement of Receipt
Applicant’s Response, filed 6/8/2026, in reply to the Office Action mailed 3/10/2026, is acknowledged and has been entered. Claims 1, 11 and 12 have been amended. Claims 1-6 and 13-20 are pending, of which claims 14-20 are withdrawn from consideration at this time as being drawn to a non-elected invention. Claims 1-6 and 8-13 encompass the elected invention and are examined herein on the merits for patentability.
Response to Arguments
Applicant’s arguments have been fully considered. Any rejection not reiterated herein has been withdrawn. New grounds for rejection are set forth herein, necessitated by claim amendment.
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.
Claim(s) 1, 5, 6 and 13 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Chen et al. (Chem. Commun., 2015, 51, 4681).
Chen discloses the potential application of artemether as a novel sonosensitizer for sonodynamic therapy (SDT) was explored and illustrated for the first time. In addition, liposome-encapsulated artemether exhibited significantly enhanced sonodynamic anticancer activity. Our findings indicated that artemisinin derivatives may serve as a new kind of sonosensitizer for SDT (page 4681).
The liposome-encapsulated artemether (LEA) was prepared by a conventional thin-film hydration method. Generally, the chloroform solution of artemether, soybean lecithin, cholesterol and vitamin E (mass ratio = 10:80:20:0.5) was evaporated to form a lipid film, and then the film was hydrated with PBS at 30 1C for 2 h. The resultant suspension was sonicated for 10 min to form liposomes (page 4682).
Accordingly, relative to 100 parts by weight of a lipid, a content of stabilizer is within the range of 20 to 100 parts by weight (25 parts cholesterol relative to lipid), and a content of the acoustic-induced deformation material is within the range of 1 to 15 parts by weight (12.5 parts artemether relative to lipid).
With regard to the limitation wherein the acoustic-induced deformation material is deformed under an acoustic wave of a characteristic response frequency for the acoustic-induced deformation material, and the characteristic response frequency is 0.01MHz to 50MHz, it is noted that Chen’s composition meets the structural limitations of the instant claims, accordingly it is interpreted that the composition would necessarily be capable of achieving the claimed functional properties.
With regard to the limitation wherein the acoustic-induced deformation material is deformed under an acoustic wave of a characteristic response frequency for the acoustic-induced deformation material, and the characteristic response frequency is 0.01MHz to 50MHz, it is noted that Chen’s composition meets the structural limitations of the instant claims, accordingly it is interpreted that the composition would necessarily be capable of achieving the claimed functional properties.
“Products of identical chemical composition cannot have mutually exclusive properties.” A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure or composition as that which is claimed, the properties applicant discloses and/or claims are necessarily present. See In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). The “discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” See Atlas Power Co. v. Ireco Inc., 51 USPQ 2d 1943, 1947 (Fed. Cir. 1999). Therefore, merely claiming a new use, new function, or new property, which is inherently present in the prior art does not make the claim patentable. See In re Best, 195 USPQ 430, 433 (CCPA 1977), and MPEP § 2112.
Claim(s) 1, 4-6 and 11-13 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Parashar et al. (Drug Deliv, 2016; 23(1), 123–129).
Parashar discloses an artemether and lumefantrine co-loaded injectable nanostructured lipidcarriers (NLCs) formulation. Artemether and lumefantrine co-loaded NLCs had ahydrodynamic diameter of 145 nm with the surface charge of 66 mV. Due to the lipophilicnature of both antimalarial drugs, both single drugs-loaded and co-loaded NLCs have shownhigh encapsulation efficiency, which is 84% for artemether and 79% for lumefantrine (page 123).
In Table 1, compositions of the formulations are set forth including ARM-NLC45 which contains 75 parts by weight of a polyoxypropylene polyoxyethylene block copolymer stabilizer (Pluronic) relative to 100 parts by weight of lipid, and 6 parts by weight arthemeter relative to 100 parts by weight of lipid.
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With regard to the intended use of the composition for ultrasound contrast,
it is noted that the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. See In re Casey, 152 USPQ 235 (CCPA 1967) and In re Otto, 136 USPQ 458, 459 (CCPA 1963).
With regard to the limitation wherein the acoustic-induced deformation material is deformed under an acoustic wave of a characteristic response frequency for the acoustic-induced deformation material, and the characteristic response frequency is 0.01MHz to 50MHz, it is noted that Chen’s composition meets the structural limitations of the instant claims, accordingly it is interpreted that the composition would necessarily be capable of achieving the claimed functional properties.
“Products of identical chemical composition cannot have mutually exclusive properties.” A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure or composition as that which is claimed, the properties applicant discloses and/or claims are necessarily present. See In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). The “discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” See Atlas Power Co. v. Ireco Inc., 51 USPQ 2d 1943, 1947 (Fed. Cir. 1999). Therefore, merely claiming a new use, new function, or new property, which is inherently present in the prior art does not make the claim patentable. See In re Best, 195 USPQ 430, 433 (CCPA 1977), and MPEP § 2112.
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.
Claim(s) 1-6, 8, 9 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. (Chem. Commun., 2015, 51, 4681) in view of Katz et al. (US 2020/0129434).
Chen teaches the potential application of artemether as a novel sonosensitizer for sonodynamic therapy (SDT) was explored and illustrated for the first time. In addition, liposome-encapsulated artemether exhibited significantly enhanced sonodynamic anticancer activity. Our findings indicated that artemisinin derivatives may serve as a new kind of sonosensitizer for SDT (page 4681).
The liposome-encapsulated artemether (LEA) was prepared by a conventional thin-film hydration method. Generally, the chloroform solution of artemether, soybean lecithin, cholesterol and vitamin E (mass ratio = 10:80:20:0.5) was evaporated to form a lipid film, and then the film was hydrated with PBS at 30 1C for 2 h. The resultant suspension was sonicated for 10 min to form liposomes (page 4682).
Accordingly, relative to 100 parts by weight of a lipid, a content of stabilizer is within the range of 20 to 100 parts by weight (25 parts cholesterol relative to lipid), and a content of the acoustic-induced deformation material is within the range of 1 to 15 parts by weight (12.5 parts artemether relative to lipid).
With regard to the limitation wherein the acoustic-induced deformation material is deformed under an acoustic wave of a characteristic response frequency for the acoustic-induced deformation material, and the characteristic response frequency is 0.01MHz to 50MHz, it is noted that Chen’s composition meets the structural limitations of the instant claims, accordingly it is interpreted that the composition would necessarily be capable of achieving the claimed functional properties.
“Products of identical chemical composition cannot have mutually exclusive properties.” A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure or composition as that which is claimed, the properties applicant discloses and/or claims are necessarily present. See In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). The “discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” See Atlas Power Co. v. Ireco Inc., 51 USPQ 2d 1943, 1947 (Fed. Cir. 1999). Therefore, merely claiming a new use, new function, or new property, which is inherently present in the prior art does not make the claim patentable. See In re Best, 195 USPQ 430, 433 (CCPA 1977), and MPEP § 2112.
With regard to claims 2-3, Chen does not specifically teach wherein relative to 100 parts by weight of the lipid, the content of the stabilizer is 30 to 60 parts by weight, and the content of the acoustic-induced deformation material is 3 to 12 parts by weight; or the content of the stabilizer is 42 to 50 parts by weight, and the content of the acoustic-induced deformation material is 4 to 10 parts by weight.
Katz teaches compositions comprising liposomes comprises cholesterol, phosphatidyl phosphoric acid and phosphatidyl choline, as well as liposomes comprising a drug or imaging agent and a peptide for targeting to the brain (abstract).
According to a first aspect, there is provided a composition comprising a liposome, the liposome comprises 30 to 50% cholesterol, 5 to 20% phosphatidyl phosphoric acid and 40 to 60% phosphatidyl choline, by molarity (paragraph 0006).
In some embodiments, the liposome comprises 40-50%, 30-50%, 20%-50%, 10-50%, 40-60%, 30-60%, 20-60%, 35-50%, 40-50%, 30-45%, or 30-40% cholesterol by molarity or weight (paragraph 0026).
In some embodiments, phosphatidyl choline includes naturally occurring, semi-synthetic or synthetic phosphatidylcholines (e.g., DSPC, DMPC, etc.) (paragraph 0044).
In one embodiment, the liposome comprises a single drug. In another embodiment, the liposome comprises more than one drug. In another embodiment, the liposome comprises a combination therapy (paragraph 0063).
Loading of the drug into the liposome was achieved by pre-dissolving the target drug during the preparation of the liposome, thereby enabling a desired and reproducible concentration of the drug in the most stabilized environment. A concentration of drug at a molar ratio, mol % or weight % between 0.1-1.5% was found to be optimal (paragraph 0126).
It would have been obvious to one of ordinary skill in the art at the time of the invention to modify the ratio of lipid:cholesterol in the compositions taught by Chen when the teaching of Chen is taken in view of Katz. One would have been motivated to do so, with a reasonable expectation of success, because each of Chen and Katz are directed to Furthermore, differences in concentration or temperature will generally not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382; or In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969).
It would have been further obvious to provide a drug in the liposomes taught by Chen because Chen teaches that the liposome formulation can serve as a model platform to further investigate the potential applications of other sonosensitizers or old drugs, and that recent work might open up new avenues as ultrasonic exposure has been shown to trigger efficient anticancer effects of current safe drugs on malignant cells; and Katz teaches that the liposomes may be used to deliver one or more drugs.
It would have been further obvious to substitute a lipid such as DSPC in the liposomal formulations because Katz teaches phosphatidyl choline includes naturally occurring, semi-synthetic or synthetic phosphatidylcholines, e.g., DSPC, to be suitable for drug delivery.
Claim(s) 1-6 and 8-13 are rejected under 35 U.S.C. 103 as being unpatentable over Unger (US 2005/0123482) in view of in view of Katz et al. (US 2020/0129434).
Unger teaches preparing temperature activated gaseous precursor-filled liposomes suitable for use as contrast agents for ultrasonic imaging or as drug delivery agents. The methods of the present invention provide the advantages, for example, of simplicity and potential cost savings during manufacturing of temperature activated gaseous precursor-filled liposomes (paragraph 0022).
Lipids which may be used to create lipid microspheres include but are not limited to: lipids such as fatty acids, lysolipids, phosphatidylcholine with both saturated and unsaturated lipids including dioleoylphosphatidylcholine; dimyristoylphosphatidyl-choline; dipentadecanoylphosphatidyl-choline, dilauroylphosphatidylcholine, dioleoylphosphatidyl-choline, dipalmitoylphosphatidylcholine; distearoyl-phosphatidylcholine; phosphatidylethanolamines, etc., including combinations thereof (paragraph 0136).
A wide variety of lipids may comprise the non-cationic lipid when cationic lipid is used to construct the microsphere. Preferably, this non-cationic lipid is dipalmitoylphosphatidylcholine, dipalmitoylphosphatidylethanolamine or dioleoylphosphatidylethanolamine (column paragraph 0139).
The most preferred lipids are phospholipids, preferably DPPC and DSPC, and most preferably DPPC (paragraph 0141).
Emulsifying or solubilizing agents include… poloxamer (paragraph 0147).
Preferably, the liposomes of the invention have a peak resonant frequency of between about 0.5 mHz and about 10 mHz. Of course, the peak resonant frequency of the gaseous precursor-filled liposomes of the invention will vary depending on the outside diameter and, to some extent, the elasticity or flexibility of the liposomes, with the larger and more elastic or flexible liposomes having a lower resonant frequency than the smaller and less elastic or flexible liposomes (paragraph 0185).
Suitable therapeutics include, but are not limited to… piroxicam (paragraph 0204).
Example 4 shows formulation of gas-filled lipid bilayers using phosphatidic acid, dipalmitoylphosphatidylethanolamine-PEG 5,000 and dipalmitoylphosphatidyl-choline. Perfluorobutane encapsulated lipid bilayers were formed, the lipid formulation contained 82% dipalmitoylphosphatidyl-choline, 10 mole % dipalmitoylphosphatidic acid, and 8 mole % dipalmitoylphosphatidylethanolamine-PEG 5,000 in a vehicle consisting of 8:1:1 (v:v:v) normal saline:propylene glycol:glycerol, yielding a foam and a lower vehicle layer that was predominantly devoid of any particulate. Variations of this vehicle yielded varying degrees of clarity to the lower vehicle layer… Sizing of the subsequent microspheres resulted in 99.5% of all particles residing below 10 µm. It is noted that the vehicle was altered with other viscosity modifiers and solubilizers in varying proportions which resulted in greater or lesser degrees of clarity and particulate. Amongst a variety of lipids and lipid analogs used in combination, it was subsequently found that the introduction of DPPE-PEG lipid significantly improved the size distribution and apparent stability of the gas-filled lipid bilayers.
Accordingly, based on the molecular weights of DPPC (734.05), DPPA (648.9), and DPPE-PEG5000 (approximately 5000), the amount of stabilizer (DPPE-PEG5000) corresponds to approximately 60 parts by weight relative to 100 parts of DPPC + DPPA.
Unger does not specifically recite wherein the therapeutic agent, e.g. piroxicam, is present at 1 to 15 parts per weight relative to the lipid.
Katz teaches compositions comprising liposomes comprises cholesterol, phosphatidyl phosphoric acid and phosphatidyl choline, as well as liposomes comprising a drug or imaging agent and a peptide for targeting to the brain (abstract).
According to a first aspect, there is provided a composition comprising a liposome, the liposome comprises 30 to 50% cholesterol, 5 to 20% phosphatidyl phosphoric acid and 40 to 60% phosphatidyl choline, by molarity (paragraph 0006).
In some embodiments, the liposome comprises 40-50%, 30-50%, 20%-50%, 10-50%, 40-60%, 30-60%, 20-60%, 35-50%, 40-50%, 30-45%, or 30-40% cholesterol by molarity or weight (paragraph 0026).
In some embodiments, phosphatidyl choline includes naturally occurring, semi-synthetic or synthetic phosphatidylcholines (e.g., DSPC, DMPC, etc.) (paragraph 0044).
In one embodiment, the liposome comprises a single drug. In another embodiment, the liposome comprises more than one drug. In another embodiment, the liposome comprises a combination therapy (paragraph 0063).
Loading of the drug into the liposome was achieved by pre-dissolving the target drug during the preparation of the liposome, thereby enabling a desired and reproducible concentration of the drug in the most stabilized environment. A concentration of drug at a molar ratio, mol % or weight % between 0.1-1.5% was found to be optimal (paragraph 0126).
It would have been obvious to one of ordinary skill in the art at the time of the invention to select approximately 1% by weight piroxicam as a therapeutic agent which is present in temperature activated gaseous precursor-filled liposomes suitable for use as contrast agents for ultrasonic imaging or as drug delivery agents, as taught by Unger when the teaching of Unger is taken in view of Katz. It is noted that the liposomes taught by Unger have a peak resonant frequency of between about 0.5 mHz and about 10 mHz and contain lipids and stabilizers according to the claimed ratios. One would have been motivated to select piroxicam as a therapeutic agent, with a reasonable expectation of success, because Unger teaches piroxicam as one of the suitable therapeutic agents which may be carried by the liposomes for drug delivery. One would have had a reasonable expectation of success in providing the therapeutic agent at approximately 1% by weight because Katz teaches it is known to do so in liposomes intended for drug delivery. It would have been further obvious to optimize the lipid content and drug concentrations, as well as as by incorporation of DPPC/DPPE, etc. in various ratios, as Unger teaches the claimed lipids and combinations to be suitable. Furthermore, with regard to relative concentrations, differences in concentration or temperature will generally not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382; or In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969).
Conclusion
No claims are allowed at this time.
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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/LHS/
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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