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 .
Election/Restrictions
Applicant’s election without traverse of Group I in the reply filed on 11/12/2025 is acknowledged. Claims 1-20 are pending, of which claims 14-20 have been withdrawn from consideration at this time as being directed to a non-elected invention. Claims 1-13 are examined herein on the merits for patentability.
Claim Objections
Claim 7 is objected to because of the following informalities: in line 2, two colons appear after consisting of::, as a minor typographical error. Appropriate correction is requested.
Claim 11 is objected to because of the following informalities: in line 2, “stabilize” is misspelled rather than “stabilizer” as a minor typographical erro. Appropriate correction is requested.
Claim Rejections - 35 USC § 112
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 12 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. The claim contains the trademark/trade name Pluronic. 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 non-ionic surfactants made of polyethylene oxide and polypropylene oxide blocks and, accordingly, the identification/description is indefinite.
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) 1-6 and 8-13 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Dong (CN 110639032).
Dong discloses a high-frequency ultrasonic contrast agent and a preparation method thereof. The high-frequency ultrasonic contrast agent consists of a lipid shell and an air inner core, wherein the lipid shell consists of phospholipid, a stabilizing agent and sodium alginate, the surface of the lipid shell is connected with superparamagnetic particles through amido bonds, the phospholipid is one or more of carboxylated DSPC, DPPC, DSPE, DPPE and DSPE-PEG2000, and the stabilizing agent is one or more of PEG4000, F68 and PEG40 s. The ultrasonic contrast agent has good response to the ultrasonic (20-50MHz) for high-frequency ultrasonic diagnosis, has long in-vivo circulation time, and can obtain obvious and clear in-vivo microvascular morphology and perfusion information by combining with a corresponding high-frequency ultrasonic imaging technology (abstract).
A high-frequency ultrasound contrast agent, comprising a lipid shell and a gas core, the lipid shell composed of phospholipid, stabilizer and sodium alginate, the lipid shell surface by amide bond with superparamagnetic particles, the phospholipid is DSPC is carboxylated. one or more of DPPC, DSPE, DPPE, DSPE-PEG2000 carboxylated, the stabilizer is one or more of PEG4000, F68, PEG40s of the gas core is inert gas and the composition of the atmospheric pressure low temperature plasma. the preparation method of said high frequency ultrasound contrast agent, comprising the following steps: (1), according to weight ratio of 3~10: 1~3: 1, adding the phospholipid, stabilizer and sodium alginate is dissolved in the chloroform, obtaining the lipid mixed solution (translation, page 2).
It is noted that such a ratio corresponds to 100:30:10 lipid, stabilizer, and acoustic deformation material according to the instant claims.
See also Example A comprising DSPC hydroxylated 100mg, DSPE-PEG2000 15mg, F68 20mg, PEG40S 10mg and sodium alginate; and Example II comprising DPPC hydroxylated 100mg, DSPE-PEG2000 15mg, F68 20mg, PEG4000 10mg and sodium alginate 10mg. See also 10ml of micro-bubble suspension adding amination super-paramagnetic ferroferric oxide particle (0.2mg/mL), as the magnetic nanoparticles are within the scope of a drug as they can be used for therapeutic treatment.
With regard to the limitation wherein the acoustic deformation material is deformed under an acoustic wave of a characteristic response frequency for the acoustic-induced deformation material, and the characteristic response frequence is 0.01 MHz to 50 MHz, it is interpreted that sodium alginate inherently meets the claimed functional property because Dong discloses that the ultrasonic contrast agent has good response to the ultrasonic (20-50MHz) for high-frequency ultrasonic diagnosis. “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) 1-9, 11 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Liang et al. (CN 109420182).
Liang teaches a multifunctional micro-bubble ultrasound/fluorescence collection double-mode imaging and photodynamic therapy as a whole, relating to the preparation method of this kind of multifunctional bubble and its use for tumour diagnosis and treatment. collecting ultrasound/fluorescence double-mode imaging and photodynamic therapy integrated multifunctional micro-bubble structure schematic diagram shown in the figure, the membrane components including lipid photosensitizer-containing functional groups for photodynamic therapy and conventional phospholipid, photosensitive drug ratio can be adjusted according to need, greatly improves the drug. Under the action of ultrasonic, the multifunctional bubble can achieve point target into nano-particle on the tumour part, which greatly improves the enrichment of drugs at tumour part and intake, effectively improve the photodynamic effect of inhibiting tumor growth (abstract).
The purpose of the invention is multi-functional ultrasonic micro-vesicle contrast agent provides a type of ultrasound/fluorescence collection double-mode imaging and photodynamic therapy together and a preparation method of the bubble (translation page 3).
A photosensitive functional group includes porphyrin, protoporphyrin, porphyrin, removing magnesium chlorophyllin (pyropheophorbide), bacterial chlorophyll, chlorophyll a, benzoporphyrin derivatives, phenyl dihydro porphyrin thiophene, benzo dihydro porphyrin thiophene, naphtho dihydro porphyrin thiophene, phthalocyanine or naphthalocyanine. said ultrasonic micro-bubble contrast agent is composed of film-forming material encapsulated with gas or liquid, the particle diameter range of said microbubble contrast agent is 300nm-8um (page 3).
The invention claims a kind of collecting ultrasound/fluorescence double-mode imaging and photodynamic therapy integrated with multifunctional microbubble preparation method, comprising the following steps: 1) a certain proportion of the phospholipids, lipid containing photosensitizer function groups and near infrared dyes are dissolved and mixed in chloroform (CHCl3) uniformly contains photosensitizer (functional group of lipid ratio of 0 to 20%) (page 3).
In the step l), the phospholipid comprises 12~24 carbon chain length and comprises phosphatidylcholine, phosphatidyl ethanolamine, phosphatidic acid, phosphatidyl glycerol and cholesterol, such as 1. 2-O distearyl-sn-glyceryl - -3 - phosphorylcholine (DSPC), 1, 2-dipalmitoyl-sn-glyceryl - -3 - phosphatidylchline (DPPC), 1, 2-dipalmitoyl-sn-glycero - -3 - phosphatidic acid (DPPA); the distearin phosphatidylethanolamine polyethylene glycol 2000 (DSPE-PEG2000), distearin phosphatidylethanolamine-polyethylene glycol 2000 (DSPE-PEG5000) and so on (page 4).
Accordingly, Liang teaches an ultrasound contrast composition comprising lipid, stabilizer and acoustic deformation material (e.g. comprising porphyrin, protoporphyrin, chlorin, etc.).
In Example 2, the lipid-porphyrin 15%mol (PGL) and 80%mol-distearoyl phosphatidylcholine (DSPC); 5 mol of distearoyl phosphatidyl ethanolamine-polyethylene glycol 2000 (DSPE-PEG2000) dissolved in 2 5mLCHCl3 %, then the chloroform, evaporating by rotary evaporator to dissolve the lipid in rotary steaming bottle bottom to form lipid film, and centering the vacuum drying box overnight to remove residual organic solvent. then adding the 1mLPBS hydration liquid in the bottle, water bath ultrasonic for 30min at 60 degrees centigrade, until obtaining a solution of transparent clear to obtain the PGL liposome (lipid concentration is 1 mg/mL). after the PGL lipidosome solution into penicillin bottle, adding glycerine and propylene glycol 100 μL are mixed uniformly, then filling the perfluoropropane gas, after sealing by VIALMIX (Lantheus company, America) for 45s, to obtain the PGL-MBs.
Accordingly, Liang teaches an ultrasound contrast agent comprising an acoustic deformation material comprising porphyrin at a concentration of approximately 15% relative to lipid, combined DSPC and DSPE-PEG2000), and 0.1 mL PPPG compared to 1 mg lipid concentration, but does not specifically exemplify a stabilizer in an amount of 20 to 100 parts by weight relative to lipid. It would have been obvious to one of ordinary skill in the art at the time of the invention to optimize the amount of acoustic deformation material and stabilizer in the microbubble formulations as a matter of routine optimization in preparation of stabilized microbubble compositions for use in ultrasound/fluorescence collection double-mode imaging and photodynamic therapy. For example, Liang teaches a functional group of lipid ratio may range from 0 to 20%). 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).
With regard to the limitation wherein the acoustic deformation material is deformed under an acoustic wave of a characteristic response frequency for the acoustic-induced deformation material, and the characteristic response frequence is 0.01 MHz to 50 MHz, it is interpreted that porphyrin, photofrin, chlorin, etc. agents inherently meet the claimed functional property. “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) 1-13 are rejected under 35 U.S.C. 103 as being unpatentable over Liang et al. (CN 109420182) in view of Toler et al. (US 6,572,840)
The rejection over Liang is applied as above.
With regard to claims 10 and 12, Liang does not specifically recite wherein the lipid is DPPC and DPPE within the claimed ratio, or Pluronic as the stabilizing material.
Toler teaches novel contrast agents for ultrasound diagnosis and a reproducible process for making the same are described, wherein the contrast agents comprise a microbubble composition comprising a lipid shell, a stabilizer coated on the lipid shell and perfluoropropane gas encapsulated in the lipid shell (abstract).
Ultrasound is a valuable diagnostic imaging technique for studying various areas of the body, for example, the vasculature, including tissue microvasculature. Ultrasound provides certain advantages over other diagnostic techniques. For example, diagnostic techniques involving nuclear medicine and X-rays generally results in exposure of the patient to ionizing electron radiation… Ultrasound involves the detection of the differentially reflected waves, generally with a transducer that can detect sound waves having a frequency of one megahertz (Mhz) to ten Mhz. The detected waves can be integrated into an image which is quantitated and the quantitated waves converted into an image of the tissue being studied.
A composition is taught comprising, in an aqueous solution, microbubbles comprising: (a) a lipid shell, (b) a stabilizer coated on the lipid shell and (c) perfluoropropane gas encapsulated in the lipid shell; wherein: the lipid shell comprises a blend of 1,2dipalmitoyl-sn-glycero-3-phosphatidic acid, monosodium salt, 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine and 1,2-dipalmitoyl-sn-glycero-3-phosphatidylethanolamine, monosodium salt and the stabilizer is selected from polyethylene glycol polymers, polyethylene-polypropylene glycol and poloxamers.
In Example 1, DPPA (9 mg), DPPC (82 mg), DPPE (7.6 mg), mPEG-5000 (55 mg) were weighed into a volumetric flask. To the flask, 20 mL of propylene glycol was added.
It would have been obvious to one of ordinary skill in the art at the time of the invention to provide a lipid composition comprising DPPC and DPPE within the claimed ratio as functionally equivalent lipids for phospholipid microbubble preparation when the teaching of Liang is taken in view of Toler. It would have been further obvious to substitute Pluronic as a functionally equivalent stabilizer. The Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. ___, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper “functional approach” to the determination of obviousness as laid down in Graham. One such rationale includes the simple substitution of one known element for another to obtain predictable results. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. See MPEP 2143. In the instant case, the substituted components and their functions were known in the art at the time of the instant invention. One of ordinary skill in the art could have substituted known phospholipid vesicle component and stabilizer for another, and the results of the substitution would have been predictable, that is preparation of a stabilized phospholipid microbubble for use in ultrasound imaging.
Claim(s) 1-9, 11 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Kim (WO 2015/141917).
Kim teaches a dual-purpose photoacoustic tomography (PAT)/ultrasound contrast agent comprising: (a) a micro-bubble containing gas and porphyrin therein; and (b) nanoparticles bound on a surface of the micro-bubble and containing a drug. The contrast agent of the present invention can be used in both the ultrasound diagnosis and the photoacoustic image diagnosis, and can significantly increase the accuracy of photoacoustic images (abstract).
Development of a contrast agent for diagnosis and treatment that can be used simultaneously for ultrasound and photoacoustic imaging, and can be simultaneously diagnosed and treated in combination with nanomedicine is taught. As a result, when porphyrin is included in a liposome-type microbubble commonly used for ultrasound diagnosis, and nanoparticles containing a drug in the microbubble can be used simultaneously for ultrasound diagnosis and photoacoustic imaging, We confirmed that the accuracy of the optoacoustic image can be significantly increased.
According to one aspect of the present invention, the present invention provides a dual-purpose photoacoustic tomography (PAT) / ultrasound contrast medium comprising: (a) a gas and porphyrin inside; Microbubble comprising; And (b) a nanoparticle containing a drug bound to the surface of the microbubble.
The term 'dual-purpose' as used herein means that the contrast agent, which is a substance of the present invention, can be used simultaneously for diagnosis and treatment, as well as for ultrasound diagnosis and photoacoustic imaging (translation pages 2+).
The forming of the lipid thin film may include mixing a molar ratio of a lipid having an emulsifier: porphyrin-lipid: lipid: NHS in a range of 5-10: 15-30: 60-75: 15-30 (translation page 9).
Example 2 shows preparation of microbubbles containing porphyrin.
Lipids include 1,2-disteraoyl-sn-glycero-3-phosphocholine (DSPC), DSPE-PEG2000-NHS (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-n- [poly (ethyleneglycol)] 2000- N-hydroxysuccinimide), porphyrin-containing lipid (porphyrin-lipid), polyoxyethylene 40 stearate (POE40s) as an emulsifier were mixed in a chloroform with a molar ratio of 50: 15: 15: 1, and then dissolved in chloroform using a rotary evaporator. Was evaporated completely to form a lipid thin film. Subsequently, distilled water, propylene glycol and glycerin were mixed at 8: 1: 1 and then added to the lipid thin film. Lipids were dissolved while maintaining the temperature at 55-60 ° C. SF6 or C3F8 gas was added to a container containing a mixed solution and filled with 200 kPa, and microbubbles (porphyrin-MBs) were prepared through sonication and mechanical agitation.
For example, an aqueous suspension comprising the functionalised lipids and containing one or more stabilising agents may provide a suitable particulate suspension. Other non-functionalised lipids, or other lipids bearing polymer groups as herein described, may also be present. Examples of stabilising agents include, but are not limited to, glycerol, cetyl alcohol, sorbitol, polyvinylalcohol, polypropylene glycol, and propylene glycol. In one embodiment a mixture of glycerol and propylene glycol may be used. Solvent systems suitable for the suspension of the lipids may readily be selected. A preferred solvent system may include saline (e.g. phosphate buffered saline), glycerol and propylene glycol, for example in a ratio of 8:1:1.
Accordingly, Kim teaches an ultrasound contrast agent comprising emulsifier (stabilizer): porphyrin-lipid (an acoustic deformation material comprising e.g. porphyrin) : lipid: NHS in a range of 5-10: 15-30: 60-75: 15-30, but does not specifically exemplify a stabilizer in an amount of 20 to 100 parts by weight relative to lipid. It would have been obvious to one of ordinary skill in the art at the time of the invention to optimize the amount of acoustic deformation material and stabilizer in the microbubble formulations as a matter of routine optimization as selection from within the claimed ranges for preparation of stabilized microbubble compositions for use in ultrasound and photoacoustic imaging. 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).
With regard to the limitation wherein the acoustic deformation material is deformed under an acoustic wave of a characteristic response frequency for the acoustic-induced deformation material, and the characteristic response frequence is 0.01 MHz to 50 MHz, it is interpreted that porphyrin, photofrin, chlorin, etc. agents inherently meet the claimed functional property. “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) 1-13 are rejected under 35 U.S.C. 103 as being unpatentable over Kim et al. (WO 2015/141917) in view of Toler et al. (US 6,572,840)
The rejection over Kim is applied as above.
With regard to claims 10 and 12, Kim does not specifically recite wherein the lipid is DPPC and DPPE within the claimed ratio, or Pluronic as the stabilizing material.
It would have been obvious to one of ordinary skill in the art at the time of the invention to provide a lipid composition comprising DPPC and DPPE within the claimed ratio as functionally equivalent lipids for phospholipid microbubble preparation when the teaching of Kim is taken in view of Toler. It would have been further obvious to substitute Pluronic as a functionally equivalent stabilizer. The Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. ___, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper “functional approach” to the determination of obviousness as laid down in Graham. One such rationale includes the simple substitution of one known element for another to obtain predictable results. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. See MPEP 2143. In the instant case, the substituted components and their functions were known in the art at the time of the instant invention. One of ordinary skill in the art could have substituted known phospholipid vesicle component and stabilizer for another, and the results of the substitution would have been predictable, that is preparation of a stabilized phospholipid microbubble for use in ultrasound imaging.
Conclusion
No claims are allowed at this time.
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/LHS/
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618