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 .
Receipt is acknowledged of Applicant’s Request for Continued Examination filed on 05/27/2025; and IDS filed on 08/05/2025 and 05/27/2025.
Claims 3, 7, 12, 15, 19, 23, 38-39, 42, 47, 50, 54-56 are pending in the instant application.
Note, rejections and objections not reiterated from previous office actions are hereby withdrawn. The following rejections or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 05/27/2025 has been entered.
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 3, 7, 12, 15, 19, 23, 38-39, 42, 47, 50, 54-56 are rejected on the ground of nonstatutory double patenting as being unpatentable over U.S. Patent No. 11,395,856, and 12,296,029 in view of UNGER et (US 6,551,576).
The patents recite a composition comprising a non-aqueous mixture comprising one or more phospholipids selected from DPPA, DPPC and PEG5000-DPPE, in propylene glycol and/or glycerol, and a perfluorocarbon gas, wherein the non-aqueous mixture comprises equal to or less than 5% w/w (weight/weight) of water (see US 11, 395,856 at claim 1), wherein the perfluorocarbon gas is perfluoropropane gas (see claim 8), wherein the one or more phospholipids are present in a concentration of about 0.9 to about 7.5 mg per ml of non-aqueous mixture (see claim 5), wherein about 7.5 mg is about 0.6 mg.
The patents do not recite a container.
UNGER teaches placing DPPC, DPPA and DPPE-PEG5000 and perfluoropropane gas in a vial container (see col. 26, line 42).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate placing the lipids in a container. The person of ordinary skill in the art would have been motivated to make those modifications, because a container is needed to hold the lipids and reasonably would have expected success because the prior art had held lipids in a container.
Claims 3, 7, 12, 15, 19, 23, 38-39, 42, 47, 50, 54-56 are rejected on the ground of nonstatutory double patenting as being unpatentable over U.S. Patent No. 10,022,460 in view of UNGER et al (US 6,551,576).
The patent recites a composition of an ultrasound contrast agent comprising a non-aqueous mixture comprising DPPA, DPPC and MPEG5000-DPPE in propylene glycol and/or glycerol, and a perfluorocarbon gas, wherein the non-aqueous mixture comprises less than 5% w/w (weight/weight) water, and wherein DPPA, DPPC and MPEG5000-DPPE are present in a ratio of about 10:82:8 (mole %) (see claim 1), wherein the perfluorocarbon gas is perfluoropropane gas (see claim 15), in a concentration of about 0.1 mg per ml (see claim 14).
The patent does not recite a container.
UNGER teaches placing DPPC, DPPA and DPPE-PEG5000 and perfluoropropane gas in a vial container (see col. 26, line 42).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate placing the lipids in a container. The person of ordinary skill in the art would have been motivated to make those modifications, because a container is needed to hold the lipids and reasonably would have expected success because the prior art had held lipids in a container.
Claim Rejections - 35 USC § 112, 2nd paragraph
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.
Claims 12, 15, 23 are 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.
Independent claim 23 recites “A composition”; however, claim 23 appears to be reciting two different compositions. The first composition comprising “a lipid solution comprising about 0.1 mg to about 0.6 mg combined of DPPA, DPPC and PEGS5000-DPPE per ml of solution, and a perfluorocarbon gas, in a container”, which appears to be a kit of the first solution composition and perfluorocarbon in a container or in separate containers, since the claim recites “comprising”, which is open language and could have another container. The second composition comprising “lipid-encapsulated gas microspheres having an average diameter of about 1 micron to about 2 microns, and (ii) the composition comprises about 0.1 x 10° to about 3.5 x 10° lipid-encapsulated gas microspheres per mL, and wherein the perfluorocarbon gas is perfluoropropane gas”, which is a microsphere composition. Solutions are different from microspheres. Thus, it’s unclear which composition is Applicant claiming.
For examination purposes, the Examiner will read Applicant’s claims as the first composition as a lipid solution and perfluorocarbon gas, since the second composition requires an active “intended use” step of “when activated”.
Claim 12 recites “PEG500-DPPE is MPEG5000-DPPE”. This appears to be a typo. Additionally, there is no difference between PEG5000-DPPE and MPEG5000-DPPE, because methoxyPEG is used to conjugate to DPPE, which results in PEG5000-DPPE.
Claims 12, 15, 23 contain the term "DPPA, DPPC and PEG5000-DPPE" and “MPEG5000-DPPE”, which is not defined by the claims. Claims must stand alone to define the invention, and should not rely on the description or the drawings to give them meaning (see Ex Parte Fressola, 27 USPQ 2d 1608). Thus, independent claim 23, at the very least, should define " DPPA, DPPC and PEG5000-DPPE " by its formal chemical name; once " DPPA, DPPC and PEG5000-DPPE" and “MPEG5000-DPPE” are defined, the term " DPPA, DPPC and PEG5000-DPPE" and ““MPEG5000-DPPE” may be subsequently recited.
Claim Rejections - 35 USC § 102
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 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) 3, 7, 12, 15, 23, 39, 42, 47, 50, 54-56 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by UNGER et al (US 6,551,576).
Regarding independent claim 23, UNGER teaches a composition comprised of: 1mg/ml, which reads on about 0.6mg/ml, of DPPC:DPPA:DPPE-PEG-5000 (see col. 26, line 39-40) and perfluoropropane (see col. 26, line 36), which is a perfluorocarbon, in a container, such as a vial (col. 26, line 45).
Regarding claim 3, UNGER teaches 80% PFP (“perfluoropropane”; see col. 26, line 45-46).
Regarding claim 7, UNGER teaches the average diameter is about 2 um (see col. 8-9, Table 2), which reads on about 1.8 microns.
Regarding claim 12, UNGER teaches 80% PFP (“perfluoropropane”; see col. 26, line 45-46).
Regarding claim 15, UNGER teaches a diluent (see col. 23, line 14), such as saline, propylene glycol and glycerol (see col. 22, line 1) can be added.
Regarding claim 39, UNGER teaches 1mg/ml (see col. 26, line 39-40), which reads on about 0.6mg. Additionally, as discussed above, it would have been obvious to optimize the concentration of the lipid solution for the desired particle size.
Regarding claim 42, UNGER teaches a vial (see col. 26, line 42).
Regarding claim 47, UNGER teaches 2 mL vial size (see col. 19, at Table 7) and 50% of PFP (“perfluorocarbon”; see col. 26, line 47).
Regarding claim 50, UNGER teaches using plastic containers (see col. 12, line 38).
Regarding claims 54-56, as discussed above, UNGER teaches using the same composition as claimed by Applicant. UNGER further teaches the same active step, such as shaking for 60 seconds, wherein the number of bubbles resulted in about 2 microns sizes and 1x109 number of particles per mL (see col. 9, Table 2).
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.
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.
Claim(s) 3, 7, 12, 15, 19, 23, 38-39, 42, 47, 50, 54-56 is/are rejected under 35 U.S.C. 103 as being unpatentable over UNGER et al (US 6,551,576).
Regarding independent claims 23 UNGER teaches a composition comprised of: 1mg/ml, which reads on about 0.6mg, of DPPC:DPPA:DPPE-PEG-5000 (see col. 26, line 39-40) and perfluoropropane (see col. 26, line 36), which is a perfluorocarbon, in a container, such as a vial (col. 26, line 45). Additional disclosures include: 1.8 um (see col. 17, at Table 5; and col. 17, line 14-20)
UNGER further teaches filters, such as 0.22 micron (see col. 20, line 34) “may be used to further refine the size distribution of the contrast agent after shaking”, wherein shaking reads on activating, such as 60 seconds (see col. 26, line 53), which reads on about 50 seconds; resulting in gas-filled liposome (see col. 26, line 54; and col. 2, line 33-35).
A variety of factors/parameters controlling liposome sizes include: (1) the ratio of the three different lipid components (see col. 16, line 40-55); (2) the concentration of a defined lipid composition mixture upon the average liposome size (see col. 16, line 60-65), such as the concentration of lipid was between 0.5 and 5.0 mg/ml (see col. 16, line 60-65), (3) concentration of perfluoropropane in the headspace (see col. 26, line 36); (4) agitation rate (see col. 17); (5) filling volume (see col. 18, line 43), in order to find the optimal size bubbles for ultrasonic diagnosis (see col. 16, line 60-65).
Note, UNGER discovered that “a 1.0 mg/ml lipid concentration produces gas-filled liposomes of about the same diameter when nitrogen is used, as the 5.0 mg/ml concentration of lipids with perfluorobutane. However, it has been found that the higher concentration may result in a distribution skewed a bit more towards larger gas-filled liposomes. This phenomenon tends to reflect the increased stability of the gas-filled liposomes at higher lipid concentration. It is therefore believed that the higher concentration of lipid either contributes to the stability by acting as a stabilizing agent in the aqueous phase or, the higher lipid concentration provides more lamellae around the gas, making them more stable, and thus allowing a greater proportion of the larger liposomes to persist” (see col. 17, line 16-30). Thus, the effect on the sizes could be different at lower concentration (in the 1 mg/ml range) when compared to the higher concentration (in the 5mg/ml range) and one of ordinary skilled in the art would obviously have to conduct experiments at different concentrations to discover the effect on the liposome sizes, wherein one skilled in the art would obviously optimize the concentration for the desired optimal size.
Regarding claim 3, UNGER teaches 80% PFP (“perfluoropropane”; see col. 26, line 45-46).
Regarding claim 7, UNGER teaches the average diameter is about 2 um (see col. 8-9, Table 2), which reads on about 1.8 microns.
Regarding claim 12, UNGER teaches 80% PFP (“perfluoropropane”; see col. 26, line 45-46).
Regarding claim 15, UNGER teaches a diluent (see col. 23, line 14), such as saline, propylene glycol and glycerol (see col. 22, line 1) can be added.
Regarding claims 19 and 38, UNGER does not specifically teach adding the lipid solution and perfluorocarbon gas ingredients in the amounts claimed by Applicant. The amount of a specific ingredient in a composition is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient to add in order to best achieve the desired results, such as the optimal size for ultrasound and magnetic imaging (see abstract). Thus, absent some demonstration of unexpected results from the claimed parameters, this optimization of ingredient amount would have been obvious at the time of Applicant's invention.
Regarding claim 39, UNGER teaches 1mg/ml (see col. 26, line 39-40), which reads on about 0.6mg. Additionally, as discussed above, it would have been obvious to optimize the concentration of the lipid solution for the desired particle size.
Regarding claim 42, UNGER teaches a vial (see col. 26, line 42).
Regarding claim 47, UNGER teaches 2 mL vial size (see col. 19, at Table 7) and 50% of PFP (“perfluorocarbon”; see col. 26, line 47).
Regarding claim 50, UNGER teaches using plastic containers (see col. 12, line 38).
Regarding claims 54-56, as discussed above, UNGER teaches using the same composition and active step, such as shaking for 60 seconds, as claimed by Applicant, wherein the number of bubbles resulted in about 2 microns sizes and 1x109 number of particles per mL (see col. 9, Table 2). Note, UNGER teaches filters can be used to obtain the desired particle sizes and numbers.
Response to Arguments
Applicant argues that surprisingly, however, the inventors of the instant application found that this was not the case when using the lipid solution and perfluoropropane gas of the instant claims. Table 3 of the instant application (reproduced below) demonstrates, unexpectedly, that lipid solutions that differed 4-fold in lipid concentration produced microspheres of about the same average diameter. For example, a lipid solution having a lipid concentration of 0.1875 mg/mL produced microspheres of roughly the same average diameter as those produced from a lipid solution having a lipid concentration of 0.75 mg/mL, despite a four-fold difference in lipid concentration. Table 1 of the instant application (reproduced below with dashed circles and boxes) similarly shows that lipid concentrations of 0.75 mg/mL and 0.43 mg/mL unexpectedly produced microspheres having an average diameter of 1.60 and 1.63 microns, respectively, even though the lipid concentration is nearly halved. Thus, the ability to produce microspheres having an average diameter in the range of 1-2 microns while using a lipid concentration in the range of 0.1 - 0.6 mg/ml using the lipid solution and perfluoropropane gas of the instant claims was clearly unexpected. Such a result could not have been predicted based on the disclosure of Unger, as supported by the Examiner's interpretation of Unger.
The Examiner finds this argument unpersuasive, because as discussed above, UNGER teaches using 1mg/1mL lipid solution, which reads on about 0.6 mg, and perfluoropropane gas, activated to achieve particles size of about 2 micron and 1x109 number of particles. Applicant’s claims are too broad.
Additionally, as discussed above, UNGER discovered that “a 1.0 mg/ml lipid concentration produces gas-filled liposomes of about the same diameter when nitrogen is used, as the 5.0 mg/ml concentration of lipids with perfluorobutane. However, it has been found that the higher concentration may result in a distribution skewed a bit more towards larger gas-filled liposomes. This phenomenon tends to reflect the increased stability of the gas-filled liposomes at higher lipid concentration. It is therefore believed that the higher concentration of lipid either contributes to the stability by acting as a stabilizing agent in the aqueous phase or, the higher lipid concentration provides more lamellae around the gas, making them more stable, and thus allowing a greater proportion of the larger liposomes to persist” (see col. 17, line 16-30). Thus, the effect on the sizes could be different at lower concentration (in the 1 mg/ml range) when compared to the higher concentration (in the 5mg/ml range) and one of ordinary skilled in the art would obviously conduct experiments at different concentrations to discover the effect on the liposome sizes, wherein one skilled in the art would obviously optimize the concentration for the desired optimal size.
Telephonic Inquiries
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAKE MINH VU whose telephone number is (571)272-8148. The examiner can normally be reached Mon-Fri 9:00am-5:30pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael Hartley can be reached at (571) 272-0616. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JAKE M VU/Primary Examiner, Art Unit 1618