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 . Claims included in prosecution are claims 12, 15-18, 20-23.
Previous Rejections
Applicants' arguments, filed 11/6/2025, 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 Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.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.
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.
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.
1. Claim(s) 12, 15-18, 20-23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bioley et al. (US 2017/0348401, Dec. 7, 2017) (hereinafter Bioley) in view of Dimcevski et al. (Journal of Controlled Release, Volume 243, Pages 172-181, Dec. 10, 2016) (hereinafter Dimcevski).
Bioley teaches gas-filled microvesicles comprising an antigen bound thereto and aqueous suspensions containing said microvesicles (Abstract). The aqueous suspension of gas-filled microvesicles comprises a stabilizing envelope, said stabilizing envelope comprising (a) an antigen covalently bound to an amphiphilic component forming said envelope, (b) a phospholipid and (c) a fatty acid (¶ [0007]). Suitable alternative terms to microvesicles include microbubbles (¶ [0016]). The ratio of fatty acid to phospholipids was found to affect the efficacy of the microvesicles and the antigen-specific antibody and/or T cell responses (¶ [0027]). Suitable fatty acids include saturated fatty acids with palmitic acid being particularly preferred (satisfies fatty acid of claim 12, 15, and 17) (¶ [0030]). Preferred phospholipids include distearoylphosphatidylcholine (DSPC) and dipalmitoylphosphatidylethanolamine (DPPE) (satisfies PC of claim 12, 15, and 17) (¶ [0040]). Phospholipids may also be modified by linking polyethyleneglycol (PEG) thereto. Examples of pegylated phospholipids are pegylated phosphatidylethanolamines (PE-PEGs such as DPPE-PEG) (satisfies PE-PEG of claim 12 and 15). Suitable molecular weights of the PEG molecule range from 300 to 20000 daltons, preferably from 500 to 5000 daltons (satisfies PE-PEG of claim 17) (¶ [0041]). Mixtures of phospholipids can also be used, such as, DPPE (including pegylated derivates) and DSPC (¶ [0043]). Particularly preferred gases for use are fluorinated gases (satisfies claim 18) (¶ [0067]). The microvesicles can be used in any medical treatment comprising or inducing a modulation of the immune response in a patient in need thereof (satisfies treatment method of claim 12) (¶ [0076]). In example B1 the PC/Palmitic acid/PE- PEG had a ratio of 78/19/5/2.5 (satisfies claim 15-16) (¶ [0094]). During testing, the composition was administered three times at two-week intervals via injection (satisfies boluses of claim 12) (¶ [0099]).
Bioley differs from the instantly recited claims insofar as not disclosing wherein the boluses are administered at intervals of at least 4 or 5 minutes or wherein ultrasound is applied in the method of treating.
However, Dimcevski discloses that the process of using ultrasound with gas microbubbles, known as sonoporation, has been known in clinics for at twenty years (Sec. 1, Para. 3). In vitro and in vivo sonoporation has been found to be a viable technique to improve drug delivery and improve therapeutic efficacy. Further, sonoporation has also been used to open the blood brain barrier (Sec. 1, Para. 4). During testing, it was found that the expected in-vivo life time of microbubbles was 4–5 min. As such, boluses were injected every 3.5 min to ensure microbubbles were present continuously throughout the whole treatment (Sec. 2.2, Para. 2).
As such, it would have been obvious for one of ordinary skill in the art to have modified Bioley’s method to include the application of ultrasound motivated by the desire to achieve a treatment method that is characterized by improved drug delivery and therapeutic efficacy.
Dimcevski discloses it was found that the expected in-vivo life time of microbubbles was 4–5 min. As such, it would have been obvious to one of ordinary skill in the art prior to filing the instant application to have administered the microvesicles of Bioley every 4 to 5 minutes because this is the in-vivo life time of microbubbles motivated by the desire of ensuring the continuous presence of microbubbles/microvesicles throughout the entire course of treatment.
Regarding claim 20 reciting increasing vessels permeabilization, since the gas microvesicles of Bioley are substantially the same as the instantly claimed microvesicles where they comprise DSPC, DPPE-MPEG-5000, palmitic acid, and fluorinated gases and are useable in substantially the same treatment method where the microvesicles of Bioley can be used in any medical treatment comprising or inducing a modulation of the immune response in a patient in need thereof, it would have been reasonable for one of ordinary skill in the art to conclude that the methods of Bioley would comprise increasing vessels permeabilization in the patient since that is achieving increased permeability of therapeutic vesicles is a primary goal of treating a patient with said vesicles.
Regarding the dosages and concentrations of microvesicles recited in instant claims 21-22, where 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 MPEP 2144.05(II)(A). As discussed above, the microvesicles contain therapeutic agents, which makes dosages/concentrations thereof a result effective variable, since dosages/concentrations directly impact the therapeutic effect. Accordingly, it would have taken no more than the relative skills of one of ordinary skill in the art through routine experimentation to have arrived at the claimed dosages/concentrations of microvesicles to yield the desired therapeutic effect.
Response to Arguments
Regarding Applicant’s argument that Dimcevski does not cure does not cure the alleged deficiencies of Bioley, the Examiner submits that Kumaran cures any alleged deficiencies of Bioley where Dimcevski discloses that the use of ultrasound with gas microbubbles has been known in clinics for years and provides motivation for such use (i.e., improved drug delivery, improved therapeutic efficacy, & blood brain barrier opening) and further discloses that the expected in-vivo life time of microbubbles is 4–5 min.
Regarding allegations of unexpected results (i.e., inducing “Cy5.5h extravasation” & “higher therapeutic efficacy”), an affidavit or declaration must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. See MPEP § 716.02(e).
Applicant does not appear to have compared their compositions to the closest prior art. Instead, Applicant compares their inventive compositions to “Sono Vue” and “Definity” microvesicles. The Examiner points to the fact that Bioley discloses microvesicles that comprise a phospholipid and a fatty acid where a particularly preferred fatty acid is palmitic acid and preferred phospholipids include distearoylphosphatidylcholine (DSPC) and dipalmitoylphosphatidylethanolamine (DPPE). Said phospholipids may be pegylated such as DPPE-PEG with preferable molecular weights of the PEG molecule from 500 to 5000 daltons. Absent a direct comparison with a comparative formulation of the closest prior art, it is unclear if the alleged improvements are indeed a surprising an unexpected change or if these results fall within the range of expected outcomes in the art, and a meaningful assessment cannot be made. In other words, if an inventive composition is compared to a distant composition, the alleged improvements or advantages may appear disproportionately more significant than they actually are. As such, it is critical to compare an inventive composition with the closest prior art. Applicant’s comparisons with “Sono Vue” and “Definity” microvesicles do not satisfy the requirement of comparing the claimed subject matter with the closest prior art.
In light of the foregoing, the Examiner does not find Applicant’s arguments to be persuasive and the rejection is maintained.
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.
1. Claims 12, 15-18, 20-23 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 11,717,570 B2 (hereinafter ‘570) in view of in view of Dimcevski et al. (Journal of Controlled Release, Volume 243, Pages 172-181, Dec. 10, 2016) (hereinafter Dimcevski).
Although the claims at issue are not identical, they are not patentably distinct from each other because they both disclose treatment methods comprising administering a suspension of gas-filled microvesicles which comprise a mixture of lipid components DSPC, DPPE-PEG and palmitic acid. The difference between the ‘570 claims and the instant claims lies in the fact that the ‘570 claims further recite a freeze-dried formulation, for preparing gas-filled microvesicles and a suspension of gas-filled microvesicles, making the instant claims a species of the generic invention of the ‘570 patent. It would have been obvious to have used the gas-filled microvesicles of the ‘570 patent in the instant method since both gas-filled microvesicles are the same in composition.
The claims of the ‘570 patent further differ insofar as not disclosing the administration of the suspensions of gas-filled microvesicles at an interval of at least five minutes and up to fifteen minutes between each other.
However, Dimcevski discloses that the expected in-vivo life time of gas microbubbles was 4–5 min (Sec. 2.2, Para. 2).
As such, it would have been obvious to one of ordinary skill in the art prior to filing the instant application to have administered the microvesicles every 4 to 5 minutes because this is the in-vivo life time of microbubbles motivated by the desire of ensuring the continuous presence of microbubbles/microvesicles throughout the entire course of treatment.
The same rationale applies in rejecting the aforementioned claims over the following U.S. Patents:
US 11,723,869 B2
US 10,010,630 B2
US 11,071,792 B2
US 12,070,512 B2
US 7,985,402 B2
US 10,232,061 B1
US 10,335,502 B1
US 10,918,605 B2
US 9,381,258 B2
US 11,426,352 B2
2. Claims 12, 15-18, 20-23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 18 and 25-28 of copending Application No. 18/214,060 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because they both a method of treatment comprising administering a suspension of gas-filled microvesicles which comprise a mixture of lipid components DSPC, DPPE-PEG5000 and palmitic acid and applying an ultrasound beam. The difference between the instant claims and the copending claims lies in the fact that the copending claims further recite a method of manufacturing said suspension, making the instant claims a species of the generic invention of the copending application. It would have been obvious to have used the gas-filled microvesicles produced by the method of the copending application in the instant method since both gas-filled microvesicles are the same in composition.
The copending claims further differ insofar as not disclosing the administration of the suspensions of gas-filled microvesicles at an interval of at least five minutes and up to fifteen minutes between each other.
However, Dimcevski discloses that the expected in-vivo life time of gas microbubbles was 4–5 min (Sec. 2.2, Para. 2).
As such, it would have been obvious to one of ordinary skill in the art prior to filing the instant application to have administered the microvesicles every 4 to 5 minutes because this is the in-vivo life time of microbubbles motivated by the desire of ensuring the continuous presence of microbubbles/microvesicles throughout the entire course of treatment.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The same rationale applies in rejecting the aforementioned claims over the following Applications:
17/620,168
17/415,974
Response to Arguments
Applicant’s arguments with respect to the nonstatutory double patenting rejections have been considered but are moot because new rejections necessitated by Applicant’s amendment have been made.
Conclusion
Claims 12, 15-18, 20-23 are rejected.
No claims are allowed.
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Abdulrahman Abbas whose telephone number is (571)270-0878. The examiner can normally be reached M-F: 8:30 - 5:30.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sahana S. Kaup can be reached at 571-272-6897. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/A.A./Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612