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 .
Claim 1 is amended.
Claims 1, 4-6, 11-13, 15-21, 23-24, 42 and 44 are pending.
Claims 3, 7-10, 14, 22, 25-41 and 43 are cancelled.
Claims 20-21, 23, 42 and 44 are withdrawn.
Note, rejections and objections not reiterated from previous office actions are hereby withdrawn.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.
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.
Claims 1, 4-5 and 24 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by NARAYAN (Mesoporous Silica Nanoparticles: A Comprehensive Review on Synthesis and Recent Advances. Pharmaceutics. 2018.).
Regarding claim 1, NARAYAN teaches a composition that comprises a
a. a 13nm nanoparticle (page 8, paragraph 2), which reads on a sub-100 nanometer nanoparticle core having an outer surface
b. a silane layer coating the outer surface (page 8, paragraph 2); and
c. PEG is attached to the silane later which reads on a stabilization layer comprising stabilizing molecules, each stabilizing molecule in the stabilization layer having a binding portion bound to the silane layer and a non-binding portion free from the silane layer,
Note, the prior art’s composition would have the same chemical/physical properties of “the stabilizing molecules in the stabilization layer being spaced apart on the silane layer by distances configured to provide bubble nucleation sites that, in response to the ultrasound equipment delivering an acoustic intensity at a mechanical index of about 1.9 or less, initiate cavitation of echogenic micron-sized bubbles.” as claimed by Applicant, because the prior art has the same ingredients as claimed by Applicant, unless proven otherwise. Additionally, the specification does not specify the specific amount of spacing/distance required.
Note, with regard to claim 1, these claims recite a composition, and the intended use recited in the preamble would reasonably appear not to be a claim limitation. “If the claim preamble, when read in the context of the entire claim, recites limitations of the claim, or, if the claim preamble is ‘necessary to give life, meaning, and vitality’ to the claim, then the claim preamble should be construed as if in the balance of the claim…If, however, the body of the claim fully and intrinsically sets forth the complete invention, including all of its limitations, and the preamble offers no distinct definition of any of the claimed invention’s limitations, but rather merely states, for example, the purpose or intended use of the invention, then the preamble is of no significance to claim construction because it cannot be said to constitute or explain a claim limitation.” Pitney Bowes, Inc. v. Hewlett Packard Co., 182 F.3d 1298, 1305, 51 USPQ2d 1161, 1165-66 (Fed. Cir. 1999). Thus, the intended use an ultrasound imaging contrast agent capable of being imaged by ultrasound equipment in the composition claims is met by the prior art, because the prior art compositions would be at least capable of performing said use.
Regarding claim 4 and 5, the nanoparticle is a mesoporous silica nanoparticle (MSN) (page 8, paragraph 2 and abstract).
Regarding claim 24, Note, the prior art’s composition would have the same chemical/physical properties of “hydrophobic nanoparticle substantially completely biodegrades within a period of less than one month after introduction into a body of a subject.” as claimed by Applicant, because the prior art has the same ingredients as claimed by Applicant, unless proven otherwise.
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.
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.
Claims 1, 4-6 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over NARAYAN (Mesoporous Silica Nanoparticles: A Comprehensive Review on Synthesis and Recent Advances. Pharmaceutics. 2018.).
NARAYAN teaches Applicant’s invention as discussed above. NARAYAN further teaches that particle size is a very important feature for the biomedical application of MSNs as drug carriers and can be effectively controlled (page 8, paragraph 2). MSNs controllable size makes it ideal for biomedical imaging and theranostic applications (page 22, paragraph 2).
NARAYAN does not specifically teach the nanoparticle diameter as claimed by Applicant in the dependent claims.
Regarding claim 6, the reference does not specifically teach the nanoparticle diameter as claimed by the Applicant. The nanoparticle diameter 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 the ordinary skill to determine the optimal nanoparticle diameter in order to best achieve desired results, such as having the optimal particle size for biomedical applications such as drug delivery and imaging. Thus, absent of some demonstration of unexpected results from the claimed parameters, this optimization of the nanoparticle diameter would have been obvious at the time of Applicant’s invention. Additionally the reference teaches the size is highly controllable with many methods to do so.
Claims 1, 4-6, 11-12 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over NARAYAN (Mesoporous Silica Nanoparticles: A Comprehensive Review on Synthesis and Recent Advances. Pharmaceutics. 2018.) in view of ZHANG (Surface Engineering of Core/Shell Iron/Iron Oxide Nanoparticles from Microemulsions for Hyperthermia. Mater Sci Eng C Biol Appl. 2010.).
NARAYAN teaches Applicant’s invention as discussed above.
NARAYAN does not teach that the silane layer is specifically hexamethyldisilazane.
Regarding claim 11 and 12, ZHANG teaches nanoparticles that comprise a saline layer of hexamethyldisilazane (HMDS), which improves the stability of the nanoparticle (page 5, paragraph 1). HMDS is a disilazane.
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate a hexamethyldisilazane layer. The person of ordinary skill in the art would have been motivated to make those modifications, because it improves the stability of the nanoparticle, and reasonably would have expected success because the references are in the same field of endeavor, such as nanoparticles coated in a saline layer.
Claims 1, 4-6, 11-13, 15-19 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over NARAYAN (Mesoporous Silica Nanoparticles: A Comprehensive Review on Synthesis and Recent Advances. Pharmaceutics. 2018.) and ZHANG (Surface Engineering of Core/Shell Iron/Iron Oxide Nanoparticles from Microemulsions for Hyperthermia. Mater Sci Eng C Biol Appl. 2010.) in view of KENNEDY (Human serum albumin stabilizes aqueous silver nanoparticle suspensions and inhibits particle uptake by cells. Environmental Science Nano. 2018.).
NARAYAN and ZHANG teach Applicant’s invention as discussed above.
NARAYAN and ZHANG do not teach that the stabilizing molecule is human serum albumin.
Regarding claim 13, KENNEDY teaches nanoparticles that have human serum albumin attached, which stabilizes the nanoparticles against aggregation and dissolution and produces particles that can be lyophilized for long-term storage and redispersed in water consistently (abstract).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate human serum albumin. The person of ordinary skill in the art would have been motivated to make those modifications, because it stabilizes the nanoparticles against aggregation and dissolution and produces particles that can be lyophilized for long-term storage and redispersed in water consistently and reasonably would have expected success because the references are in the same field of endeavor, such as nanoparticles with surface modifications for stability.
Regarding claim 15-19, as discussed above, NARAYAN teaches that nanoparticle is a mesoporous silica and that the diameter can be optimized. ZHANG teaches adding a disilazane. KENNEDY teaches adding human serum albumin.
Response to Arguments
Applicant argues the application describes acoustic responsiveness as sensitive to both surface coverage and preparation conditions. For the F127-coated particles, the application describes acoustic responsiveness as sensitive to both surface coverage and preparation conditions. Increasing F127 concentration reduced the generated ultrasound intensity, and a large amount of F127 at the nanoparticle surface could prevent nanobubble formation or cause destabilization. See Spec. [0058]-[0059], [0068], and Figs. 6-7B. The application also explains that, for the F127-coated particles, bath sonication may consume surface nanobubbles and reports an almost complete decrease in ultrasound responsiveness after five minutes of bath sonication. See Spec. [0068]-[0069] and Figs. 18-19. These F127 results show that acoustic responsiveness can depend on coating conditions, including sonication time. Yildirim, by contrast, prepared its phospholipid-coated particles using three minutes of bath sonication, followed by stirring at 75 °C for 45 minutes, precipitation by centrifugation, and washing. See Yildirim at 36793. Because the application describes surface coverage and preparation conditions as affecting nanobubble formation, dissolution, and acoustic responsiveness, Yildirim's description of cavitation under HIFU does not establish that its particles necessarily have the stabilizer spacing and low-Ml cavitation response recited in amended claim 1.
Examiner does not find the argument persuasive because as discussed above, NARAYAN teaches Applicant’s claim 1. The prior art’s composition would have the same chemical/physical properties of “the stabilizing molecules in the stabilization layer being spaced apart on the silane layer by distances configured to provide bubble nucleation sites that, in response to the ultrasound equipment delivering an acoustic intensity at a mechanical index of about 1.9 or less, initiate cavitation of echogenic micron-sized bubbles.” as claimed by Applicant, because the prior art has the same ingredients as claimed by Applicant, unless proven otherwise. Furthermore, instant claim 1 is general and does not specifically recite what is needed for this property nor does the specification define the distance needed to achieve this effect. Additionally, the claims are towards aa composition not a method.
Applicant argues The Office action reasons that HMDS would improve nanoparticle stability. The stability described in Zhang, however, concerns protection of an iron core against oxidation and dispersion of the particles in aqueous solution. It does not account for the cavitation response recited in amended claim 1. As discussed above, the application describes the acoustic responsiveness of the F127-coated particles as sensitive to surface coverage and sonication conditions. See Spec. [0058]-[0059], [0068] [0069], and Figs. 6-7B and 18-19.
Examiner does not find the argument persuasive because as discussed above, NARAYAN teaches Applicant’s claim 1. The prior art’s composition would have the same chemical/physical properties of “the stabilizing molecules in the stabilization layer being spaced apart on the silane layer by distances configured to provide bubble nucleation sites that, in response to the ultrasound equipment delivering an acoustic intensity at a mechanical index of about 1.9 or less, initiate cavitation of echogenic micron-sized bubbles.” as claimed by Applicant, because the prior art has the same ingredients as claimed by Applicant, unless proven otherwise.
Applicant argues Kennedy is relied upon for using human serum albumin to stabilize silver nanoparticles against aggregation and dissolution and to permit lyophilization, storage, and redispersion. Even accepting that characterization, Kennedy fails to describe ultrasound cavitation or the recitation in amended claim 1 that "the stabilizing molecules in the stabilization layer [are] spaced apart on the silane layer by distances configured to provide bubble nucleation sites that, in response to ultrasound acoustic intensity at a mechanical index of about 1.9 or less, initiate cavitation of echogenic micron-sized bubbles." A reason to use human serum albumin to stabilize a nanoparticle against aggregation and dissolution does not account for the arrangement and cavitation response recited in amended claim 1. The application describes hydrophobic MSNs coated with bovine serum albumin, recombinant human serum albumin, mouse serum albumin, or pooled human plasma as generating ultrasound contrast using a 2.5 MHz imaging transducer operated at a mechanical index of about 1.5. See Spec. [0079][0080] and Figs. 27-28. Kennedy fails to describe a relationship between an albumin coating and cavitation initiated at a mechanical index of about 1.9 or less.
Examiner does not find the argument persuasive because as discussed above, NARAYAN teaches Applicant’s claim 1. The prior art’s composition would have the same chemical/physical properties of “the stabilizing molecules in the stabilization layer being spaced apart on the silane layer by distances configured to provide bubble nucleation sites that, in response to the ultrasound equipment delivering an acoustic intensity at a mechanical index of about 1.9 or less, initiate cavitation of echogenic micron-sized bubbles.” as claimed by Applicant, because the prior art has the same ingredients as claimed by Applicant, unless proven otherwise.
Applicant argues the application describes biodegradation as varying with the degree of hydrophobic modification and the coating applied to the particle. Paragraph [0076] states that nanoparticles functionalized with a reduced amount of hydrophobic monomer unexpectedly exhibited enhanced biodegradability, particularly when stabilized with proteins. BSA-coated hydrophobic MSNs completely degraded in simulated body fluid in four days, whereas F127-coated particles only partially degraded after four weeks under the same experimental conditions. See Spec. [0084] and Figs. 31A-31 B. The in vivo results likewise differed according to the particle formulation. Protein coated particles almost completely degraded by four weeks, while fluorescence from F127-coated particles remained for more than four weeks. See Spec. [0085] and Fig. 32. One week after intravenous administration, almost no fluorescence was detected for the protein-coated particles, which the application describes as indicating almost complete degradation, while a strong fluorescence signal remained in the liver for F127-coated particles. See Spec. [0086] and Fig. 33. These comparisons show that the biodegradation recited in claim 24 does not necessarily follow from the general presence of a nanoparticle core, silane layer, and stabilizing coating. Kennedy describes human serum albumin as stabilizing silver nanoparticles against dissolution; it does not describe the resulting particles as "substantially completely biodegrad[ing] within a period of less than one month after introduction into a body of a subject."
Examiner does not find the argument persuasive because in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., functionalized with a reduced amount of hydrophobic monomer) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Additionally, in response to applicant's argument that the composition unexpectedly exhibited enhanced biodegradability, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). This is since NARAYAN teaches Applicant’s instant claim 1.
Conclusion
No claims are allowable.
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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/S.L.M./ Examiner, Art Unit 1618
/JAKE M VU/ Primary Examiner, Art Unit 1618
