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 .
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement(s) (IDS) was/were submitted on 6/17/2022, 12/01/2023, and 4/12/2024 before the mailing of a first office action. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Status
Claims 1-3, 5, and 9, filed 12/3/2025, are pending. Claims 1-3, 5, and 9 are currently under examination. Claims 4, 6-8, and 10 are canceled.
Claim Objections
Response to Arguments
Applicant’s arguments, see Applicant Reply page 4, para. 3, filed 12/3/2025, with respect to claim 3 have been fully considered and are persuasive. The objection to claim 3 has been withdrawn.
Examiner Note: Examiner previously recommended text that recited “gas generated nanoparticle”. That recommendation should have been “gas generating nanoparticle”. Please amend this in the next claim set.
Claim Rejections - 35 USC § 112
Response to Arguments
Applicant’s arguments, see Applicant Reply page 4, para. 6, filed 12/3/2025, with respect to claims 1-10 have been fully considered and are persuasive. Amended claim 1 resolves the issue of whether claim 1 is a method or product. The rejection of claims 1-3, 5, and 9 has been withdrawn. Claims 4, 6-8, and 10 have been canceled, rendering that rejection moot.
Response to Arguments
Applicant’s arguments, see Applicant Reply page 5, para. 5, filed 12/3/2025, with respect to claims 1-10 have been fully considered and are persuasive. Amended claim 1 now provides sufficient structure to convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The rejection of claims 1-3, 5, and 9 has been withdrawn. Claims 4, 6-8, and 10 have been canceled, rendering that rejection moot.
Response to Arguments
Applicant’s arguments, see Applicant Reply page 7, para. 3, filed 12/3/2025, with respect to claims 1-10 have been fully considered and are persuasive. Amended claim 1 no longer requires undue experimentation for a person of ordinary skill in the art to use the claimed invention for the state purpose. The rejection of claims 1-3, 5, and 9 has been withdrawn. Claims 4, 6-8, and 10 have been canceled, rendering that rejection moot.
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.
Maintained Rejection
Claims 1-3 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al. (US 10,576,170, filed 6/12/2015, published 12/17/2015) in view of Arap et al. (WO2004020999, published 3/11/2004).
Regarding claim 1, Lee discloses the following invention: “the present invention provides gas-generating nanoparticles including fine-grained calcium carbonate crystals and a biocompatible polymer, the fine-grained calcium carbonate crystals being encapsulated inside the biocompatible polymer.” (Lee, col. 4, line 14). Lee also discloses that the surface of the biocompatible polymer may be modified to induce targeting to a target of interest: “In one embodiment of the present invention, the biocompatible polymer of the present invention is surface-modified with the rabies virus glycoprotein (RVG) peptide. The RVG peptide of the present invention may include a rabies virus glycoprotein peptide, or a variant, polypeptide fragment, or derivative thereof. The RVG peptide of the present invention has neuroblastoma-specific targeting.” (Lee, col. 4, line 64).
Lee discloses that “Preferably, a polylactide-polyglycolide copolymer (PLGA) may be used.” (Lee, col. 5, line 37). Lee also uses PLGA as a primary biocompatible polymer in the example section (Lee, col. 9, line 7).
Lee recites the case where the ratio of RVG peptide to polymer is 1:1: “The functionalized gas-generating nanoparticles with primary amine were re-suspended in the MES buffer (pH 7.0), and then EDC/Sulfo-NHS and RVG peptide were added to the suspension (RVG/PLGA=1, mol/mol).” (Lee, col. 9. Line 43).
More specifically, Lee recites a process that is almost identical to the process used by the present application.
Lee discloses: “ Briefly, the gas-generating nanoparticles (0.5 mM) were suspended in 0.1 M MES buffer (pH 7.0), and EDC (0.5 mM) and Sulfo-NHS (0.25 mM) were added to the suspension in order to pre-activate the carboxylic groups of nanoparticles. The NHS-activated nanoparticles then were reacted with ethylene diamine (0.5 mM) for overnight. The resulting nanoparticles were separated and washed three times with deionized water, and freeze-dried. The functionalized gas-generating nanoparticles with primary amine were re-suspended in the MES buffer (pH 7.0), and then EDC/Sulfo-NHS and RVG peptide were added to the suspension (RVG/PLGA=1, mol/mol). RVG peptide-conjugated nanoparticles (RVG-PNP) and gas-generating nanoparticles (RVG-GNPs (0.01-1)) were collected, washed with deionized water, and then stored in 4° C.” (Lee et al., col. 9, line 34).
Applicant specification discloses: “Specifically, the PLGA gas-generating nanoparticle (0.5 mM) was suspended in 0.1 M MES buffer (pH 7.0), and EDC (0.5 mM)/sulfo-NHS (0.5 mM) was added to activate the terminal carboxyl group present in the PLGA gas-generating nanoparticle. The activated PLGA gas- generating nanoparticle was reacted with ethylenediamine (0.5 mM) for one day, and then, washed three times with deionized water, and then resuspended in MES buffer (pH 7.0). EDC/sulfo-NHS and the optimal peptide (molar ratio of optimal peptide: PLGA = 1:1) described in Table 1 below were added to a solution in which the PLGA gas-generating nanoparticle functionalized with primary amine groups was suspended and reacted, and washed with deionized water, and then freeze-dried.” (Specification, page 17, para. 8).
Lee discloses a weight ratio of fine-grained calcium carbonate crystals and the biocompatible polymer as 0.001 to 1:1. Converting the (w/v)% to (w/w), claim 8 gives a range of 0.0076% to 7.69% and Lee gives a range of 0.1% to 50%. These ranges substantially overlap. MPEP 2144.05(I) recites: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).
An alternate way to show this overlap to convert the (w/w)% of Lee to the (w/v)% of the current application. On the low end, the (w/w)% of Lee of .001 converts to 0.1786 (w/v)% after using the density of PLGA (https://www.chemsrc.com/en/cas/34346-01-5_1470921.html, accessed 2/11/2026). On the high end, 1 (w/w)% converts to 178.6% (w/v)%. This substantially overlaps the calcium carbonate crystal in the pharmaceutical composition of 0.01 (w/v) % to 10 (w/v) % as claimed in amended claim 1. Consequently, this range is prima facie obvious and is taught by Lee et al.
Lee does not disclose that the biocompatible polymer surface is modified by an adipocyte-targeting or cell-penetrating peptide.
However, Arap discloses a peptide CKGGRAKDC, which corresponds to Applicant SEQ ID NO: 1 and targets an adipose tissue endothelial receptor: “It is concluded that the adipose tissue endothelial receptor for CKGGRAKDC (SEQ TD NO: 81) is prohibitin (Genbank Accession No. NM_008831).” (Arap, page 119, para. 2) Furthermore, Arap concludes that this peptide targets adipose tissue in both mouse systems and in human systems: “The results obtained in a mouse model system were confirmed in human tissue sections.” (Arap page 119, para. 3) Arap further discloses that: “Prohibitin is expressed in the vascular endothelium of a number of human organs (HG. 30, arrows), including white fat tissue (HG. 30A), skin (HG. 30B), prostate (HG. 30C) and bone (HG. 30E). However, the level of prohibitin expression in white fat blood vessels is much higher than in other types of human tissues (HG. 30).” (Arap, page 119, para. 4). “ Finally, Arap notes that: “The skilled artisan will realize that other prohibitin-binding targeting peptides, antibodies, etc. may be used within the scope of the claimed methods and compositions to control weight and/or to induce weight loss. Further, other known cytocidal, cytotoxic and/or cytostatic agents may be used in place of (KLAKAK)2 (SEQ ID NO:1) to control weight or induce weight loss within the scope of the claimed subject matter.” (Arap, page 119, para. 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the gas-generating nanoparticle of Lee with the adipose targeting peptide of Arap to arrive at the invention recited by claim 1. Based off the disclosures of the prior art, a person of ordinary skill in the art would have substituted the RVG targeting peptide of Lee with the adipose targeting peptide of Arap. A person of ordinary skill in the art would have a reasonable expectation of success because Lee already shows that the gas-generating nanoparticle system is compatible with peptide targeting technology. Furthermore, the method of cellular disruption disclosed by Lee would be target agnostic: “The present invention provides a composition for cell necrosis induction using cell bursting due to the eruption of condensed gas, the composition containing gas-generating nanoparticles.” (Lee, col. 8 line 16). Consequently, the gas-generating nanoparticle of Lee could be targeted to adipose tissue by the peptide of Arap and disrupt said adipose cells by cell bursting. Consequently, claim 1 is obvious over Lee in view of Arap and rejected.
Regarding claim 2, claim 1 is obvious as described above. Claim 2 further recites: “wherein the surface-modified gas-generating nanoparticle selectively causes apoptosis of the adipocyte.”
The properties of the surface-modified gas-generating nanoparticle as described by claim 1 already encompass these properties. MPEP 2112.01(II) states: “A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.”
Furthermore, fusing an adipose-targeting peptide to a biopolymer composition known to induce apoptosis through cell bursting would reasonably yield a composition described by the limitations of claim 2. Consequently, claim 2 is also obvious over Lee in view of Arap and rejected.
Regarding claim 3, claim 1 is obvious as described above. Claim 3 further recites: “wherein the surface- modified gas-generating nanoparticle does not cause apoptosis of cell other than the adipocyte.”
The particles of Lee do not appear to be cytotoxic when not targeted to a target tissue: “Viability of cells treated with gas-generating nanoparticles containing different CaCO3 contents (PLGA-GNPs, no RVG conjugation) was investigated by MTT assay. No significant cytotoxicity of gas-generating nanoparticles was observed up to polymer concentration of 500 μg/ml (FIG. 4a ) (Lee, col. 13, line 36). Furthermore, Arap discloses that: “However, the level of prohibitin expression in white fat blood vessels is much higher than in other types of human tissues.” (Arap, page 119, para. 3).
Therefore, without the presence of the targeted motif, the particles resulting from Lee combined with Arap would not be cytotoxic to any cells other than adipose tissue. Therefore, claim 3 is rejected as obvious over Lee in view of Arap.
Response to Arguments
Applicant's arguments, see Applicant Reply page 8, para. 5, filed 12/3/2025 have been fully considered but they are not persuasive.
Regarding amended claim 1, Applicant asserts: “The cited references neither recognizes nor contemplates a surface-modified gas-generated nanoparticle wherein the molar ratio of the peptide and the biocompatible polymer is 0.05:1 to 1:1. Lee is cited for allegedly teaching certain features of a gas-generating nanoparticle; however, the Examiner acknowledges that "Lee does not disclose that the biocompatible polymer surface is modified by an adipocyte-targeting or cell-penetrating peptide," let alone one that specifically consists of an amino acid sequence set forth in any one of SEQ ID NOs: 1 to 6, as recited in amended claim 1. (Applicant Reply, filed 12/3/2025, page 10, para. 2)
As previously discussed, Lee discloses the following invention: “the present invention provides gas-generating nanoparticles including fine-grained calcium carbonate crystals and a biocompatible polymer, the fine-grained calcium carbonate crystals being encapsulated inside the biocompatible polymer.” (Lee et al., col. 4, line 14). Lee also discloses that the surface of the biocompatible polymer may be modified to induce targeting to a target of interest: “In one embodiment of the present invention, the biocompatible polymer of the present invention is surface-modified with the rabies virus glycoprotein (RVG) peptide. The RVG peptide of the present invention may include a rabies virus glycoprotein peptide, or a variant, polypeptide fragment, or derivative thereof. The RVG peptide of the present invention has neuroblastoma-specific targeting.” (Lee et al., col. 4, line 64). Lee does not disclose that the biocompatible polymer surface is modified by an adipocyte-targeting or cell-penetrating peptide.
Lee also recites the case where the ratio of RVG peptide to polymer is 1:1: “The functionalized gas-generating nanoparticles with primary amine were re-suspended in the MES buffer (pH 7.0), and then EDC/Sulfo-NHS and RVG peptide were added to the suspension (RVG/PLGA=1, mol/mol).” (Lee et al., col. 9., line 43).
Furthermore, Lee recites a process that is almost identical to the process used by the present application.
Lee discloses: “ Briefly, the gas-generating nanoparticles (0.5 mM) were suspended in 0.1 M MES buffer (pH 7.0), and EDC (0.5 mM) and Sulfo-NHS (0.25 mM) were added to the suspension in order to pre-activate the carboxylic groups of nanoparticles. The NHS-activated nanoparticles then were reacted with ethylene diamine (0.5 mM) for overnight. The resulting nanoparticles were separated and washed three times with deionized water, and freeze-dried. The functionalized gas-generating nanoparticles with primary amine were re-suspended in the MES buffer (pH 7.0), and then EDC/Sulfo-NHS and RVG peptide were added to the suspension (RVG/PLGA=1, mol/mol). RVG peptide-conjugated nanoparticles (RVG-PNP) and gas-generating nanoparticles (RVG-GNPs (0.01-1)) were collected, washed with deionized water, and then stored in 4° C.” (Lee et al., col. 9, line 34).
Applicant specification discloses: “Specifically, the PLGA gas-generating nanoparticle (0.5 mM) was suspended in 0.1 M MES buffer (pH 7.0), and EDC (0.5 mM)/sulfo-NHS (0.5 mM) was added to activate the terminal carboxyl group present in the PLGA gas-generating nanoparticle. The activated PLGA gas- generating nanoparticle was reacted with ethylenediamine (0.5 mM) for one day, and then, washed three times with deionized water, and then resuspended in MES buffer (pH 7.0). EDC/sulfo-NHS and the optimal peptide (molar ratio of optimal peptide: PLGA = 1:1) described in Table 1 below were added to a solution in which the PLGA gas-generating nanoparticle functionalized with primary amine groups was suspended and reacted, and washed with deionized water, and then freeze-dried.” (Specification, page 17, para. 8).
A person of ordinary skill in the art would expect these two processes yield surface-modified gas- generated nanoparticles wherein the molar ratio of the peptide and the biocompatible polymer are the same or nearly the same.
Therefore, Lee discloses a surface-modified gas- generated nanoparticle wherein the molar ratio of the peptide and the biocompatible polymer is 0.05:1 to 1:1.
Regarding the targeting peptide, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Lee discloses modification of gas-generating nanoparticles with RVG peptide, not an adipose targeting peptide. However, as previously discussed, Arap discloses a peptide CKGGRAKDC which targets an adipose tissue endothelial receptor: “It is concluded that the adipose tissue endothelial receptor for CKGGRAKDC (SEQ ID NO: 81) is prohibitin (Genbank Accession No. NM_008831).” (Arap, page 119, para. 2) Furthermore, Arap concludes that this peptide targets adipose tissue in both mouse systems and in human systems: “The results obtained in a mouse model system were confirmed in human tissue sections.” (Arap page 119, para. 3) Arap further discloses that: “Prohibitin is expressed in the vascular endothelium of a number of human organs (HG. 30, arrows), including white fat tissue (HG. 30A), skin (HG. 30B), prostate (HG. 30C) and bone (HG. 30E). However, the level of prohibitin expression in white fat blood vessels is much higher than in other types of human tissues (HG. 30).” (Arap, page 119, para. 4). “ Finally, Arap notes that: “The skilled artisan will realize that other prohibitin-binding targeting peptides, antibodies, etc. may be used within the scope of the claimed methods and compositions to control weight and/or to induce weight loss. Further, other known cytocidal, cytotoxic and/or cytostatic agents may be used in place of (KLAKAK)2 (SEQ ID NO:1) to control weight or induce weight loss within the scope of the claimed subject matter.” (Arap et al., page 119, para. 2).
A person of ordinary skill in the art would have a reasonable expectation of success because Lee already shows that the gas-generating nanoparticle system is compatible with peptide targeting technology. Furthermore, the method of cellular disruption disclosed by Lee would be target agnostic: “The present invention provides a composition for cell necrosis induction using cell bursting due to the eruption of condensed gas, the composition containing gas-generating nanoparticles.” (Lee, col. 8 line 16). Consequently, the gas-generating nanoparticle of Lee could be targeted to adipose tissue by the peptide of Arap and disrupt said adipose cells by cell bursting. Consequently, claim 1 is obvious over Lee in view of Arap and rejected.
Therefore, it is the combination of Lee and Arap, not Lee or Arap individually that renders these elements of amended claim 1 obvious.
Applicant further asserts: “Neither Lee nor Arap teaches or suggests the combination of a peptide-conjugated gas-generating nanoparticle, nor do they provide any guidance regarding the level of peptide conjugation required to achieve a significant lipolytic effect in adipocytes.” (Applicant Reply, filed 12/3/2025, page 10, para. 4).
As discussed above. Lee discloses a peptide-conjugated gas-generating nanoparticle. Lee provides guidance on how to conjugate the desired peptide to the nanoparticle: “ Briefly, the gas-generating nanoparticles (0.5 mM) were suspended in 0.1 M MES buffer (pH 7.0), and EDC (0.5 mM) and Sulfo-NHS (0.25 mM) were added to the suspension in order to pre-activate the carboxylic groups of nanoparticles. The NHS-activated nanoparticles then were reacted with ethylene diamine (0.5 mM) for overnight. The resulting nanoparticles were separated and washed three times with deionized water, and freeze-dried. The functionalized gas-generating nanoparticles with primary amine were re-suspended in the MES buffer (pH 7.0), and then EDC/Sulfo-NHS and RVG peptide were added to the suspension (RVG/PLGA=1, mol/mol). RVG peptide-conjugated nanoparticles (RVG-PNP) and gas-generating nanoparticles (RVG-GNPs (0.01-1)) were collected, washed with deionized water, and then stored in 4° C.” (Lee et al., Col. 9, line 33).
The disclosed peptide-nanoparticle ratio is 1:1, which falls within the claimed range in claim 1, and therefore is prima facie obvious.
Applicant further asserts: ” In contrast, the present application demonstrates, for example in Example 6, that the amount of peptide conjugation directly affects adipocyte viability, and that a meaningful effect was achieved within the recited peptide-to-nanoparticle ratio of 0.05:1-1:1, as recited in amended claim 1. Neither Lee nor Arap provides any teaching that would lead a person of ordinary skill in the art (POSITA) into specifically arriving at a molar ratio of the recited peptide and the recited biocompatible polymer of 0.05:1 to 1:1, let alone with a reasonable expectation of success.” ((Applicant Reply, filed 12/3/2025, page 10, para. 5).
As described above, Lee discloses a peptide-nanoparticle ratio of 1:1. Absent a fundamental chemical difference between RVG peptide and an adipose-targeting peptide disclosed by Arap, a person of ordinary skill in the art would have a reasonable expectation of success of following the protocol disclosed by Lee above while substituting the adipose-targeting peptide of Arap for the original RVG peptide. Furthermore, barring evidence of a critical ratio, minor differences can be alleviated with routine optimization. MPEP 2144.05(II)(A) states: “Generally, differences in concentration or temperature will 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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).”
According to Fig. 5 of the specification, the invention still works with a ratio of 0.05 to 1, albeit somewhat less effectively. Consequently, no evidence of a critical ratio is present. In fact, the trend is exactly what a person of ordinary skill in the art would expect: more peptide loaded onto the nanoparticles results in more nanoparticle arriving at the target destination resulting in decreased viability due to the bursting effect of the invention.
Applicant further asserts: “Further, claim 1, as amended, also recites that "the concentration of the fine-grained calcium carbonate crystal in the pharmaceutical composition is 0.01 (w/v) % to 10 (w/v) %." Such a concentration is supported by the Examples of the present application, including in combination with the recited molar ratio of the recited peptide and the recited biocompatible polymer of 0.05:1 to 1:1, which in combination achieves an advantageous apoptotic effect. See generally Examples of the present application.
According to MPEP § 2144.05(III)(C): "Applicants may rebut a prima face case of
obviousness based on optimization of a variable disclosed in a range in the prior art by showing that the claimed variable was not recognized in the prior art to be a result-effective variable." The MPEP explains that the reasoning that this supports non-obviousness is that "a person of ordinary skill would not always be motivated to optimize a parameter 'if there is no evidence in the record that the prior art recognized [that] particular parameter affected the result."' See id.
As discussed above, the recited molar ratio of the recited peptide and the recited
biocompatible polymer of 0.05:1 to 1:1 and the recited concentration of the fine-grained calcium carbonate crystal in the pharmaceutical composition of 0.01 (w/v) % to 10 (w/v) % reflects result-effective variables that the Examples of the present application demonstrates results in an improved apoptotic effect.
Neither Lee nor Arap recognizes the recited molar ratio or recited concentration as being a result-effective variable, let alone in combination, particularly since neither reference teaches or suggests the combination of the recited peptide and the recited biocompatible polymer. “ (Applicant Reply, filed 12/3/2025, page 11, para. 1).
As discussed in the previous office action, Lee discloses a weight ratio of fine-grained calcium carbonate crystals and the biocompatible polymer as 0.001 to 1:1. Converting the (w/v)% to (w/w), claim 8 gives a range of 0.0076% to 7.69% and Lee gives a range of 0.1% to 50%. (Lee et al., claim 1). These ranges substantially overlap. MPEP 2144.05(I) recites: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).
An alternate way to show this overlap to convert the (w/w)% of Lee to the (w/v)% of the current application. On the low end, the (w/w)% of Lee of .001 converts to 0.1786 (w/v)% after using the density of PLGA (https://www.chemsrc.com/en/cas/34346-01-5_1470921.html, accessed 2/11/2026). On the high end, 1 (w/w)% converts to 178.6% (w/v)%. This substantially overlaps the calcium carbonate crystal in the pharmaceutical composition of 0.01 (w/v) % to 10 (w/v) % as claimed in amended claim 1. Consequently, this range is prima facie obvious and is taught by Lee et al.
Regarding the issue of a results-effective variable, Lee et al. discloses that the calcium carbonate ratio influences ultrasound imaging effect and cell bursting effect. “In one embodiment of the present invention, the weight ratio of the fine-grained calcium carbonate crystals and the biocompatible polymer is 0.001:1 to 1:1 (calcium carbonate:polymer). The weight ratio of the fine-grained calcium carbonate crystals and the biocompatible polymer is preferably 0.005:1 to 0.5:1, and more preferably 0.005:1 to 0.05:1. The fine-grained calcium carbonate crystals and the biocompatible polymer corresponding to the weight ratio can maximize the ultrasound imaging contrast effect and the cell bursting effect” (Lee et al., col. 5, line 47).
The cell bursting effect is critical to the activity of the claimed invention, so therefore this ratio is a results-effective variable. Based off the disclosure of Lee, a person of ordinary skill in the art would be motivated to optimize this variable to maximize the ultrasound imaging contrast effect and the cell bursting effect.
Regarding the claimed biocompatible polymer element, PLGA is one of the recited biocompatible polymers recited in claim 6. Lee discloses that “Preferably, a polylactide-polyglycolide copolymer (PLGA) may be used.” (Lee et al., col. 5, line 37). Lee also uses PLGA as a primary biocompatible polymer in the example section (Lee et al., col. 9, line 7).
Regarding the claimed peptide sequences in amended claim 1, Arap discloses a peptide CKGGRAKDC (SEQ ID NO: 81), which corresponds to Applicant SEQ ID NO: 1. This peptide is disclosed to target adipose tissue: “The tropism of CKGGRAKDC (SEQ ID NO:81)-phage for adipose tissue was confirmed by immunohistochemistry: CKGGRAKDC (SEQ ED NO:81)-phage showed marked localization to the vasculature of subcutaneous and peritoneal white fat (HG. 24a, arrows), whereas the control phage was undetectable in fat blood vessels (HG. 24b). To test whether targeting of the CKGGRAKDC (SEQ JD NO: 81) motif to the fat vasculature would also occur when the peptide is outside of the context of the phage, the in vivo distribution of intravenously injected CKGGRAKDC (SEQ JD NO:81) peptide fused to fluorescent (HTC) was determined. Immunofluorescence in subcutaneous and peritoneal fat from peptide-injected ob/ob mice showed that CKGGRAKDC (SEQ ID NO:81)-HTC localized to and was internalized by cells of white adipose vasculature (HG. 24c, arrows), whereas a control CARAC (SEQ JD NO:71)-FTTC conjugate was undetectable in adipose tissue (HG. 24d).” (Arap et al., page 114, para. 3).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the gas-generating nanoparticle of Lee with the adipose targeting peptide of Arap to arrive at the invention recited by claim 1. Based off the disclosures of the prior art, a person of ordinary skill in the art would have substituted the RVG targeting peptide of Lee with the adipose targeting peptide of Arap.
A person of ordinary skill in the art would have a reasonable expectation of success because Lee already shows that the gas-generating nanoparticle system is compatible with peptide targeting technology. Lee also discloses the molar ratio of peptide to biocompatible polymer is obvious over Lee as well as the concentration of fine-grained calcium carbonate crystal. Lee also discloses the usage of PLGA nanoparticles. Given the success disclosed by Lee, it would have been obvious to a person of ordinary skill in the art to also use a PLGA nanoparticle with the obvious ranges recited above.
Furthermore, the method of cellular disruption disclosed by Lee would be target agnostic: “The present invention provides a composition for cell necrosis induction using cell bursting due to the eruption of condensed gas, the composition containing gas-generating nanoparticles.” (Lee et al., col. 8 line 16). Consequently, the gas-generating nanoparticle of Lee could be targeted to adipose tissue by CKGGRAKDC (SEQ ID NO:81) of Arap and disrupt said adipose cells by cell bursting. Consequently, amended claim 1 is obvious over Lee in view of Arap and rejected.
Regarding claims 2 and 3, specific arguments were not provided for these claims. The allowability of these claims are dependent upon the status of claim 1 and are still obvious as described above in the rejection.
Maintained Rejection
Claim 5 was previously rejected under 35 U.S.C. 103 as being unpatentable over Lee et al. (US10,576,170, filed 6/12/2015, published 12/17/2015) in view of Arap et al. (WO2004020999, published 3/11/2004) and further in view of McCarron et al. (McCarron, et al. Journal of Biomedical Materials Research Part A: An Official Journal of The Society for Biomaterials, TheJapanese Society for Biomaterials, and The Australian Society for Biomaterials and the Korean Society for Biomaterials 87.4: 873-884 (2008)).
Regarding claim 5, claim 1 is obvious as described above. Claim 5 further recites “wherein the surface modification is formed by carbodiimide bonding between an amine group at an end of the biocompatible polymer and an amine group at an end of the peptide.” Lee and Arap do not specifically disclose such a bond. However, McCarron describes this procedure for PLGA: “NP produced in this step were of the post-formation activated type. Activation of blank and drug-loaded NP was performed without further purification or removal from the precipitating medium. MES buffer at pH 5 was chosen so as to maximize the reaction of carboxylic acid groups on the PLGA contained within the nanoparticulate matrix. Using a molar ratio of 1:2:1 (nanoparticulate-COOH: EDC:NHS), EDC and NHS were dissolved into the nanoparticulate suspension and kept agitated for 1 h under moderate stirring. Samples were then centrifuged at
50,000g for 1 h at 58C and the pellet was washed three times to remove residual reagents and PVA. Finally, NP were resuspended with phosphate buffered saline (pH 7.4), ready for protein conjugation.” (McCarron, page 875, para. 2 and 3).
It would have obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the method of McCarron to attach the targeting peptide of Arap to the biocompatible polymer of Lee to result in the invention claimed by claim 5. A person of ordinary skill in the art would have a reasonable expectation of success because McCarron uses this process to attach bovine serum albumin to PLGA as described on page 876 para. 3. This procedure would reasonably be expected to work for most protein targets. Consequently, claim 5 is obvious over Lee in view of Arap and in further view of McCarron and rejected.
Response to Arguments
Applicant's arguments, see Applicant Reply page 11, para. 6, filed 12/3/2025, have been fully considered but they are not persuasive.
Applicant asserts: “However, claim 5 is non-obvious over Lee in view of Arap and in further view of McCarron for at least the reasons why pending claim 1, and dependent claims thereof including those discussed above, are non-obvious over Lee in view of Arap. For instance, McCarron does not remedy the deficiencies of rejection of claim 1 discussed above, including, inter alia, the combination of the recited polypeptide and the recited biocompatible polymer, let alone the recited molar ratio of 0.05:1 to 1:1 in combination with the recited concentration of the fine- grained calcium carbonate crystal, nor is McCarron alleged to do so.” (Applicant Reply, filed 12/3/2025, page 12, para. 2).
Regarding claim 5, McCarron is not invoked to address the issues of molar ratio discussed above. McCarron is used to disclose carbodiimide bonding. Consequently, this rejection is maintained.
Maintained Rejection
Claim 9 was previously rejected under 35 U.S.C. 103 as being unpatentable over Lee et al. (US 10,576,170, filed 6/12/2015, published 12/17/2015) in view of Arap et al. (WO2004020999, published 3/11/2004) and further in view of Cleland et al. (Cleland, et al. Current opinion in biotechnology 12.2: 212-219 (2001)).
Regarding claim 9, claim 1 is obvious as described above. Claim 9 further recites wherein the pharmaceutical composition is a form of an injection or transdermal administration. Lee and Arap do not specifically disclose injection or transdermal administration, however, as Leland describes, these methods were well-known in the art before the effective filing date of the invention (Leland, Introduction). Cleland describes the situations where injection would be favored as opposed to transdermal administration (Cleland, page 213, Fig. 1). It would have been obvious to a person of ordinary skill in the art before the effective filing date of the invention to combine the administration routes described by Cleland with the composition of Lee and targeting peptide of Arap to arrive at the invention of claim 9. A person of ordinary skill in the art would have a reasonable expectation of success because Cleland describes how these administration techniques are well-known and extensively used in the prior art for peptide-based therapeutics. Consequently, claim 9 is obvious over Lee in view of Arap and further in view of Cleland and rejected.
Response to Arguments
Applicant's arguments, see Applicant Reply page 12, para. 4, filed 12/3/2025, have been fully considered but they are not persuasive.
Applicant asserts: “However, claim 9 is non-obvious over Lee in view of Arap and in further view of Cleland for at least the reasons why pending claim 1, and dependent claims thereof including those discussed above, are non-obvious over Lee in view of Arap. For instance, Cleland does not remedy the deficiencies of rejection of claim 1 discussed above, including, inter alia, the combination of the recited polypeptide and the recited biocompatible polymer, let alone the recited molar ratio of 0.05:1 to 1:1 in combination with the recited concentration of the fine- grained calcium carbonate crystal, nor is Cleland alleged to do so.” (Applicant Reply, filed 12/3/2025, page 12, para. 6).
Cleland is only invoked to address the issue of transdermal or injection delivery. Consequently, this rejection is maintained.
Double Patenting
Response to Arguments
Applicant has requested that the rejection be held in abeyance. (Applicant Reply, filed 12/3/2025, page 13, para. 2).
In view of the amendments to claim 1, the Examiner has determined that claim 2 of U.S. Patent No. 10,576,170 in view of Arap et al. (WO2004020999, published 3/11/2004) no longer reads on claims 1 and 2. The NSDP rejection of claims 1 and 2 has been withdrawn.
Response to Arguments
Applicant has requested that the rejection be held in abeyance. (Applicant Reply, filed 12/3/2025, page 13, para. 4).
In view of the amendments to claim 5, the Examiner has determined that claim 2 of U.S. Patent No. 10,576,170 in view of Arap et al. (WO2004020999, published 3/11/2004) and MacCarron et al. (McCarron, et al. Journal of Biomedical Materials Research Part A: An Official Journal of The Society for Biomaterials, The Japanese Society for Biomaterials, and The Australian Society for Biomaterials and the Korean Society for Biomaterials 87.4: 873-884 (2008)) no longer reads on claim 5. The NSDP rejection of claim 5 has been withdrawn.
Response to Arguments
Applicant has requested that the rejection be held in abeyance. (Applicant Reply, filed 12/3/2025, page 13, para. 6).
In view of the amendments to claim 1, the Examiner has determined that claim 2 of U.S. Patent No. 10,576,170 in view of Arap et al. (WO2004020999, published 3/11/2004) and Cleland et al. (Cleland, et al. Current opinion in biotechnology 12.2: 212-219 (2001)) no longer reads on claim 9. The NSDP rejection of claim 9 has been withdrawn.
Duplicate Claim Warning
Applicant was previously advised that should claim 1 be found allowable, claim 10 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Response to Arguments
Claim 10 has been canceled, rendering this warning moot. This warning is withdrawn.
Conclusion
No claim is allowed.
Claims 1-3, 5, and 9 are rejected.
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 David Paul Bowles whose telephone number is (571)272-0919. The examiner can normally be reached Monday-Friday 8:30-5:00.
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/DAVID PAUL BOWLES/ Examiner, Art Unit 1654
/LIANKO G GARYU/ Supervisory Patent Examiner, Art Unit 1654