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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 October 1, 2025 has been entered.
Response to Arguments
Applicants' arguments, filed October 1, 2025, have been fully considered but they are not deemed to be fully persuasive. The following rejections and/or objections constitute the complete set presently being applied to the instant application.
While new grounds of rejection are set forth below, some of the same references are used in the rejections below as in the Final Office Action mailed April 7, 2025. Therefore, Applicants arguments regarding the previous applied prior art references still used in the rejections are addressed below and the arguments regarding Doller and Brisander are moot as they are no longer used to reject the pending claims.
Applicants argue that Zhang does not discuss mononuclear phagocyte system (MPS) cells, provides no in vivo data and does not describe subcutaneous administration. The in vitro data would not provide one of ordinary skill in the art with a reasonably expectation of success in reducing effector nanoparticle uptake by MPS cells.
These arguments are unpersuasive. In response to applicant's arguments against the references individually, 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). Features such as subcutaneous administration are taught by other applied prior art references. That the applied prior art does not provide in vivo data does not mean that one of ordinary skill in the art would not have contemplated in vivo nanoparticle administration, particularly given the ubiquity of in vitro experimentation prior to moving to in vivo applications given the general ease and lower cost of in vitro experiments compared to in vivo experiments. A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton (MPEP 2141(II)(C). The active step of the instant claims is administration of two different populations of nanoparticles to a subject – one loaded with an endocytosis inhibitor that can be latrunculin A or B and another population of nanoparticles loaded with a therapeutic agent or diagnostic payload. As discussed in greater detail below, the combined teachings of the applied prior art render obvious the administration of two such different populations of nanoparticles to a subject – one loaded with latrunculin and another population of nanoparticles loaded with sorafenib as both agents are taught in the art for the treatment of cancer. A reasonable expectation of success for the active step exists as one of ordinary skill would expect that that such nanoparticles can be prepared, loaded with the desired active agent, and administered to a subject. The preamble and wherein clause at the end of claim 14 merely express in words an effect that occurs when the single active step of the claimed method is performed. That Applicants have an additional or alternative reason for administration of the latrunculin containing nanoparticles of altering MPS cell uptake of the other population of nanoparticles does not mean that one of ordinary skill would not reasonably expect that two such populations of nanoparticles could be administered to a subject with cancer to treat the cancer.
Applicants also argue that Velluto fails to cure the deficiencies of the other references. Velluto does not disclose a nanostructure that is a micelle, a polymersome, a filamentous worm-like micelle, or a bicontinuous nanosphere; endocytosis inhibitors or subcutaneous administration. Functional equivalence of the PCL-PEG micelles and the PEG-b-PPS micelles has not been established nor have any advantages of PEG-b-PPS micelles compared to PEG-PCL micelles been described. Velluto is limited to in vitro delivery under conditions devoid of MPS cells. Applicants indicate disagreement with the motivation paragraph on p 8 and 9 of the previous Office Action mailed April 7, 2025 given that Velluto is not concerned with treating hepatocarcinoma cells but solubilizing hydrophobic drugs such as cyclosporin A. Solubilizing micelles was already solved by Zhang et al. and one would not turn to the untried PEG-b-PPS diblock copolymer aggregates of Velluto. The Examiner’s motivation can only be realized with the hindsight benefit of Applicant’s disclosure.
These arguments are unpersuasive. The abstract of Velluto and elsewhere the article itself indicate formation of drug-loaded polymeric micelles using the disclosed PEG-b-PPS materials (such as p 635, section entitled “Preparation and Characterization of PEG-b-PPS Micelles”). While not preceded by “filamentous”, the description of Figure 3B states that “wormlike” micelles were observed. The arguments about functional equivalence are not fully understood by the Examiner. Both PEG-PCL and PEG-b-PPS can form micelles and be loaded with drugs as taught in the applied prior art. The applied references are analogous art and that that one reference has disclosed one solution for solubilizing hydrophobic molecules does not mean that those working in the field would not continue to investigate other materials that can be used to prepare drug delivery structures and/or solubilize molecules of interest with low solubility. As cited previously and reiterated below, Velluto et al. discusses that various PEG-hydrophobic block combinations have given rise to various micellar systems with distinct physicochemical properties and different characteristics important to their suitability as drug carriers and PEG-b-PPS micelles have burst free sustained release along with interesting solubilization characteristics due to the low glass transition temperature, highly hydrophobic nature and good solvent properties of the PPS block burst free sustained release along with interesting solubilization characteristics due to the low glass transition temperature, highly hydrophobic nature and good solvent properties of the PPS block. Micelles made from different PEG-hydrophobic blocks have different properties that can motivate one of ordinary skill in the art to use different materials and advantages of PEG-b-PPS containing systems are set forth by Velluto et al. An explicit teaching, suggestion or motivation to use PEG-b-PPS micelles in place of PEG-PCL micelles is not required to render such a change obvious. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Applicants argue that the rejection of record is effectively premised on the notion that it would be obvious for one of ordinary skill in the art to selectively utilize the PEG-b-PPS micelles of Velluto to the exclusion of the PEG-PCL used in Zhang and those of Brisander, both being similarly designated for use with hydrophobic or poorly soluble drug but no compelling technical reason is provided that would have led the skilled artisan to selectively employ Velluto’s nanoparticles rather than those of Zhang or Brisander. The alleged motivation to combine can only be derived from the hindsight benefit of Applicant’s disclosure since there is insufficient evidence to support the knowledge that the sum total of the modifications takes into account only knowledge within the level of ordinary skill in the art at the time the claimed invention was made. The rejection is based on a series of largely unrelated references with different compositions and technical objectives, each necessitating selective retainment of certain feature and rejection or substitution or other without sufficient guidance or suggestion to do so.
These arguments are unpersuasive. Applicants have not identified knowledge only gleaned from the instant specification that was used in the obviousness rejection. The rationale used in an obviousness rejection need not be the same as Applicants (see MPEP 2144(IV)) and here the obviousness rejection argues the inclusion of latrunculin containing nanoparticles not because of alterations in the behavior of MPS cells but because of their art appreciated function of treating cancer. It is also noted that "[t]he test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference .... Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art." In re Keller, 642 F.2d 413,425 (CCPA 1981) MPEP 2145(III). The fact that there are other possible materials that can be used to prepare drug loaded micelles does not render the use of PEG-b-PPS micelles any less obvious.
Regarding Allen, the reference used to render obvious the claims requiring a bicontinuous nanosphere (BCN), Applicants argue that this reference does not disclose subcutaneous administration but rather intravenous administration. Allen is not seeking to decrease uptake of PSs [polymersomes] or BCNs by macrophages and dendritic cells but seeks the opposite effect.
These arguments are unpersuasive. Allen is not relied on to teach subcutaneous administration as this feature is taught by El Sayed et al. and Reddy et al. "The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference .... Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art." In re Keller, 642 F.2d 413,425 (CCPA 1981) MPEP 2145(III) so intravenous administration as in Allen et al. is not a required feature. As discussed above, the active step of the instant claims is administration of two different populations of nanoparticles to a subject – one loaded with an endocytosis inhibitor that can be latrunculin A or B and another population of nanoparticles loaded with a therapeutic agent or diagnostic payload, called the effector nanoparticles. In claim 14, the endocytosis inhibitor nanoparticles must comprise PEG-b-PPS but the preamble indicates that is it uptake of the other population of nanoparticles, the effector nanoparticles, by MPS cells that is altered. The wherein clause of claim 14 does not relate to whether or not nanoparticles are taken up by the MPS but if fewer effector nanoparticles are taken up when the PEG-b-PPS and latrunculin containing nanoparticles (first population) “compared to effector nanoparticles administered in the absence of the first population of nanoparticles”. There is no evidence of record as to the criticality of the nanoparticulate form. Claim 29 requires that the effector nanoparticles are comprised of PEG-b-PPS and does not otherwise specify the form of the nanoparticles. Claim 30 requires the endocytosis inhibitor containing nanoparticles, not the effector nanoparticles, to be in the form of a bicontinuous nanosphere. The question is would one have ordinary skill in the art been motivated to prepare latrunculin loaded BCNs comprised of PEG-b-PPS and administer such nanoparticles to a subject. The differential uptake of nanostructures of the same compositions and different biodistribution discussed in the paragraph bridging cols 1 and 2 on p 3386 1 of Allen et al. means that depending on the desired biodistribution, different forms may be preferred when one of ordinary skill in the art is preparing a drug delivery formulation and there is no evidence of record establishing unexpected results that outweigh the prima facie case of obviousness.
Applicants argue that the cited references do not lead to the claimed invention as the invention employs a novel strategy to inhibit internalization of effector nanoparticles by the MPS in macropinocytosis inhibitory nanoparticles (MiNP) are pre- or co-administered with the effector nanoparticles. As demonstrated in the examples, MiNP containing latrunculin A significantly improved the s.c. injection of effector nanoparticles, achieving systemic bioavailability of the effector nanoparticles on par with intravenous injection. This problem is not mentioned in any of the references.
These arguments are unpersuasive. Prior art can, but need not, explicitly disclose every single claim limitation in order to render a claim obvious. The single active step of the instant claims has been discussed above and is rendered obvious by the applied prior art as a combination treatment for cancer. The other recitations reading particle uptake in the claims necessarily flow from administration of the latrunculin containing nanoparticles and therapeutic/diagnostic containing nanoparticles. “[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). That Applicants appreciated and explicitly recite features that are not explicitly taught in the prior art does render the instant claims patentable as the method step is rendered obvious. There is no evidence of record that the dosages of nanoparticles that are therapeutically effective for the treatment of cancer do not result in reduced uptake of effector nanoparticles compared to if only the therapeutic/diagnostic agent loaded nanoparticles were administered. The cited examples show there were differences in behavior but the question is if those differences in behavior are in fact unexpected given the known effects of latrunculin A. LatA complexes with actin monomers to disrupt actin polymerization and therefore alters the cytoskeletal elements of cells that amongst other functions regulate endocytosis (¶¶ [0005] and [0006] of El Sayed et al.). Without clearly establishing what effects one of ordinary skill in the art would have expected with latrunculin administration to do to effector nanoparticle behavior, it cannot be determined if the observed results are in fact unexpected.
Applicants argue that there is no expectation of success for reducing uptake of an effector nanoparticle by MPS cells in a subject. The Examiner does not provide sufficient expectation of success in view of the cited references and none of those references discloses any examples of subcutaneously administering a nanoparticle in vivo, let alone the two claimed populations of nanoparticles.
These arguments are unpersuasive. The claims are rejected as obvious and not anticipated so there need not be explicit, implicit or inherent disclosure of all claim elements of the single active step in a single applied prior art reference. A conclusion of obviousness must take into consideration the explicit, implicit and inherent teachings of the prior art and the knowledge of one of ordinary skill in the art. One of ordinary skill in the art would reasonably expect that the two required populations of nanoparticles prepared, loaded with the appropriate substances and then subcutaneously administered to a subject as required by the instant claims. Nothing in the claim language regarding nanoparticle uptake limits the subject population to whom the nanoparticles are administered. Relevant teachings of the applied prior art documents are set forth below. The lack of a specific example of subcutaneous nanoparticle administration in the prior art does not mean that one of ordinary skill in the art before the effective filing date of the claimed invention would reasonably expect that such nanoparticles could not be administered subcutaneously. What is conventional or well known to one of ordinary skill in the art need not be disclosed in detail. See Hybritech Inc. v. Monoclonal Antibodies, Inc., 802 F.2d at 1384, 231 USPQ at 94. See also Capon v. Eshhar, 418 F.3d 1349, 1357, 76 USPQ2d 1078, 1085 (Fed. Cir. 2005) MPEP 2163(II)(A)(3)(a).
Applicants argue that even if there was a prima facie case of obviousness, it is overcome by the unexpectedly superior results shown in the specification as filed. Greater than expected results are shown, which is pertinent to the legal conclusion of obviousness. Figures 3A – 3G show splenic and liver accumulation of loaded nanoparticles in the absence of MiNPs administration and to a significantly greater extent when administration subcutaneously than intravenous administration. The significant increase in loaded nanoparticles circulating in the serum permits the intended delivery to cells without sequestration, lowering the dose of effector nanoparticles administered to achieve the intended effects with a range of benefits for safety, efficacy and efficiency. The presence of a property not possessed by the prior art is evidence of non-obviousness. A person of skill in the art would have no expectation of any synergistic effect being exerted upon a second population as shown in Figure 3.
These arguments are unpersuasive. Any differences between the claimed invention and the prior art may be expected to result in some differences in the observed effects. The issue is whether the results differ to such an extent that the difference is really unexpected (MPEP 716.02). In some cases, synergy can be an expected result so even a synergistic effect may be the expected result. The burden is on Applicant to establish that the results are unexpected and unobvious and of both statistical and practical significance (MPEP 716.02(b)). It is not clear how the conclusion of greater than expected results was arrived at as the Examiner is unable to locate in the disclosure are filed or in the remarks any indication of what the expected results would be. Without knowing what the expected results would be, how was it determined that the results obtained were greater than expected and any differences from the expected results are of a significant and practical advantage? The claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). Applicants appear to be interpreting the prior art’s silence as to the property of latrunculin A altering uptake of nanoparticles by MPS cells as that the property is not present in the prior art. The lack of an explicit description of such an effect does not require that property is not present in the prior art, as such a property could be unappreciated but that does not render the instant claims patentable.
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.
Claim(s) 14 – 16, 20, 23 - 25, 27 – 29 and 31 are rejected under 35 U.S.C. 103 as being unpatentable over El Sayed et al. (US 2011/0136880) and Zhang et al. (Int J Nanomed, 2013) in view of Velluto et al. (Mol Pharm, 2008) and Reddy et al. (J Cont Rel, 2005).
El Sayed et al. discloses anti-invasive and cytotoxic uses for latrunculins and latrunculin derivatives that are useful, for example, in treating cancers (whole document, e.g., abstract). Latrunculins such as latrunculin A and B have antiangiogenic, antiproliferative, antimicrobial and antimetastatic activity and disrupt microfilament organization without affecting the microtubular system (¶ [0006]). Compounds as in the present invention may be administered to a patient by any suitable means including subcutaneously (¶ [0104]). A method of controlling the duration of action comprises incorporating the active compound into particles of a polymeric substance or alternatively encapsulated in nanoparticles or microcapsules by techniques known in the art (¶ [0107]).
Treatment of tumor cells with an agent capable of treating cancer other than a latrunculin such as latrunculin A or latrunculin derivatives in nanoparticle form is not disclosed.
Zhang et al. discloses the inhibitory effects of targeted folate-functionalized micelles containing superparamagnetic iron oxide nanoparticles (SPIONs) and sorafenib on HepG2 human hepatic carcinoma (whole document, e.g., abstract). Sorafenib is currently the only agent currently proven to prolong survival time significantly in patients with advanced hepatocellular carcinoma but there are many side effects that limit the therapeutic effects that can be achieved (p 1518, col 1, ¶ 1). Polyethylene glycol-block-poly(ε-caprolactone (PEG-PCL) micelles have been shown to have a number of attractive features as drug carriers with polymeric micelles being widely used to improve the efficacy of drug delivery and reduce toxicity (p 1518, col 1, ¶ 2). SPIONs are used to observe drug absorption (p 1518, col 1, ¶ 2). Both the sorafenib and SPION were loaded in the core of PEG-PCL micelles with folate used to target tumor cells (p 1518, col 1, ¶ 3). Uptake of the targeted micelles into HepG2 cells was observed that increased cellular sorafenib concentrations (p 1520, col 2, ¶ 3 and figure 3) and higher apoptotic rates were observed for targeted micelles (p 1521, col 1, ¶ 2 and figures 4A and 4B). The targeted micelles could be used as a drug delivery carrier to improve the therapeutic effects of sorafenib and to reduce while toxicity while the SPIONs allow for monitoring using a clinical MRI scanner (p 1523, col 2, ¶ 2).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to administer both a latrunculin such as latrunculin A as taught by El Sayed et al. and the targeted folate-functionalized micelles comprising sorafenib of Zhang et al. to a patient suffering from cancer such as hepatocarcinoma to treat the tumor cells of the subject. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because both LatA and the sorafenib containing micelles are disclosed as treating cancer cells. “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) MPEP 2144.06. There are no claim limitations on the amount of endocytotic inhibitory materials administered and there is no evidence of record that the dosages of nanoparticles that are therapeutically effective for the treatment of cancer do not result in reduced uptake of the sorafenib loaded nanoparticles by MPS cells when both types of nanoparticles are administered compared to if only the sorafenib loaded nanoparticles were administered.
While El Sayed et al. generally discloses encapsulation of the latrunculin compounds in nanoparticles or microcapsules, that the latrunculin is provided in a micelle of poly(ethylene glycol)-block-poly(propylene sulfide) (PEG-b-PPS) nanostructure is not disclosed.
Velluto et al. discloses PEG-b-PPS polymeric micelles (whole document, e.g., title) and that different core- and shell-forming structures have been developed that remain intact, retain the drug content and target the encapsulated drug away from sites of drug toxicity and toward diseases sites (p 633, col 1, ¶ 3). Various PEG-hydrophobic block combinations have given rise to various micellar systems with distinct physicochemical properties and different characteristics important to their suitability as drug carriers (p 633, col 2, ¶ 1). Polymeric amphiphiles with hydrophilic PEG blocks and hydrophobic block that is a liquid or amorphous and well above its glass transition temperature should be capable of much higher drug loadings than glassy or crystalline cores (sentence bridging p 633 and 634). AB block copolymers of PEG and poly(propylene sulfide) (PPS) were studied (p 634, col 1) and demonstrated burst free sustained release along with interesting solubilization characteristics due to the low glass transition temperature, highly hydrophobic nature and good solvent properties of the PPS block (abstract). Depending on the size of the PPS blocks, spherical or wormlike micelles were formed (p 637, col 1, ¶¶ 3 and 4) and also influenced the loading of the hydrophobic drug cyclosporin A (CsA; p 639, col 1, ¶ 2). The micelles greatly increased the effective water solubility of the CsA compared to water only (¶ bridging p 638 and 639). The in vitro release rate of CsA was a function of PPS block length and was more or less linear in time and sustained over 9 – 12 days at 37°C (p 639, col 2, ¶ 2). The high hydrophobicity of the PPS block can easily solubilize the CsA by means of hydrophobic interactions (p 641, col 2, ¶ 3). The delayed release of CsA may be clinically less important than the achieved high effective solubility but is interesting in providing more constant drug concentrations between disease and/or more convenient dosing regimens (p 642, col 2, ¶ 2).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the therapeutic agents such as LatA and sorafenib into a micelle comprised of PEG-PPS as disclosed by Velluto et al. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because Velluto et al. discloses that PEG-PPS micelles can solubilize and release hydrophobic drugs. One of ordinary skill in the art would reasonably expect that the LatA could be formulated in such micelles to not only experience increased solubilization but also provide for a controlled duration of action. While the sorafenib and SPIONs in Zhang et al. are already present in micelles, the use of PEG-PPS instead of the PEG-PCL used in Zhang et al. to encapsulate the sorafenib and SPIONs would also be contemplated by one of ordinary skill in the art due to the different characteristics of the hydrophobic segments of the micelles resulting in altered solubilization of the agents contained therein and the properties such as burst free sustained release and drug solubilization due to the low glass transition temperature, highly hydrophobic nature and good solvent properties of the PPS block taught by Velluto et al. for micelles comprised of PEG-b-PPS.
Subcutaneous administration is generally disclosed by El Sayed et al. but explicit motivation to administer two populations of nanoparticles for treating cancer as taught by El Sayed et al., Zhang et al. and Velluto et al. subcutaneously is not disclosed.
Reddy et al. studied the influence of administration route on the tumor uptake of etoposide containing tripalmitin nanoparticles that were administered subcutaneously, intravenously or intraperitoneally (whole document, e.g., abstract). Different routes of administration may result in varying effects on the biodistribution pattern of drug carriers (p 186, col 1, ¶ 2). Subcutaneous and intraperitoneal routes have been suggested for improved lymphatic transport of drug carriers (p 186, col 2, ¶ 2). For the particular nanoparticles studied, subcutaneous administration was preferred given the relatively low tissue distribution, tumor uptake and the nanoparticles accumulation at the administration site after subcutaneous injection is advantageous in facilitating prolonged tumor therapy (¶ bridging p 196 and 197; abstract).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to subcutaneously administer both the LatA and sorafenib/SPION containing nanoparticles to a subject with cancer. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because the nanoparticle must be administered to the subject and Reddy et al. discloses that the administration route is a results effective parameter that can influence the distribution of administered nanoparticles and for at least some nanoparticles, subcutaneous administration can be result in higher tumor uptake and prolonged tumor therapy due to accumulation at the administration site. The selection of the administration route from those that are known to one of ordinary skill in the art is well within their skill and is prima facie obvious absent secondary considerations such as unexpected results. There is no persuasive evidence of record as to the criticality of the claimed administration route.
The applied prior art does not explicitly disclose that when administered, the two populations of nanoparticles, one loaded with the endocytosis inhibitor LatA and the other with an agent capable of treating cancer results in reduced uptake of the effector nanoparticle by the mononuclear phagocyte system (MPS) cells or increased accumulation in the serum of the subject. However, the combination of the applied prior art renders obvious the administration of the same compositions as claimed to a subject. As the same step recited in the body of the claims with the same two populations of nanoparticles is rendered obvious by the applied prior art, the same effects such as reduced uptake of the effector nanoparticle by the mononuclear phagocyte system (MPS) cells compared to accumulation in the absence of co-administration with the other population of nanoparticles or increased accumulation in the serum of the subject must necessarily occur even if they are not explicitly taught in the applied prior art. The fact that applicant 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). “[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).
Claim(s) 29 and 30 are rejected under 35 U.S.C. 103 as being unpatentable over El Sayed et al., Zhang et al., Velluto et al. and Reddy et al. as applied to claims 14 – 16, 20, 23 - 25, 27 – 29 and 31 above, and further in view of Allen et al. (ACS Appl Mater Interfaces, 2018).
El Sayed et al., Zhang et al., Velluto et al. and Reddy et al. are discussed above.
That the LatA containing nanostructures are bicontinuous nanospheres is not disclosed by El Sayed et al., Zhang et al., Velluto et al. and Reddy et al.
Allen et al. discloses that polymersomes (PSs) present numerous benefits over liposomes and polymeric bicontinuous nanospheres (BCNs) present similar advantages including higher stability, increased stealth characteristics and greater amenability to chemical modification for triggered payload release and surface engineering for cell targeting, compared to the lipid analogs of BCNs, cubosomes (p 33857, col 1). BCNs have cubic internal organization of aqueous channels capable of loading hydrophilic compounds and increased hydrophobic volume for loading lipophilic compounds along with a more sustained and size dependent release profile of the payloads trapped within their interconnected narrow channels compared to PSs (p 33857, col 2, ¶ 1). Among the short list of polymers capable of forming BCNs is PEG-b-PPS that is relatively simple compared to some other BCN-forming polymers and BCNs can be prepared using a rapid, scalable, sterile process of flash nanoprecipitation (FNP) that is also capable of forming uniform PEG-b-PPS nanocarriers of numerous morphologies (p 33858, col 1, ¶ 2). Since PEG-b-PPS is oxidation sensitive, bioresponsive or triggered cargo delivery is possible (p 33858, col 1, ¶ 2). BCNs were better able to maintain their morphology in the presence of saturating levels of hydrophobic payloads and both hydrophilic and hydrophobic payloads were loaded with higher efficiency in BCNs compared to PSs (p 33864, col 2, ¶ 3).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to load BCNs made from PEG-b-PPS with either LatA or sorafenib/SPIONs that are then administered subcutaneously to a subject with cancer. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because Velluto et al. discloses solubilization and sustained release of hydrophobic drugs in PEG-b-PPS liposomes and based on the teachings of Allen et al., at least higher loading of this drug would be possible when a BCN made of PEG-b-PPS is used as the carrier. Based on the ability of BCNs to be loaded with both hydrophilic and hydrophobic drugs given their structure, one of ordinary skill in the art would also reasonably have expected success that BCNs as in Allen et al. can be loaded with LatA or sorafenib. By using the same nanoparticle carrier containing different agents, such as the BCNs comprised of PEG-b-PPS disclosed by Allen et al. that can be loaded with hydrophilic and/or hydrophobic drugs, factors such as the biodistribution and clearance of the particles should be very similar. Providing and administering two separate populations of carriers, rather than loading BCNs with multiple agents will prevent any possible interactions within the particle and allow for the facile and independent adjustment of the dose of the agents even if the two populations of nanoparticles are administered at the same time to the subject.
Conclusion
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/Nissa M Westerberg/Primary Examiner, Art Unit 1618