DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . Claims 1, 12-14, 20, 27, 29-30, 35-39, 42, 50-52 filed January 05, 2026 are currently pending.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 02/23/2026 has been entered.
Response to Amendment
The claims filed 01/05/2026 do not contain any amendments. The claims filed 01/05/2026 are the same as those that were filed on 08/11/2025 and the subject of the Final Office Action of 11/07/2025 and the advisory action of 02/04/2026. Applicant's arguments, filed 01/05/2026 have been fully considered. Rejections and/or objections not reiterated from the previous Office Action are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set of rejections and objections presently being applied to the instant application.
Claim Rejections - 35 USC § 103-Rejection(s) Maintained
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.
Claim(s) 1 ,12, 20, 27, 35-37, 42 and 50-52 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Hu et al (International Journal of Molecular Medicine Vol. 37 pages 690-702. Published 2016) and Li (Materials Science and Engineering C Vol. 77 pages 803-810 published online 03/27/2017).
Claim interpretation is as follows: Claim 1 is directed to a pharmaceutical composition, comprising: synergistic amounts of: at least one anti-cancer agent, wherein the at least one anti-cancer agent is temozolomide; and a nanoparticle formulation consisting of an anti-cancer response modulator, wherein the anti-cancer response modulator is quercetin ,wherein the synergistic amounts of the at least one anti-cancer agent and the nanoparticle formulation, are effective for treatment of a neoplasm, and wherein quercetin is in solution at a concentration of 10 mg/mL to 500 mg/mL. Given the broadest reasonable interpretation of the present claims, the pharmaceutical composition of claim 1 embraces two separate dosage forms composed of i) a synergistic amount of the at least one anti-cancer agent temozolomide and ii) a synergistic amount of a nanoparticle formulation consisting of an anti-cancer response modulator, wherein the anti-cancer response modulator is quercetin.
Hu teaches a pharmaceutical nanoparticle compositions comprising the anti-cancer response modulator quercetin (QUE-NL) (abstract, pages 691-693, Table 1, pages 699-700, Figures 1-6). Hu teaches formulating said nanoparticle with the pharmaceutically acceptable carriers DSPE and PEG and that the average particle size of the nanoparticle is 196 nanometers (abstract, Figure 1, Table 1). Regarding the limitation of “nanoparticle formulation” the specification and claims defines “nanoparticle formulation” as comprising a particle size of 100 nm to 250 nm ([0134]-[0135], claim 50). Thus, the 196 nm particle size of the quercetin nanoparticle found in Figure 1 and Table 1 of Hu lies inside this purported range. In addition, paragraphs [0152], Figure 5 and Table 6 of present specification teaches that the nanoparticle formulation comprises PEG and DPSE just like the nanoparticle composition Hu.
In Table 1 and Figures 1-6 of Hu, Hu teaches preparing nanoliposomes comprising quercetin that exclude temozolomide (QUE-NL) as well as nanoliposomes comprising both quercetin and temozolomide wherein both quercetin and temozolomide are encapsulated within the nanoliposome (QUE-TMZ-NL) (page 691 right col., page 693 right col.). In Figure 6A-C, Hu teaches a biodistribution study, wherein the QUE-TMZ-NL composition was intragastrically administered to a U-87 xenograft glioblastoma patient. As a comparative control, Hu teaches intragastrically administering a dose of 25 mg/kg QUE-NL by itself. Hu also teaches administration of a 25 mg/kg dose of free temozolomide in a separate dosage form from QUE-NL (page 692 right col. through page 693 left col., pages 699-700). Thus, the intragastric formulation comprising 25 mg/kg QUE-NL as well as a separate 25 mg/kg free temozolomide administered to the U87 xenograft glioblastoma patient in Figure 6B reads on a composition comprising i) a nanoparticle comprising quercetin in itself and ii) temozolomide. Regarding the limitation directed to “synergistic amounts” of temozolomide and quercetin nanoparticle, see [0189] of the instant specification wherein said “synergistic amount” of temozolomide is 10-1000 mg/m2. See [0150] of the instant specification wherein the dose of quercetin is 100 mg-10 g. See also Table 1 of Reagan-Shaw (FASEBJ Vol. 22 pages 659-661 published 2007) wherein the conversion of mg/m2 to mg/kg is to divide by the Km. Thus, the 10-1000 mg/m2 of temozolomide reads on a dose of 1.66 to 166.6 mg/kg temozolomide to a rat patient. In the present case, Hu teaches an intragastric formulation consisting of 25 mg/kg QUE-NL by itself as well as a separate 25 mg/kg free temozolomide by itself, wherein each of the components are administered to the U87 rat xenograft glioblastoma patient in Figure 6B. Said doses of each component reads on the “synergistic amount” of temozolomide and quercetin embodied within the instant specification.
Regarding claims 12, 20, 27, Hu teaches that said nanoparticle composition comprising the intragastric injection formulation consisting of 25 mg/kg QUE-NL as well as a separate 25 mg/kg free temozolomide prior to administration comprise all the required limitations and is therefore “suitable for IV administration” (page 691-693 left col., page 699-700 Figure 1 and Figure 6).
Regarding the limitation of claims 35, 37 and 42, as shown in [0058] of the specification, experimental animals read on a patient in need. In the present case, said experimental animal (rat) comprises a glioma generated by U-87 glioma cells and is treated by administration of an intragastric formulation consisting of 25 mg/kg QUE-NL as well as separate 25 mg/kg free temozolomide (see page 692 right col. through page 693 left col., Figure 6B, pages 699-700).
The difference between the presently claimed and the intragastric formulation comprising 25 mg/kg QUE-NL as well as a separate 25 mg/kg free temozolomide administered to the U87 xenograft glioblastoma patient taught by Hu, is that Hu does not specifically teach wherein the quercetin is present in a concentration of 10 mg/mL to 500 mg/mL.
Li (Materials Science and Engineering C Vol. 77 pages 803-810 published online 03/27/2017) teaches the preparation of quercetin-loaded nanoliposomes (QUE-NLs) to treat cancer in a subject in need (abstract). Li teaches preparation of said quercetin nanoliposome wherein quercetin is present in a concentration of 10 mg/mL (page 804 right col., section 2.6). Regarding claim 36, Li teaches that said quercetin nanoparticles are intravenously administered to treat cancer in a subject in need (page 805 left col., Figure 3).
Therefore, one of ordinary skill in the art prior to the time of the invention would have found it prima facie obvious to adjust the dose of quercetin in the intragastric formulation comprising 25 mg/kg QUE-NL as well as a separate 25 mg/kg free temozolomide as taught by Hu, to a dose wherein the concentration of quercetin in the quercetin-nanoliposome is present in a range from 10 mg/mL to 500 mg/mL in view of Li, arriving at the presently claimed.
MPEP 2143 provides rationale for a conclusion of obviousness including (A): Combining prior art elements according to known methods to obtain predictable results;
In the present case, Li teaches the preparation of quercetin-loaded nanoliposomes (QUE-NLs) to treat cancer in a subject in need wherein said quercetin is present in the nanoliposome in a concentration of 10 mg/mL. Accordingly, said skilled artisan would have applied the methodology of Li to the intragastric formulation comprising QUE-NL as well as a separate 25 mg/kg free temozolomide administered to the U87 xenograft glioblastoma patient taught by Hu above, arriving at the presently claimed with a reasonable expectation of success.
Applicant is reminded of MPEP 2144.05 wherein “[A] range can be disclosed in multiple prior art references instead of in a single prior art reference depending on the specific facts of the case. Iron Grip Barbell Co., Inc. v. USA Sports, Inc., 392 F.3d 1317, 1322, 73 USPQ2d 1225, 1228 (Fed. Cir. 2004). The patent claim at issue was directed to a weight plate having 3 elongated openings that served as handles for transporting the weight plate. Multiple prior art patents each disclosed weight plates having 1, 2 or 4 elongated openings. 392 F.3d at 1319, 73 USPQ2d at 1226. The court stated that the claimed weight plate having 3 elongated openings fell within the "range" of the prior art and was thus presumed obvious. 392 F.3d at 1322, 73 USPQ2d at 1228. The court stated that the "range" disclosed in multiple prior art patents is "a distinction without a difference" from previous range cases which involved a range disclosed in a single patent since the "prior art suggested that a larger number of elongated grips in the weight plates was beneficial... thus plainly suggesting that one skilled in the art look to the range appearing in the prior art." The court further stated that “[Nonetheless, where there is a range disclosed in the prior art, and the claimed invention falls within that range, there is a presumption of obviousness. But the presumption will be rebutted if it can be shown: (1) That the prior art taught away from the claimed invention, In re Geisler, 116 F.3d 1465, 1471 [43 USPQ2d 13621 (Fed. Cir. 1997); or (2) that there are new and unexpected results relative to the prior art, In re Woodruff, 919 F.2d 1575, 1578 M6 USPQ2d 19341 (Fed. Cir. 1990).
In the instant case, there is no teaching away of adjusting the dose of quercetin in the intragastric formulation comprising 25 mg/kg QUE nanoliposome and separate 25 mg/kg free temozolomide as taught by Hu to wherein the quercetin nanoliposome contains quercetin in a concentration of 10 mg/mL to 500 mg/mL disclosed by the combination of Li. Secondly, there are no unexpected results demonstrating the criticality of the claimed quercetin concentration in the quercetin nanoliposome relative to the prior art.
Thirdly, regarding the limitation wherein quercetin is in a solution at a concentration of 50 mg/mL to 500 mg/mL (claim 52), it is considered well within the capabilities of one of ordinary skill in the art to optimize the concentration of quercetin in the quercetin nanoliposome to provide optimal therapeutically effective amounts of the antineoplastic agent in the nanoliposome formulation. The concentration of quercetin in the quercetin nanoliposome is a result effective parameter that will affect the physical properties of the final composition. The concentration of quercetin in the quercetin nanoliposome is clearly a results effective parameter that a person of ordinary skill would routinely optimize. Optimization of parameters is a routine practice that would have been obvious for a person of ordinary skill in the art to employ and reasonably would expect success. Moreover, the therapeutically effective amount of quercetin in the quercetin nanoliposome disclosed by Hu and Li provide a range of workable conditions and it would have been customary for an artisan of ordinary skill to determine the optimal concentration of quercetin in the nanoliposome to best achieve the desired result. Furthermore, absent any evidence demonstrating a patentable difference between the composition and the criticality of the claimed amounts, the determination of the optimum workable range(s) given the guidance of the prior art would have been generally prima facie obvious to the skilled artisan. Please see MPEP 2144.05 [R-2](II) (A) and In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) “[W]here the general conditions of the claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.").
Fourthly, regarding the properties (such as an improved effect on treating the neoplasm compared to temozolomide monotherapy or quercetin monotherapy) that accrue from a process step of administering said free temozolomide along with the quercetin nanoliposome composition to the glioblastoma subject are considered characteristic features of the claimed product.
It is noted that MPEP 2112 discusses the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions that are newly cited or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to "prove that subject matter shown to be in the prior art does not possess characteristic relied on" (205 USPQ 594, second column, first full paragraph).
In the present case the burden is shifted to Applicant to prove that the intragastric composition comprising free temozolomide along with a separate quercetin nanoparticle does not yield an improved effect on treating the neoplasm compared to temozolomide monotherapy or quercetin monotherapy).
Claim(s) 14 and 39 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Hu et al (International Journal of Molecular Medicine Vol. 37 pages 690-702. Published 2016) and Li (Materials Science and Engineering C Vol. 77 pages 803-810 published online 03/27/2017) as applied to claims 1 ,12, 20, 27, 35-37, 42 and 50-52 above, in view of Pandol (US2004/0259816 published 12/23/2004).
As disclosed above, the combination of Hu and Li render obvious an intragastrically administered composition containing (i) 25 mg/kg of a nanoliposome composition consisting of quercetin (QUE-NL) in combination with a separate 25 mg/kg dose of free temozolomide to a U87 xenograft mediated glioblastoma patient, wherein said quercetin was present in the nanoliposome in a concentration of 10 mg/mL (Hu: page 691 right col. through page 693 left col., pages 699-700; Li: page 804 right col.). Thus, the intragastric formulation comprising 25 mg/kg QUE-NL as well as separate 25 mg/kg free temozolomide prior to administration to the U87 xenograft glioblastoma patient in Figure 6B reads on a composition comprising i) a nanoparticle comprising quercetin in itself and ii) temozolomide. Hu and Li teach formulating said nanoparticle with the pharmaceutically acceptable carriers DSPE and PEG and that the average particle size of the nanoparticle is 196 nanometers (Hu: abstract, Figure 1; Li page 805 right col). Regarding claims 12, 20, 27-28, 35 and 37 Hu teaches that said nanoparticle composition comprising quercetin and free temozolomide are administered via injection to a subject comprising a glioblastoma (U-87 xenograft animal model) in order to treat the neoplastic disorder (page 693 left col., Figure 1 and Figure 6).
The difference between the presently claimed and the 25 mg/kg of a nanoliposome composition consisting of quercetin (QUE-NL) in combination with a separate 25 mg/kg dose of free temozolomide wherein the quercetin in the quercetin nanoliposome is present in a concentration of 10 mg/mL as taught by Hu and Li above is that neither Hu nor Li specifically teach wherein quercetin is present in a dose of 100 mg to 2.5 g.
Pandol (US2004/0259816 published 12/23/2004) teaches the method of treating cancer in a subject comprising administering a therapeutically effective amount of the polyphenolic compound quercetin ([0104]-[0109], claims 1, 5, 11-13). Treatment of glioblastomas and brain tumors with the polyphenolic compound is embodied within the teachings of Pandol ([0145]-[0146], claims 1, 5, 11-13). Intravenous administration of said polyphenolic compound and treating human and mammalian patients with the polyphenolic compound is embraced within the teachings of Pandol ( [0104]-[0109], [0232]-[0236). Pandol teaches administration of the polyphenolic compound in doses of 10-1000 mg/kg ([0232]-[0235]). As evidenced by Reagan-Shaw (FASEBJ Vol. 22 pages 659-661 published 2007) the average weight of a human is 60 kg (Table 1). Thus, the 10-1000 mg/kg dose of quercetin to a human neoplastic patient embodied within Pandol corresponds to a dose of 600 mg-60 g, which overlaps with the amount embraced in the present claims. Applicant is reminded of MPEP 2144.05 wherein 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).
Therefore, said skilled artisan prior to the time of the invention knowing that a intragastric formulation comprising 25 mg/kg QUE-NL as well as a separate 25 mg/kg free temozolomide, wherein quercetin is present in the nanoliposome in a concentration of 10 mg/mL is efficacious at treating a U87 xenograft glioblastoma in a subject in need as taught by the combination of Hu and Li above, said skilled artisan would have found it prima facie obvious to adjust the dose of quercetin the in the quercetin nanoliposome to a dose of 0.1 g to 2.5 g quercetin in view of Pandol, arriving at the presently claimed.
Motivation to adjust the anti-neoplastic dose of quercetin in in the intragastric formulation comprising 25 mg/kg QUE-NL as well as a separate 25 mg/kg free temozolomide of Hu and Li from a 25 mg/kg dose to a dose containing 100 mg to 2.5 g quercetin logically flows from the fact that it is known in the prior art that administration of the polyphenolic compound quercetin, in doses of 600 mg-60 g is efficacious at treating cancer in a subject in need. Accordingly, said artisan would have readily predicted that administration of the composition of Hu wherein the polyphenolic compound quercetin is administered in a dose of 100 mg to 2.5 g, said regimen would have effectively treated the neoplastic patient.
Claim(s) 1, 12-13, 20, 27, 29-30, 35-38, 42 and 50-51 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Hu et al (International Journal of Molecular Medicine Vol. 37 pages 690-702. Published 2016), Li (Materials Science and Engineering C Vol. 77 pages 803-810 published online 03/27/2017), Pickett (US2007/0112053 published 05/17/2007), Jalili (US2004/0258674 published 12/23/2004) and Chang (CA2806896 published 03/19/2014).
As disclosed above, the combination of Hu and Li render obvious an intragastrically administered composition containing (i) 25 mg/kg of a nanoliposome composition consisting of quercetin (QUE-NL) in combination with a separate 25 mg/kg dose of free temozolomide to a U87 xenograft mediated glioblastoma patient, wherein said quercetin was present in the nanoliposome in a concentration of 10 mg/mL (Hu: page 691 right col. through page 693 left col., pages 699-700; Li: page 804 right col.). Thus, the intragastric formulation comprising 25 mg/kg QUE-NL as well as separate 25 mg/kg free temozolomide prior to administration to the U87 xenograft glioblastoma patient in Figure 6B reads on a composition comprising i) a nanoparticle comprising quercetin in itself and ii) temozolomide. Hu and Li teach formulating said nanoparticle with the pharmaceutically acceptable carriers DSPE and PEG and that the average particle size of the nanoparticle is 196 nanometers (Hu: abstract, Figure 1; Li page 805 right col). Regarding claims 12, 20, 27-28, 35 and 37 Hu teaches that said nanoparticle composition comprising quercetin and free temozolomide are administered via injection to a subject comprising a glioblastoma (U-87 xenograft animal model) in order to treat the neoplastic disorder (page 693 left col., Figure 1 and Figure 6; Li: page 805 left col. Figure 3).
The difference between the presently claimed and the 25 mg/kg of a nanoliposome composition consisting of quercetin (QUE-NL) in combination with a separate 25 mg/kg dose of free temozolomide wherein the quercetin in the quercetin nanoliposome is present in a concentration of 10 mg/mL as taught by Hu and Li above is that neither Hu nor Li specifically teach a kit wherein the compositions comprising the quercetin nanoparticle formulation (QUE-NL) and free temozolomide are in a kit formulation, wherein said components are in separate containers. Nor does Hu nor Li teach wherein temozolomide is in the range of 20 mg to 5000 mg per day. Nor does Hu nor Li teach wherein temozolomide is administered in a dose of 0.0075 mg/m2 to about 20 mg/m2.
Pickett (US2007/0112053 published 05/17/2007) teaches kit compositions comprising temozolomide in combination with a second chemotherapeutic agent, wherein the second chemotherapeutic agent is a protein kinase C subtype B inhibitor for the treatment of cancer (abstract, [0009]-[0010], claim 17). Pickett teaches said kit composition is used to treat brain tumors in a subject in need ([0009]-[0010], [0071]-[0078, Figures 1-3). Regarding claims 29-30, Pickett teaches that temozolomide is contained in one container and the protein kinase C inhibitor is housed in a second container ([0016]-[0019]). Regarding claim 13, Pickett teaches administration of 150-200 mg/m2 temozolomide each day to treat the neoplastic disorder in patients, including experimental animals and human ([0037], [0083], [0085], [0105]). Oral and intravenous administration of said temozolomide dosage form is embraced within the teachings of Pickett ([0083], [0105]). As evidenced by Reagan-Shaw (FASEBJ Vol. 22 pages 659-661 published 2007), the aforementioned 150-200 mg/m2 dose in a human patient corresponds to a daily dose of 93-125 mg, which reads on the claimed amount (pages 1-3; See Reagan-Shaw Table 1).
Jalili (US2004/0258674 published 12/23/2004) teaches that quercetin and its relationship with protein kinase C (abstract, [0013], [0035]-[0036]). Jalili teaches that quercetin is a potent inhibitor of protein kinase C subtype B ([0055],[0056], Figure 2).
Chang (CA2806896 published 03/19/2014) teaches preparation of liposomal formulations of temozolomide targeted to treat brain cancer in a subject in need (abstract, [0006], [0175]-[0181], claims 25, 29 and Figures 1-2). Chang teaches that the temozolomide is administered to patients in a range of 10 mg/m2 to 500 mg/m2, which overlaps with the range embraced in claim 38 ([0126], claims 25, 29). Applicant is reminded of MPEP 2144.05 wherein 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).
Therefore, one of ordinary skill in the art prior to the time of the invention would have found it prima facie obvious to prepare the composition of Hu and Li comprising a quercetin nanoliposome (QUE-NL) with a quercetin concentration of 10 mg/mL in combination with temozolomide in a kit, wherein the temozolomide and quercetin are housed in separate containers within the kit in view of the combined teachings of Pickett and Jalili. MPEP 2143 provides rationale for a conclusion of obviousness including (A): Combining prior art elements according to known methods to obtain predictable results;
In the present case, it was known in the prior art to prepare kits for treating neoplastic disorders comprising temozolomide in one container and a second container comprising a PKC beta inhibitor. Considering Jalili teaches that quercetin is a potent PKC beta inhibitor, said artisan would have applied the kit composition comprising temozolomide in one container and a second container comprising a PKC beta inhibitor teachings of Pickett and Jalili to the quercetin-nanoparticle and temozolomide composition of Hu and Li, arriving at the presently claimed kit composition wherein the quercetin-nanoparticle and temozolomide composition are housed in separate containers with a reasonable expectation of success.
Secondly, one of ordinary skill in the art prior to the time of the invention would have found it prima facie obvious to adjust the amount of temozolomide in composition comprising a quercetin nanoparticle and free temozolomide as taught by Hu and Li above to a dose between 93-200 mg in view of Pickett, arriving at the claimed composition.
MPEP 2143 provides rationale for a conclusion of obviousness including (A): Combining prior art elements according to known methods to obtain predictable results;
In the instant case , a temozolomide dose between 93-200 mg/day was taught in the prior art of Pickett as the current standard care dose of temozolomide for the treatment of glioblastoma in a subject in need. Accordingly, said artisan would have combined the teachings of Pickett to the temozolomide and quercetin nanoparticle formulation of Hu and Li, arriving at the instantly claimed composition with a reasonable expectation of success.
Thirdly, one of ordinary skill in the art prior to the time of the invention would have found it prima facie obvious to adjust the amount of temozolomide in composition comprising a quercetin nanoparticle and free temozolomide as taught by Hu and Li to a dose between 0.0075 mg/m2 to 20 mg/m2 in view of Chang, arriving at the claimed composition. In the instant case, a temozolomide dose between 10 mg/m2 to 500 mg/m2 was taught in the prior art of Chang as a suitable dose of temozolomide to administer to treat glioblastoma in a subject in need. Accordingly, said artisan would have combined the temozolomide dosing regimen embraced within Chang to the temozolomide and quercetin nanoparticle formulation of Hu and Li above arriving at the instantly claimed composition with a reasonable expectation of success.
Applicant traverses. Applicant asserts that Hu does not teach the claimed pharmaceutical composition comprising a synergistic amount of temozolomide and a synergistic amount of QUE-NL. Applicant argues that the only use of quercetin nanoliposomes in Hu was as a control as is the case with temozolomide. Additionally, Applicant argues that Hu does not disclose either a synergistic amount of temozolomide or a synergistic amounts of the quercetin nanoparticle in the pharmaceutical composition.
Applicant argues that there is no disclosure in Hu that contains the claimed synergistic amounts of quercetin-nanoparticle and temozolomide, nor would there be motivation or suggestion to look to Li to modify a concentration of quercetin in a pharmaceutical composition. Applicant further asserts that Li fails to cure the deficiencies of Hu as Li does not teach a concentration of 10 mg/mL quercetin to 500 mg/mL quercetin.
Applicant further traverses the 35 U.S.C. 103 rejection of claims 14 and 39 in view of the combined teachings of Hu, Li and Pandol (US2004/0259816) and the 35 U.S.C 103 rejection of claims 1, 12-13, 20, 27, 29, 30, 35-38, 50-52 in view of Hu, Li, Jalili, and Chang. Applicant argues that the combination of Hu and Li fail to teach the instantly claimed and that the combination of Pandol fails to cure the deficiencies of the combination of Hu and Li with respect to the subject matter of claims 14 and 39 in order to arrive at the presently claimed. Additionally, with respect to the 35 U.S.C. 103 rejection of claims 1, 12-13, 20, 27, 29, 30, 35-38, 50-52 in view of Hu, Li, Jalili, and Chang, Applicant argues that the combination of Hu and Li fail to teach the instantly claimed and that the combination of Jalili, and Chang fails to cure the deficiencies of the combination of Hu and Li.
Response to Arguments
Applicant’s arguments, filed 01/05/2026 are acknowledged and have been carefully considered. Regarding Applicant’s contention that Hu does not teach the claimed pharmaceutical composition comprising a synergistic amount of temozolomide and a synergistic amount of QUE-NL and that the only use of quercetin nanoliposomes in Hu was as a control as was TMZ, this argument is unavailing. As recited in the previous Office Action, given the broadest reasonable interpretation of the present claims, the pharmaceutical composition of claim 1 embraces two separate dosage forms composed of i) a synergistic amount of the at least one anti-cancer agent temozolomide and ii) a synergistic amount of a nanoparticle formulation consisting of an anti-cancer response modulator, wherein the anti-cancer response modulator is quercetin.
Hu teaches a pharmaceutical nanoparticle compositions comprising the anti-cancer response modulator quercetin (QUE-NL) (abstract, pages 691-693, Table 1, pages 699-700, Figures 1-6). Hu teaches formulating said nanoparticle with the pharmaceutically acceptable carriers DSPE and PEG and that the average particle size of the nanoparticle is 196 nanometers (abstract, Figure 1, Table 1). Regarding the limitation of “nanoparticle formulation” the specification and claims defines “nanoparticle formulation” as comprising a particle size of 100 nm to 250 nm ([0134]-[0135], claim 50). Thus, the 196 nm particle size of the quercetin nanoparticle found in Figure 1 and Table 1 of Hu lies inside this purported range. In addition, paragraphs [0152], Figure 5 and Table 6 of present specification teaches that the nanoparticle formulation comprises PEG and DPSE just like the nanoparticle composition Hu.
In Table 1 and Figures 1-6 of Hu, Hu teaches preparing nanoliposomes comprising quercetin that exclude temozolomide (QUE-NL) as well as nanoliposomes comprising both quercetin and temozolomide wherein both quercetin and temozolomide are encapsulated within the nanoliposome (QUE-TMZ-NL) (page 691 right col., page 693 right col.). In Figure 6A-C, Hu teaches a biodistribution study, wherein the QUE-TMZ-NL composition was intragastrically administered to a U-87 xenograft glioblastoma patient. As a comparative control, Hu teaches intragastrically administering a dose of 25 mg/kg QUE-NL by itself. Hu also teaches administration of a 25 mg/kg dose of free temozolomide in a separate dosage form from QUE-NL (page 692 right col. through page 693 left col., pages 699-700). Thus, the intragastric formulation comprising 25 mg/kg QUE-NL as well as a separate 25 mg/kg free temozolomide administered to the U87 xenograft glioblastoma patient in Figure 6B continues to read on a composition comprising i) a nanoparticle comprising quercetin in itself and ii) temozolomide. The fact that each of the QUE-NL and temozolomide in the intragastric formulation comprising 25 mg/kg QUE-NL as well as a separate 25 mg/kg free temozolomide administered to the U87 xenograft glioblastoma patient taught by Hu are used as controls as Applicant asserts is immaterial as the separated 25 mg/kg QUE-NL as well as a separate 25 mg/kg free temozolomide reads on all of the structural limitations of a “pharmaceutical composition” as recited in paragraphs [0089] and [0100] of the specification, as well as the present claims.
Next, regarding Applicant’s contention that Hu does not disclose synergistic amount of temozolomide, this argument also remains unavailing. Regarding the limitation directed to “synergistic amounts” of temozolomide and quercetin nanoparticle, see [0189] of the instant specification wherein said “synergistic amount” of temozolomide is 10-1000 mg/m2. See [0150] of the instant specification wherein the dose of quercetin is 100 mg-10 g. See also Table 1 of Reagan-Shaw (FASEBJ Vol. 22 pages 659-661 published 2007) wherein the conversion of mg/m2 to mg/kg is to divide by the Km. Thus, the 10-1000 mg/m2 of temozolomide reads on a dose of 1.66 to 166.6 mg/kg temozolomide to a rat patient. The 25 mg/kg dose of temozolomide administered lies inside the 1.66 mg/kg to 166.6 mg/kg range embodied within the specification that is identified as “synergistic” and therefore reads on the “synergistic amount” of temozolomide embodied within the instant specification.
Applicant also argues that there is no disclosure in Hu that contains the claimed synergistic amounts of quercetin-nanoparticle and temozolomide, nor would there be motivation or suggestion to look to Li to modify a concentration of quercetin in a pharmaceutical composition. Applicant further argues that Li fails to cure the deficiencies of Hu as Li does not teach a concentration of 10 mg/mL quercetin to 500 mg/mL quercetin. These arguments are also unpersuasive. Regarding Applicant’s assertion that there is no motivation nor suggestion to look to Li to modify a concentration of quercetin in the pharmaceutical composition, Applicant is reminded that a suggestion, teaching or motivation to combine prior art teachings to achieve the claimed invention does not have to be found explicitly in the prior art references, but rather, it may be found within other sources, including common knowledge, the prior art as a whole or the nature of the problem itself. Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 82 USPQ2d 1321 (Fed. Cir. 2007).
Applicant is also reminded that “Non-obviousness cannot be established by attacking references individually where the rejection is based upon the teachings of a combination of references” In re Merck and Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986). In the present case, Li (Materials Science and Engineering C Vol. 77 pages 803-810 published online 03/27/2017) also represents the prior art as a whole in regard to formulating quercetin nanoparticles to treat cancer. Li teaches the preparation of quercetin-loaded nanoliposomes (QUE-NLs) to treat cancer in a subject in need (abstract). Li teaches preparation of said quercetin nanoliposome wherein quercetin is present in a concentration of 10 mg/mL (page 804 right col., section 2.6). Regarding claim 36, Li teaches that said quercetin nanoparticles are intravenously administered to treat cancer in a subject in need (page 805 left col., Figure 3).
As such, said skilled artisan would have found it prima facie obvious to adjust the dose of quercetin in the intragastric formulation comprising 25 mg/kg QUE-NL as well as a separate 25 mg/kg free temozolomide as taught by Hu, to a dose wherein the concentration of quercetin in the quercetin-nanoliposome is present in a range from 10 mg/mL to 500 mg/mL in view of Li, arriving at the presently claimed.
MPEP 2143 provides rationale for a conclusion of obviousness including (A): Combining prior art elements according to known methods to obtain predictable results;
In the present case, Li teaches the preparation of quercetin-loaded nanoliposomes (QUE-NLs) to treat cancer in a subject in need wherein said quercetin is present in the nanoliposome in a concentration of 10 mg/mL Accordingly, said skilled artisan would have applied the methodology of Li to the intragastric formulation comprising QUE-NL as well as a separate 25 mg/kg free temozolomide administered to the U87 xenograft glioblastoma patient taught by Hu above, arriving at the presently claimed with a reasonable expectation of success.
Applicant is reminded of MPEP 2144.05 wherein “[A] range can be disclosed in multiple prior art references instead of in a single prior art reference depending on the specific facts of the case. Iron Grip Barbell Co., Inc. v. USA Sports, Inc., 392 F.3d 1317, 1322, 73 USPQ2d 1225, 1228 (Fed. Cir. 2004). The patent claim at issue was directed to a weight plate having 3 elongated openings that served as handles for transporting the weight plate. Multiple prior art patents each disclosed weight plates having 1, 2 or 4 elongated openings. 392 F.3d at 1319, 73 USPQ2d at 1226. The court stated that the claimed weight plate having 3 elongated openings fell within the "range" of the prior art and was thus presumed obvious. 392 F.3d at 1322, 73 USPQ2d at 1228. The court stated that the "range" disclosed in multiple prior art patents is "a distinction without a difference" from previous range cases which involved a range disclosed in a single patent since the "prior art suggested that a larger number of elongated grips in the weight plates was beneficial... thus plainly suggesting that one skilled in the art look to the range appearing in the prior art." The court further stated that “[Nonetheless, where there is a range disclosed in the prior art, and the claimed invention falls within that range, there is a presumption of obviousness. But the presumption will be rebutted if it can be shown: (1) That the prior art taught away from the claimed invention, In re Geisler, 116 F.3d 1465, 1471 [43 USPQ2d 13621 (Fed. Cir. 1997); or (2) that there are new and unexpected results relative to the prior art, In re Woodruff, 919 F.2d 1575, 1578 M6 USPQ2d 19341 (Fed. Cir. 1990).
In the instant case, there is no teaching away of adjusting the dose of quercetin in the intragastric formulation comprising 25 mg/kg QUE nanoliposome and separate 25 mg/kg free temozolomide as taught by Hu to wherein the quercetin nanoliposome contains quercetin in a concentration of 10 mg/mL to 500 mg/mL disclosed by the combination of Li. Secondly, there are no unexpected results demonstrating the criticality of the claimed quercetin concentration in the quercetin nanoliposome relative to the prior art.
Lastly, regarding the 35 U.S.C. 103 rejection of claims 14 and 39 in view of the combined teachings of Hu, Li and Pandol (US2004/0259816) or the 35 U.S.C 103 rejection of claims 1, 12-13, 20, 27, 29, 30, 35-38, 50-52 in view of Hu, Li, Jalili, and Chang, arguments pertaining to the combined teachings of Hu and Li have been addressed above. Considering Applicant has not specifically pointed out the deficiencies of Pandol with respect to claims 14 and 39, nor specifically pointed out the deficiencies of Jalili and Chang with respect to claims 1, 12-13, 20, 27, 29, 30, 35-38, 50-52, as such, the rejections of record are maintained for the reasons above.
Conclusion
In view of the rejections set forth above, no claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/GEORGE W KOSTURKO/Primary Examiner, Art Unit 1621
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