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
The present application, filed August 24, 2022, is a national stage application of PCT/US2021/019726, filed February 25, 2021, which claims the benefit of U.S. provisional application 62/982557, filed February 27, 2020.
Status of the Application
Applicant’s communication, received May 1, 2026, wherein claims 1, 5, 22, and 32 are amended and claims 3, 7, and 21 are canceled, is acknowledged.
Claims 1, 2, 4-6, 9, 14, 18, 19, 22, 23, 26, 28, 29, and 31-33 are pending in this application.
Claims 22, 23, 26, 28, 29, and 31 were withdrawn as directed to a non-elected invention in the office action mailed December 3, 2025.
Claims 1, 2, 4-6, 9, 14, 18, 19, and 32-33 are examined on the merits herein.
Withdrawn Rejections
Applicant’s amendment, received May 1, 2026, with respect to the rejection of claims 1-7, 9, 14, 18-19, 21, and 32-33 under 35 USC § 112(b) over uncertainty associated with the relative term “sustained”, has been fully considered and found to be persuasive to remove the rejection because claims 3, 7, and 21 are canceled and because independent claims 1 and 32 are amended to remove the term “sustained” from the claim. Therefore the rejection is withdrawn.
Applicant’s amendment, received May 1, 2026, with respect to the rejection of claim 3 under 35 USC § 112(b) over uncertainty associated with “an intermediate powder product,” has been fully considered and found to be persuasive to remove the rejection because claim 3 is canceled. Therefore the rejection is withdrawn.
Applicant’s amendment, received May 1, 2026, with respect to the rejection of claims 1, 2, 5-7, 9, and 14 under 35 USC § 102 as anticipated by Meng, has been fully considered and found to be persuasive to remove the rejection because claim 7 is canceled and claim 1 is amended to require the dispersion remains stable for at least 2 weeks when stored at 25 °C, which Meng does not teach. Therefore the rejection is withdrawn.
Applicant’s amendment, received May 1, 2026, with respect to the rejection of claims 1 and 19 under 35 USC § 103 as unpatentable over Meng in view of Nel, has been fully considered and found to be persuasive to remove the rejection because claim 1 is amended to require the dispersion remains stable for at least 2 weeks when stored at 25 °C, which the combination of Meng and Nel does not teach. Therefore the rejection is withdrawn.
Applicant’s amendment, received May 1, 2026, with respect to the rejection of claims 1-6, 9, 14, 18-19, 21, and 32 under 35 USC § 103 as unpatentable over Zhang in view of Mu, Freeling, and Meng, has been fully considered and found to be persuasive to remove the rejection because claims 3 and 21 are canceled and claims 1 and 32 are amended to require the aqueous dispersion aqueous dispersion comprises each chemotherapeutic agent combination in an amount of 5 wt % or more and 30 wt % or less, which embodiments cited in the previous rejection under 35 U.S.C. § 103 do not teach. Therefore the rejection is withdrawn.
Applicant’s amendment, received May 1, 2026, with respect to the rejection of claim 33 under 35 USC § 103 as unpatentable over Zhang in view of Mu, Freeling, and Meng, and further in view of Krūkle-Bērziņa, has been fully considered and found to be persuasive to remove the rejection because claim 32 is amended to require the aqueous dispersion aqueous dispersion comprises each chemotherapeutic agent combination in an amount of 5 wt % or more and 30 wt % or less, which embodiments cited in the previous rejection under 35 U.S.C. § 103 do not teach. Therefore the rejection is withdrawn.
Applicant’s amendment, received May 1, 2026, with respect to the provisional nonstatutory double patenting rejection of claims 1-6, 9, 14, 18-19, and 32-33 as unpatentable over the claims of co-pending U.S. patent application 17/422074 in view of Zhang, Meng, Freeling, and Krūkle-Bērziņa, has been fully considered and found to be persuasive to remove the rejection because the claims of 17/422074 are amended such that the composition claimed therein requires lopinavir, ritonavir, and tenofovir as the therapeutic agent. Thus the present claims are no longer obvious in view of the claims of 17/422074, Zhang, Meng, Freeling, and Krūkle-Bērziņa. Therefore the rejection is withdrawn.
The following are new and/or modified grounds of rejection, necessitated by Applicant’s amendment received May 1, 2026. Applicant’s arguments are moot in view of the new and/or modified grounds of rejection below.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35
U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 32 is rejected under 35 U.S.C. 103 as being unpatentable over Meng (Meng, H.; et al. ACS Nano 2015, vol. 9, pp. 3540-3557; cited in restriction requirement mailed June 18, 2025) in view of Fonte (Fonte, P.; et al. Journal of Controlled Release 2016, vol. 225, pp. 75-86; cited in PTO-892).
Claim 32 claims a powder composition comprising a combination of chemotherapeutic agents selected from: gemcitabine and paclitaxel; and venetoclax and zanubrutinib; and
one or more compatibilizers comprising a lipid, a lipid conjugate, or a combination thereof; wherein the powder composition comprises each chemotherapeutic agent combination in
an amount of 5 wt % or more and 30 wt % or less.
Meng teaches a mesoporous silica nanoparticle (MSNP) carrier for pancreatic cancer to co-deliver a synergistic gemcitabine and paclitaxel combination (p. 3540, Abstract, lines 7-10). Meng teaches that high drug loading was achieved by a custom-designed coated lipid film technique to encapsulate a calculated dose of GEM (40 wt %) by using a supported lipid bilayer (LB).
Meng teaches that a uniform coating of the nanoparticles by a lipid membrane allowed incorporation of a sublethal amount of hydrophobic PTX, which could be co-delivered with GEM in pancreatic cells and tumors (p. 3540, Abstract, lines 10-12).
Meng teaches formulation of these nanoparticles for intravenous injection in mice, and that drug co-delivery provided more effective tumor shrinkage than GEM-loaded LB-MSNP, free GEM, or free GEM plus Abraxane (p. 3540, Abstract, lines 13-15).
Meng teaches that a series of GEM/PTX LB-MSNPs were prepared in which a fixed amount of GEM (25%, w/w) was used with 0.25-5 wt % PTX to yield GEM/PTX ratios of 100:1, 10:1, and 5:1, and that each particle type was used to assess cytotoxicity and to determine the concentration of each drug in the mixture for a 50% killing effect (p. 3545, left column, lines 12-18). The compositions with 25 wt % gemcitabine and 0.25-5 wt % paclitaxel satisfies the limitations of claim 32, which requires each chemotherapeutic agent combination in the composition is present in an amount of 5 wt % or more and 30 wt % or less.
Finally, Meng teaches that uncoated and coated particles were characterized for morphology, size distribution, and surface charge. Meng teaches that for TEM analysis,
microfilms were made by placing a drop of the respective MSNP suspensions onto a 200 mesh copper TEM grid and then drying at room temperature for 2 hours (p. 3553, right column, Physicochemical Characterization section, lines 1-8). Therefore, in view of Meng, one of ordinary skill in the art would have recognized that the particles of Meng may be characterized as solids.
Meng does not teach their product as a powder composition, as required by claim 32.
Fonte teaches nanoparticles are often produced in an aqueous suspension form, but that nanoparticles suspended in an aqueous medium are physically unstable, so particle aggregation and fusion are frequent phenomena during long periods of storage. Fonte teaches the hydrolytic action of water on the polymer matrix can lead to drug leakage, hamper or eliminate the sustained release properties and lead to the formation of undesirable degradation products, and a nanoparticle suspension is also prone to the development and growth of microorganisms. Fonte teaches that to overcome all these problems, the transformation of the nanoparticle suspension into a solid dosage form is the obvious solution (p. 76, left column, second paragraph, lines 1-10).
Fonte teaches lyophilization or freeze-drying is a dehydration process used to overcome the instability of a nanoparticle suspension, increasing its shelf-life and simultaneously facilitating its handling and storage (p. 76, left column, third paragraph, lines 1-3). Moreover, Fonte teaches that the elemental composition of the nanoparticles lyophilizate may be assessed by electron spectroscopy for chemical analysis (ESCA) (p. 83, left column, section 4.3, lines 1-2) and specifically refers to ESCA as analyzing the powder surface of a lyophilizate (p. 83, left column, section 4.3, lines 10-15). Therefore, the expected product of a nanoparticle lyophilizate is reasonably considered as a powder.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to formulate the GEM/PTX LB-MSNPs of Meng as a powder composition. One of ordinary skill in the art would have been motivated to formulate the GEM/PTX LB-MSNPs of Meng as a powder composition because Meng teaches their compositions may be dried for analysis as a solid product, and because Fonte teaches nanoparticles suspended in an aqueous medium are physically unstable, so particle aggregation and fusion are frequent phenomena during long periods of storage, and that the transformation of the nanoparticle suspension into a solid dosage form is an obvious solution to this problem. Moreover, Fonte teaches lyophilization to a powder as one such method to overcome nanoparticle suspension instability. Accordingly, in view of Meng and Fonte, one of ordinary skill in the art would have considered a powder lyophilizate of the product taught by Meng for producing a product to store, because said product would be expected to be physically unstable if stored as an aqueous suspension, and lyophilization to a powder would overcome this instability.
Therefore the invention taken as a whole is prima facie obvious.
Claim 33 is rejected under 35 U.S.C. 103 as being unpatentable over Meng (Meng, H.; et al. ACS Nano 2015, vol. 9, pp. 3540-3557; cited in restriction requirement mailed June 18, 2025) in view of Fonte (Fonte, P.; et al. Journal of Controlled Release 2016, vol. 225, pp. 75-86; cited in PTO-892) as applied to claim 32 above, and further in view of Krūkle-Bērziņa (Krūkle-Bērziņa, K.; et al. Journal of Pharmaceutical and Biomedical Analysis 2015, vol. 107, pp. 168-174; cited in previous office action).
Claim 33 requires the powder composition of claim 32, wherein the composition comprises a phase transition temperature different from the transition temperature of each individual chemotherapeutic agent when assessed by differential scanning calorimetry.
Meng and Fonte teach as described in the above rejection under 35 U.S.C. § 103.
Meng and Fonte do not teach the composition comprising a phase transition temperature different from the transition temperature of each individual chemotherapeutic agent when assessed by differential scanning calorimetry.
Krūkle-Bērziņa teaches that a physical or chemical interaction between the drug and excipients can be identified from the shifting, disappearance, or appearance of new analytical signal, and that in thermal analysis, the interactions between drug molecules and excipients can also introduce changes in enthalpy values (p. 168, right column, lines 8-13).
It would have been prima facie obvious to one of ordinary skill in the art that the composition of claim 32 comprises a phase transition temperature different from the transition temperature of each individual chemotherapeutic agent when assessed by differential scanning calorimetry. One of ordinary skill in the art would have expected that the composition comprises a phase transition temperature different from the transition temperature of each individual chemotherapeutic agent when assessed by differential scanning calorimetry because Meng teaches a composition comprising gemcitabine and paclitaxel formulated with a lipid coating, and because Krūkle-Bērziņa teaches interactions between drug molecules and excipients can also introduce changes in enthalpy values. Accordingly, the composition of gemcitabine and paclitaxel formulated with a lipid obvious over Meng and Fonte as described above, would have been expected to result in a phase transition temperature different from the transition temperature of each individual chemotherapeutic agent due to interactions within said composition.
Therefore the invention taken as a whole is prima facie obvious.
Claims 1, 2, 4-6, 9, 14, 18, 19 and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang (WO 2011143201 A2; cited in previous office action) in view of Mu (Mu, Q.; et al. Journal of Drug Targeting 2018, vol. 26, pp. 435-447; cited in previous office action), Freeling (Freeling, J. P.; et al. AIDS Research and Human Retroviruses 2015, vol. 31, pp. 107-114; cited in previous office action), Meng (Meng, H.; et al. ACS Nano 2015, vol. 9, pp. 3540-3557; cited in restriction requirement mailed June 18, 2025), and Frese (Frese, K. K.; et al. Cancer Discovery 2012, vol. 2, pp. 260-269; cited in PTO-892).
Claim 1 claims an injectable aqueous dispersion, comprising: an aqueous solvent, and a chemotherapeutic agent composition dispersed in the aqueous solvent to provide an injectable aqueous dispersion, the chemotherapeutic agent composition comprising a combination of chemotherapeutic agents selected from: gemcitabine and paclitaxel; and venetoclax and zanubrutinib; and the chemotherapeutic agent composition further comprising one or more compatibilizers comprising a lipid, a lipid conjugate, or a combination thereof; wherein the aqueous dispersion comprises each chemotherapeutic agent combination in an amount of 5 wt % or more and 30 wt % or less, and wherein the dispersion remains stable for at least 2 weeks when stored at 25 °C.
Claim 2 requires the chemotherapeutic agents and the one or more compatibilizers together form an organized composition, claim 4 requires formation of a multiple-drug-domain pattern, claim 5 requires the aqueous dispersion does not comprise a structural feature of a lipid layer, a lipid bilayer, a liposome, or a micelle, claim 6 requires the aqueous solvent is selected from a buffered aqueous solvent, saline, and an aqueous solution of 10-100 mM sodium bicarbonate and 0.45 wt% to 0.9 wt% NaCl, claim 9 requires the gemcitabine:paclitaxel molar ratio is from about 1:1 to about 50:1, claim 14 requires the venetoclax and zanubrutinib molar ratio is from about 10:1 to about 1:10, claim 18 requires a molar ratio of chemotherapeutic agents to the one or more compatibilizers of from about 1:10 to about 1:1, and claim 19 requires the one or more compatibilizers are selected from those listed.
Claim 32 claims a powder composition comprising a combination of chemotherapeutic agents selected from: gemcitabine and paclitaxel; and venetoclax and zanubrutinib; and
one or more compatibilizers comprising a lipid, a lipid conjugate, or a combination thereof; wherein the powder composition comprises each chemotherapeutic agent combination in
an amount of 5 wt % or more and 30 wt % or less.
Zhang teaches that combination chemotherapy is usually more effective than individual chemotherapy as drugs with similar mechanisms act synergistically to enhance therapeutic efficacy, whereas drugs with different mechanisms give cancer cells a higher hurdle in developing resistance (p. 1, [0004], lines 5-7). As one strategy for delivering combination chemotherapy, Zhang teaches the conjugation of paclitaxel with gemcitabine (p. 65, [0254]-[0255]) and formulation of said conjugate as a nanoparticle (p. 66, [0258]-[0259]).
Although the method of Zhang does not teach the presently claimed compositions because Zhang teaches conjugation of gemcitabine to paclitaxel, Zhang acknowledges the challenges of the co-administering different chemotherapeutic agents, including the different chemotherapeutic agents paclitaxel and gemcitabine. Zhang states: “While the focus of this article is to report a novel chemical approach to loading dual chemotherapy drugs into a single nanoparticle for combinatorial drug delivery, it would be interesting to compare the cytotoxicity of PTXL-GEM conjugates loaded nanoparticles with that of a cocktail mixture of the same type of nanoparticles containing either free PTXL or free GEM. However, the vast hydrophobicity (or solubility) difference between PTXL and GEM makes it practically undoable to load them into the same type of nanoparticles, such as the lipid-coated polymeric nanoparticles used in this study. These nanoparticles can encapsulate hydrophobic drugs such as PTXL with high encapsulation and loading yields but can barely encapsulate hydrophilic drugs such as GEM. In fact, the inability of loading different drugs to the same type of nanoparticles represents a generic challenge to many pairs of drugs for combination therapy. (p. 71, [0270], lines 1-11) (emphasis added). Therefore, in view of Zhang, one of ordinary skill in the art would have recognized the difficulty of co-formulating drugs of different hydrophobicity values, specifically gemcitabine and paclitaxel, and would have contemplated alternative methods that may successfully formulate these combinations of drugs with different hydrophobicity values.
Zhang does not teach the injectable aqueous lipid dispersion comprising gemcitabine and paclitaxel, as required by claim 1, or the powder composition comprising gemcitabine and paclitaxel, as required by claim 32.
Mu teaches that to overcome drug resistance, a common practice in the clinic is the combination of multiple agents that have diverse molecular targets. Mu teaches these drugs are administered separately into the body and improve the overall therapeutic outcome compared to monotherapy (p. 436, right column, second full paragraph, lines 1-5).
However, Mu teaches that certain challenges still exist for combination therapy, including that concomitant administration of multiple agents is complicated by the divergent physicochemical properties of the cytotoxic agents, which translate into variable disposition and clearance mechanisms and thus different concentration–time courses for each cytotoxic agent (p. 436, right column, second full paragraph, lines 10-15) (emphasis added). Mu further teaches that additional innovation in drug delivery that harnesses the advantages of drug combination therapy may be particularly beneficial for cancers (p. 437, left column, lines 4-7) (emphasis added).
Mu further describes the challenges of co-formulating drugs with different solubilities. Mu teaches that the physical consideration challenges of formulating of two or more drugs in one formulation include how to incorporate drugs with varying degrees of water solubility, and that while hydrophobic excipients (e.g., fatty acids, lipids and poly(lactate-co-glycolate)) polymers are used to encapsulate or incorporate water insoluble drugs such as paclitaxel, and lipid membranes and hydrogels are used to encapsulate water soluble drugs such as cytarabine, formulation of both soluble and insoluble drugs into these nanomaterials has been challenging due to their disparate physical characteristics (p. 439, right column, last paragraph, lines 1-11) (emphasis added).
Finally, Mu compares two formulations for drug combinations. Mu teaches TCL-ART 101, which includes a combination of anti-HIV drugs, and CPX-351, which includes a combination of anti-cancer drugs (p. 443, Table 4). Mu teaches the lipid constituents in TLC-ART 101 allow unique interactions with both hydrophobic and hydrophilic drugs (p. 443, left column, lines 9-11), and that unlike the complex process to manufacture CPX 351, TLC-ART 101 uses a simple and less complex formulation strategy (solubilizing drugs and lipid excipient in a suitable organic solvent, the controlled removal of the solvent (drying), hydration of the stabilized drug–lipid combination and homogenization to produce specified drug-particle size), keeping all components intact during the process without exchanging buffer systems (p. 443, left column, lines 18-24). Mu concludes the comparison of CPX 351 and TLC-ART 101 by stating that the simplified manufacturing processes associated with TLC-ART 101 reduce both sample loss and the risk of contamination while providing consistent and predictable drug loading efficiency (p. 443, left column, lines 24-26). When discussing TLC-ART 101, Mu cites Freeling as the source of this method (reference 59 in Mu, cited on p. 443, left column).
This teaching from Mu is interpreted herein as a suggestion that the method of Freeling, considering it uses a simple and less complex formulation strategy, which reduces both sample loss and the risk of contamination while providing consistent and predictable drug loading efficiency, may be utilized for other combinations of therapeutics, including formulation of both hydrophobic and hydrophilic drugs.
Freeling teaches multidrug anti-HIV lipid nanoparticles (anti-HIV LNPs) containing lopinavir (LPV), ritonavir (RTV), and tenofovir (PMPA) (p. 107, Abstract, lines 1-4). Freeling teaches that macaques treated with the anti-HIV LNPs demonstrated elevated plasma concentrations of LPV and RTV at all time points evaluated and higher peak plasma concentrations of LPV and RTV ( p < 0.05). Freeling states that all three drugs remained detectable in plasma at 7 days (168 h) post-administration (p. 109, right column, Effects of Effects of LNP association on plasma time course and total drug exposure, lines 1-10).
Freeling teaches their product as a lipid nanoparticle, which is interpreted herein as an organized composition as required by claim 2. In addition, Freeling does not teach these lipid nanoparticles as comprising any of a lipid layer, a lipid bilayer, a liposome, or a micelle, as required by claim 5.
Freeling teaches dissolving of the lipids DSPC and MPEG-2000-DSPE (present in an 8:2 or 9:1 molar ratio), and the protease inhibitors LPV and RTV in chloroform and ethanol, adding an aqueous solution of PMPA and removing solvent by evaporation (p. 108, left column, Lipid nanoparticle preparation and in vitro characterization section, lines 1-9). Freeling teaches the dry film was rehydrated to 200 mM lipid in 0.4% NaCl with 20 mM NaHCO3 buffer at 60 °C, sonicated, and LNPs were maintained at 60 °C to anneal for 30 min prior to cooling and stored at 4 °C (p. 108, left column, lines 9-14).
Freeling teaches these preparations as formulated for injection (p. 108, right column, Sterility of preparations for injection section, lines 1-5). The 0.4% NaCl with 20 mM NaHCO3 buffer taught above used for reconstitution of the dry film satisfies the limitations of an aqueous solution with 10-100 mM sodium bicarbonate and 0.45 wt% to 0.9 wt% NaCl, as recited in claim 6.
Freeling teaches that these lipid nanoparticles include lipid:LPV:RTV:PMPA in a 115:10:5:15 molar ratio (p. 108, left column, Lipid nanoparticle preparation and in vitro characterization section, lines 1-4). The molar ratio of therapeutic agents to lipid in this instance is 30:115, which is a ratio of about 1:3.8 and falls within the range required by claim 18. In addition, the lipids DSPC and MPEG-2000-DSPE are lipids required by claim 19.
Finally, Freeling that in their lipid particle, LPV and RTV were selected due to their acid stability and hydrophobicity, which promotes lipid association (p. 107, right column, first full paragraph, lines 3-5). Freeling teaches that by employing a simple, reproducible, and scalable production method, these nanoparticles stably incorporate LPV and RTV with > 90% efficiency while simultaneously encapsulating a hydrophilic reverse transcriptase inhibitor, PMPA (p. 111, Discussion, second paragraph, lines 1-4). This is interpreted as teaching that these lipid nanoparticles may be used to encapsulate drugs that are both hydrophobic (e.g., LPV and RTV) and drugs that are hydrophilic (e.g., PMPA).
Meng teaches as described in the above rejections under 35 U.S.C. § 103. In addition, Meng teaches the above formulation with 100 mg/kg gemcitabine and 10 mg/kg paclitaxel. The molecular weight of gemcitabine is 263.201 g/mol, and the molecular weight of paclitaxel is 853.918 g/mol (see instant specification, pp. 14-15). The molar ratio of gemcitabine to paclitaxel in this formulation is approximately 32:1.
In addition, Meng teaches that a series of GEM/PTX LB-MSNPs were prepared in which a fixed amount of GEM (25%, w/w) was used with 0.25-5 wt % PTX to yield GEM/PTX ratios of 100:1, 10:1, and 5:1, and that each particle type was used to assess cytotoxicity and to determine the concentration of each drug in the mixture for a 50% killing effect (p. 3545, left column, lines 12-18). Meng teaches that at an encapsulation ratio of 10:1, the GEM concentration required for 50% cell killing was reduced from 5.2 μg/mL (using GEM-only particle) to 2.3 μg/mL (using dual delivery particle), in the presence of a PTX dose of 0.23 μg/mL. Meng teaches that this falls into the low or nontoxic dose of PTX, as shown by an independent experiment using PTX-only LB-MSNP (p. 3545, left column, lines 19-26).
Frese teaches that nanoparticle albumin-bound (nab)-paclitaxel, an albumin-stabilized paclitaxel formulation, demonstrates clinical activity when administered in combination with gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma (PDA). Frese teaches use of a mouse model of PDA to show that the coadministration of nab-paclitaxel and gemcitabine uniquely demonstrates evidence of tumor regression. Frese teaches the combination treatment increases intratumoral gemcitabine levels attributable to a marked decrease in the primary gemcitabine metabolizing enzyme, cytidine deaminase. Frese teaches their findings support the concept that suboptimal intratumoral concentrations of gemcitabine represent a crucial mechanism of therapeutic resistance in PDA (p. 261, Abstract, lines 1-3 and 7-14) (emphasis added).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to formulate a combination of paclitaxel and gemcitabine using the method of preparing lipid nanoparticles taught by Freeling. One of ordinary skill in the art would have been motivated to formulate a combination of paclitaxel and gemcitabine using the method of preparing lipid nanoparticles taught by Freeling because Zhang, Meng, and Freese teach the benefits of co-administration of different chemotherapies and the formulation challenges of combining paclitaxel and gemcitabine, because Mu teaches the formulation benefits of the method of formulation taught by Freeling for combinations of hydrophobic and hydrophilic drugs, and because Freeling teaches their method is effective for preparing formulations comprising both hydrophobic and hydrophilic compounds.
In this instance, the rationale “combining prior art elements according to known methods to yield predictable results” would apply. Because Zhang teaches the challenges of co-administration of paclitaxel and gemcitabine due to their different hydrophobicity, and because Freeling teaches a method of formulating combinations of drugs that may be used to prepare a combination of a hydrophobic and hydrophilic agent in a single formulation, one of ordinary skill in the art would have contemplated the method of Freeling as one option for solving the co-formulation challenge of gemcitabine and paclitaxel presented by Zhang.
Regarding the stability requirement of claim 1, the specification provides that their aqueous dispersion composed of DSPC and DSPE-mPEG2000 as lipid excipients, paclitaxel, and gemcitabine (90:10:2.5:80 molar ratio) were prepared by solubilizing lipid excipients and drugs together in ethanol at 60°C, removing ethanol by solvent evaporation at 60°C, followed by vacuum desiccation to remove residual solvent, and rehydrating the dry film to 100 mM lipids in 0.45% NaCl with 20 mM NaHCO3 buffer at 60°C (p. 40, lines 4-9). This method is sufficiently similar to the method obvious over Zhang in view of Mu, Freeling, Meng, and Frese that the product produced by practicing the method obvious Zhang in view of Mu, Freeling, Meng, and Frese would, absent evidence to the contrary, necessarily have the property of remaining stable when stored at 25 °C for at least 2 weeks (see specification, p. 26, lines 19-20).
Regarding the concentration of claim 1, in view of Meng teaching their compositions comprising 25% gemcitabine by weight and 0.25-5 wt % paclitaxel, one of ordinary skill in the art would have seen these as starting points when preparing the aqueous dispersion obvious over Zhang, Mu, Freeling, Meng, and Frese. Moreover, because Frese teaches the importance of optimal chemotherapy concentration for therapeutic efficacy and avoiding therapeutic resistance with paclitaxel and gemcitabine, including that the administration of paclitaxel affects the concentration of gemcitabine, one of ordinary skill in the art would have recognized the ratio and concentrations of gemcitabine and paclitaxel as affecting the anti-cancer activity of the combination therapy. Accordingly, one of ordinary skill in the art would have considered the dose and ratio of gemcitabine and paclitaxel as result-effective variables, and would have optimized the amount and ratio of these compounds via routine experimentation to optimize the anti-cancer activity of this composition.
MPEP 2144.05 at 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).” In this instance, absent a showing of the criticality of the amount of the combination chemotherapy in the composition, the loading of the gemcitabine and paclitaxel would have been adjusted via routine experimentation to achieve a desired anti-cancer activity of said composition.
Regarding the organized composition of claim 2, because Freeling teaches their method as producing lipid nanoparticles, which are interpreted herein as an organized composition, one of ordinary skill in the art would have reasonably expected the formation of nanoparticles when practicing the method of Freeling with gemcitabine and paclitaxel.
Regarding the limitations of claim 4, as stated, the method is sufficiently similar to the method obvious over Zhang in view of Mu, Freeling, Meng, and Frese that the product produced by practicing the method obvious Zhang in view of Mu, Freeling, Meng, and Frese would necessarily have the chemotherapeutic agents and the one or more compatibilizers together comprise a repetitive multidrug motif structure, absent evidence to the contrary.
Regarding the gemcitabine:paclitaxel ratio of from about 1:1 to about 50:1 as recited in claim 9, because Zhang teaches 1:1 ratio due to the nature of their conjugate, and because Meng teaches a ratio of gemcitabine to paclitaxel of approximately 32:1, one of ordinary skill in the art would have reasonably considered molar ratios of gemcitabine:paclitaxel between 1:1 and about 32:1, because such ratios have been recognized by the prior art as effective for treating cancer, and would have further optimized these ratios to achieve a desired anti-cancer activity of the composition. See MPEP 2144.05 at II A.
Regarding the limitations of claim 32, the product taught by Freeling with solvent removed, prior to dispersion in an aqueous solvent, would satisfy the limitations of the powder composition required by claim 32.
Therefore the invention taken as a whole is prima facie obvious.
Regarding the rejection of claim 14, claim 14 depends from claim 1 and further limits the molar ratio of venetoclax and zanubrutinib. However, because claim 1 recites venetoclax and zanubrutinib as an alternative to paclitaxel and gemcitabine, venetoclax and zanubrutinib are not required to practice the method of claim 1, and thus claim 14 further limits an alternative limitation not required by claim 1. Accordingly, claim 14 is also obvious over Zhang in view of Mu, Freeling, Meng, and Frese, which renders obvious the aqueous dispersion of claim 1 with paclitaxel and gemcitabine.
Claim 33 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang (WO 2011143201 A2; cited in previous office action) in view of Mu (Mu, Q.; et al. Journal of Drug Targeting 2018, vol. 26, pp. 435-447; cited in previous office action), Freeling (Freeling, J. P.; et al. AIDS Research and Human Retroviruses 2015, vol. 31, pp. 107-114; cited in previous office action), Meng (Meng, H.; et al. ACS Nano 2015, vol. 9, pp. 3540-3557; cited in restriction requirement mailed June 18, 2025), and Frese (Frese, K. K.; et al. Cancer Discovery 2012, vol. 2, pp. 260-269; cited in PTO-892) as applied to claim 32 above, and further in view of Krūkle-Bērziņa (Krūkle-Bērziņa, K.; et al. Journal of Pharmaceutical and Biomedical Analysis 2015, vol. 107, pp. 168-174; cited in previous office action).
Claim 33 requires the powder composition of claim 32, wherein the composition comprises a phase transition temperature different from the transition temperature of each individual chemotherapeutic agent when assessed by differential scanning calorimetry.
Zhang, Mu, Freeling, Meng, and Frese teach as described in the above rejection under 35 U.S.C. 103. Specifically, Mu teaches that the lipid constituents in TLC-ART 101 allow unique interactions with both hydrophobic and hydrophilic drugs.
Zhang, Mu, Freeling, Meng, and Frese do not teach wherein the composition comprises a phase transition temperature different from the transition temperature of each individual chemotherapeutic agent when assessed by differential scanning calorimetry, as recited in claim 33.
Krūkle-Bērziņa teaches as described in the above rejection under 35 U.S.C. § 103.
It would have been prima facie obvious to one of ordinary skill in the art that the composition of claim 32 comprises a phase transition temperature different from the transition temperature of each individual chemotherapeutic agent when assessed by differential scanning calorimetry. One of ordinary skill in the art would have expected that the composition comprises a phase transition temperature different from the transition temperature of each individual chemotherapeutic agent when assessed by differential scanning calorimetry because Mu teaches interaction between the lipid constituents in the composition produced by TLC-ART 101, which is the method of Freeling, and because Krūkle-Bērziņa teaches interactions between drug molecules and excipients can also introduce changes in enthalpy values. Accordingly, formulation of gemcitabine and paclitaxel using the method of Freeling would have been expected to result in a phase transition temperature different from the transition temperature of each individual chemotherapeutic agent.
Therefore the invention taken as a whole is prima facie obvious.
Allowable Subject Matter
Claim 1 is drawn to an aqueous dispersion composition comprising gemcitabine and paclitaxel, or venetoclax and zanubrutinib, with a compatibilizer that remains stable for at least 2 weeks when stored at 25 °C. The presently claimed composition comprising venetoclax and zanubrutinib is free of prior art. The closest prior art is considered Tarantelli (Tarantelli, C.; et al. Haematologica 2019, vol. 104, e307; cited in PTO-892), who teaches zanubrutinib exhibits synergies with other anti-lymphoma targeted agents (p. 1, title). Tarantelli teaches that used in combination in the ibrutinib-sensitive models, zanubrutinib achieved synergism in all of the cell lines tested with the addition of the BCL2 inhibitor venetoclax (p. 1, last paragraph to p. 2). Accordingly, one of ordinary skill in the art would have recognized the benefit of a combined therapy comprising zanubrutinib and venetoclax.
However, the above rejection over the aqueous dispersion of claim 1 is based on recognition in the prior art that gemcitabine and paclitaxel show advantageous activity when administered in combination, and that gemcitabine and paclitaxel are difficult to formulate together because of their very different hydrophobicity properties. In this instance, the Office has not identified prior art that recognizes the different hydrophobicity values of venetoclax and zanubrutinib, and thus one of ordinary skill in the art would not have been motivated to look to methods for formulating venetoclax and zanubrutinib using lipids that demonstrate the stability and include the amount of chemotherapeutic agent combination required by claim 1.
Accordingly, the scope of claim 1 that requires venetoclax and zanubrutinib would be allowable.
However, present claim 32 does not include functional limitations describing the stability of the composition, and thus the scope of claim 32 is different than the scope of claim 1. Accordingly, the scope of claim 32 that requires venetoclax and zanubrutinib would not necessarily be allowable and would require additional search and consideration.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/B.M.B./Examiner, Art Unit 1693
/ANDREA OLSON/Primary Examiner, Art Unit 1693
