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.
Election/Restrictions
Applicant’s election of the invention of Group I in the reply filed on August 19, 2025, is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 22, 23, 26, 28, 29, and 31 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on August 19, 2025.
Status of the Application
Claims 1-7, 9, 14, 18-19, 21-23, 26, 28-29, and 31-33 are pending in this application.
Claims 22, 23, 26, 28, 29, and 31 are withdrawn as being directed to a non-elected invention.
Claims 1-7, 9, 14, 18-19, 21, and 32-33 are examined on the merits herein.
Claim Interpretation
Claim 5 recites wherein the aqueous dispersion does not comprise a structural feature of a lipid layer, a lipid bilayer, a liposome, or a micelle. Because these structural features are recited in the alternative (i.e., reciting “or”), the claim appears to require the aqueous dispersion to not require a lipid bilayer, a liposome, or a micelle, and is interpreted as such herein.
If Applicant intended for claim 5 to require an aqueous dispersion that does not include any of a lipid bilayer, a liposome, or a micelle, claim 5 may be amended to recite does not comprise a structural feature of any of a lipid layer, a lipid bilayer, a liposome, and a micelle.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-7, 9, 14, 18-19, 21, and 32-33 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The term “sustained” in claims 1 and 32 is a relative term which renders the claim indefinite. The term “sustained” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The specification states: “As used herein, a sustained plasma concentration is a plasma drug concentration that is maintained for a defined period (e.g., 14 days or more and/or 90 days or less) above the EC50 value of each chemotherapeutic agent in the combination of therapeutic agents, and at a dosage without adverse effects.” However, the claim does not define the period in which the drug plasma concentration must remain above the EC50 level, and therefore, claims 1 and 32 are indefinite.
In addition, it is unclear the conditions under which a sustained chemotherapeutic effect must be observed. These claims are drawn to an aqueous dispersion and powder composition, and they do not require administering the composition to a subject or describe conditions under which a sustained chemotherapeutic must be exhibited.
Because claims 1-7, 9, 14, 18-19, and 21 depend from claim 1 and fail to cure these deficiencies, and because claim 33 depends from claim 32 and fails to cure these deficiencies, these claims are also indefinite.
Claim 3 depends from claim 1 and recites: “wherein the chemotherapeutic agents and the one or more compatibilizers together comprise a long-range physical order in the form of a repeating multiple-drug-domain pattern in an intermediate powder product in producing aqueous dispersion.” It is unclear what the intermediate powder product in producing aqueous dispersion refers to in this claim. Claim 1 is drawn to an injectable aqueous dispersion and does not require an intermediate powder product, and does not recite steps for producing an aqueous dispersion.
It is thus unclear how an intermediate powder product of claim 1 would be obtained. Claim 3 appears to claim a property of a different product (i.e., an intermediate product) than the claim upon which it depends. Thus claim 3 is indefinite.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 2, 5-7, 9, and 14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Meng (Meng, H.; et al. ACS Nano 2015, vol. 9, pp. 3540-3557; cited in restriction requirement mailed June 18, 2025).
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 chemotherapeutic agents of the chemotherapeutic agent composition exhibit a synergistic and sustained chemotherapeutic effect. Claim 2 requires the chemotherapeutic agents and the one or more compatibilizers together form an organized composition, 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 7 requires the aqueous dispersion comprises each chemotherapeutic agent composition in an amount of 5 wt % or more and 30 wt % or less, claim 9 requires the gemcitabine:paclitaxel molar ratio is from about 1:1 to about 50:1, and claim 14 requires the venetoclax and zanubrutinib molar ratio is from about 10:1 to about 1:10.
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). This is taken as teaching that the composition of Meng provides a synergistic chemotherapeutic effect.
Because Meng teaches paclitaxel as an inhibitor of the gemcitabine-inactivating enzyme, cytidine deaminase (p. 3540, Abstract, lines 1-6), coadministration of paclitaxel and gemcitabine would have been expected to prolong the chemotherapeutic effect of gemcitabine. In addition, Meng teaches that administration of the paclitaxel and gemcitabine LB-MSNP formulation shows increased concentration of gemcitabine and active gemcitabine in tumors compared to administration of gemcitabine alone or gemcitabine alone formulated as a in the LB-MSNP formulation (p. 3549, Figure 3B). Meng teaches that administration of the paclitaxel and gemcitabine LB-MSNP formulation showed a lower concentration of inactive gemcitabine in tumors compared to administration of gemcitabine alone or gemcitabine alone in the LB-MSNP formulation (p. 3549, Figure 3B). Therefore, because paclitaxel inhibits the gemcitabine-inactivating enzyme cytidine deaminase, and because administration of paclitaxel and gemcitabine LB-MSNP formulation shows a lower concentration of inactivated gemcitabine compared to administration of gemcitabine alone, administration of this composition is interpreted as providing a sustained chemotherapeutic effect compared to administration of gemcitabine alone.
Regarding the requirement for an aqueous solvent, Meng teaches that tumor-bearing mice were intravenously (IV) injected with these PTX/GEM-loaded LB-MSNPs. Meng teaches that each animal received a particle dose of 250 mg/kg (GEM, 100 mg/kg; PTX, 10 mg/kg) per injection, and that the controls included animals receiving IV injection with saline, free GEM (100 mg/kg), Abraxane (PTX dose, 10 mg/kg), GEM-loaded LB-MSNPs (GEM, 100 mg/kg; particle, 250 mg/kg), as well as a mixture of free GEM (100 mg/kg) plus Abraxane (PTX dose, 10 mg/kg) (p. 3545, right column, third full paragraph, lines 5-14). Because Meng teaches these compositions formulated as formulations that were injected into mice, and because Meng teaches saline as a control, these compositions formulated for injection are interpreted herein to include an aqueous solvent, absent evidenced to the contrary. Therefore, the product of Meng satisfies all limitations of present claim 1. In addition, Because Meng teaches their product as nanoparticles, they are interpreted as having an ordered structure as required by claim 2.
Meng teaches these products as having a lipid bilayer, but does not teach them as having, for example, a micelle structure. Accordingly, the product of Meng is interpreted as satisfying the limitations of claim 5.
Meng teaches the GEM encapsulation stability and release profile of LB-MSNPs in the absence or presence of PTX loading, and that in both particle types, GEM encapsulation was stable in phosphate-buffered saline (PBS) (p. 3545, right column, first full paragraph, lines 1-5). PBS is interpreted herein as a buffered aqueous solvent, as required by claim 6, and thus the nanoparticles of Meng dispersed in PBS would satisfy the structural requirements of an injectable formulation, absent evidence to the contrary.
Regarding the gemcitabine to paclitaxel molar ratio recited in claim 9, 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, which is within the range recited in claim 9.
Moreover, 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 composition that includes 25 wt % gemcitabine and 5 wt % paclitaxel satisfies the limitations of claim 7, which requires each chemotherapeutic agent in the composition is present in an amount of 5 wt % or more and 30 wt % or less.
Thus Meng anticipates claims 1, 2, 5-7, 9, and 14.
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 anticipated by Meng, which anticipates the aqueous dispersion of claim 1 with paclitaxel and gemcitabine.
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.
Claims 1 and 19 are 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 Nel (U.S. pre-grant publication no. 20160008283 A1; cited in IDS received March 28, 2024).
Claim 19 depends from claim 1 and requires the one or more compatibilizers are selected from 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[poly(ethylene glycol2000], and a combination thereof.
Meng teaches as described in the above rejections under 35 U.S.C. 102. In addition, Meng teaches their nanoparticles included a lipid bilayer coating comprising a combination of DPPC/cholesterol/DSPE-PEG at a molar ratio of 77.5:20:2.5 (p. 3553, Methods section, second paragraph, lines 13-15).
Meng does not teach the one or more compatibilizers as 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[poly(ethylene glycol2000], specifically with PEG2000, as required by claim 19.
Nel teaches lipid-bilayer coated mesoporous silica nanoparticles that may be loaded with anti-cancer agents (cover page, Title). Nel teaches formulations for loading gemcitabine in said nanoparticles, including teaching a gemcitabine-loaded nanoparticle with lipids DPPC:Cholesterol:DSPE-PEG2K in a ratio of 6:3:1 (p. 16, Table 1). Finally, Nel teaches that different liposomal compositions can be selected based on drug, targeting purpose, and other considerations, further teaching that paclitaxel can be co-dissolved in the organic solution to prepare gemcitabine and paclitaxel loaded nanoparticles. (p. 19, [0194], lines 7-9; p. 19, [0199]). DSPE-PEG2K is interpreted as equivalent to 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[poly(ethylene glycol2000] as recited in claim 19.
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 select 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[poly(ethylene glycol2000] as the one or more compatibilizers in the formulation taught by Meng. One of ordinary skill in the art would have been motivated to select the 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[poly(ethylene glycol2000] as the one or more compatibilizers because Meng teaches DSPE-PEG as one component of the lipid bilayer of their nanoparticle compositions, and because Nel teaches similar lipid bilayer-coated nanoparticles that includes a lipid bilayer coating comprising DSPE-PEG2K. Therefore, one of ordinary skill in the art would have contemplated selecting DSPE-PEG2K (with PEG as PEG-200) as the specific type of DSPE-PEG used to prepare the nanoparticles taught by Meng.
Therefore the invention taken as a whole is prima facie obvious.
Claims 1-6, 9, 14, 18-19, 21, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang (WO 2011143201 A2; cited in PTO-892) in view of Mu (Mu, Q.; et al. Journal of Drug Targeting 2018, vol. 26, pp. 435-447; cited in PTO-892), Freeling (Freeling, J. P.; et al. AIDS Research and Human Retroviruses 2015, vol. 31, pp. 107-114; cited in PTO-892), and Meng (Meng, H.; et al. ACS Nano 2015, vol. 9, pp. 3540-3557; cited in restriction requirement mailed June 18, 2025).
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 chemotherapeutic agents of the chemotherapeutic agent composition exhibit a synergistic and sustained chemotherapeutic effect. Claim 2 requires the chemotherapeutic agents and the one or more compatibilizers together form an organized composition, claims 3 and 4 require 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, and claim 18 requires a
molar ratio of chemotherapeutic agents to the one or more compatibilizers of from about 1:10 to
about 1:1, claim 19 requires the one or more compatibilizers are selected from those listed, and claim 21 requires the dispersion remains stable when stored at 25 °C for at least 2 weeks.
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 chemotherapeutic agents of the combination of chemotherapeutic agents
exhibit a synergistic and sustained chemotherapeutic effect.
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, including 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 the present claim 1, the powder composition comprising gemcitabine and paclitaxel, as required by claim 32.
Mu teaches that to overcome drug resistance, a common practice in 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 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). This is interpreted as teaching that the LNPs of the Freeling provided sustained delivery of their drug cocktail.
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 having, for example, a micelle structure, and thus Freeling satisfies the limitations of 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 the 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 teaches that by employing a simple, reproducible, and scalable production method (p. 107, right column, first full paragraph, lines 3-5). Freeling concludes by stating 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 taken 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. 102 and 35 U.S.C. 103.
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 and Meng 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 reasonably contemplated the method of Freeling as one option for solving the co-formulation challenge of gemcitabine and paclitaxel presented by Zhang. In addition, because Zhang and Meng teach the benefits of administering both gemcitabine and paclitaxel, including Meng teaching synergistic activity of gemcitabine and paclitaxel, and because Freeling teaches their compositions offer a sustained release of therapeutic agent, one of ordinary skill in the art would have reasonably expected a both sustained and synergistic effect from a formulation of gemcitabine and paclitaxel prepared using the method of Freeling.
Regarding 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 claims 3 and 4, the present specification provides that the chemotherapeutic agent compositions have a unified repetitive multi-drug motif (MDM) structure, such that, unlike amorphous powders, the chemotherapeutic agent compositions of the present disclosure have long range order, in the form of repetitive multi-drug and unified motifs (p. 21, lines 21-25). In addition, 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 were 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, and Meng that the product produced by practicing the method obvious Zhang in view of Mu, Freeling, and Meng would, absent evidence to the contrary, necessarily have the chemotherapeutic agents and the one or more compatibilizers together comprise a long-range physical order in the form of a repeating multiple-drug-domain pattern in an intermediate powder product in producing aqueous dispersion, as recited in claim 3, and would have the chemotherapeutic agents and the one or more compatibilizers together comprise a repetitive multidrug motif structure, as recited in claim 4.
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.
Regarding the stability requirement of claim 19, because the instant specification states that the chemotherapeutic agent compositions can remain stable when stored at 25 °C for at least 2 weeks (p. 26, lines 19-20), the product of the method obvious over Zhang in view of Mu, Freeling, and Meng, prepared by a method very similar to the present application, would also remain stable when stored at 25 °C for at least 2 weeks, absent evidence to the contrary.
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, and Meng, 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 PTO-892) in view of Mu (Mu, Q.; et al. Journal of Drug Targeting 2018, vol. 26, pp. 435-447; cited in PTO-892), Freeling (Freeling, J. P.; et al. AIDS Research and Human Retroviruses 2015, vol. 31, pp. 107-114; cited in PTO-892), and Meng (Meng, H.; et al. ACS Nano 2015, vol. 9, pp. 3540-3557; cited in restriction requirement mailed June 18, 2025) as applied to claims 1-6, 9, 14, 18-19, 21, and 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 PTO-892).
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, and Meng 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, and Meng 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 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 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.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-6, 9, 14, 18-19, and 32-33 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 20, 23, and 26 of co-pending U.S. patent application 17/422074 (reference patent, herein referred to as ‘074) in view of Zhang (WO 2011143201 A2; cited in PTO-892), Meng (Meng, H.; et al. ACS Nano 2015, vol. 9, pp. 3540-3557; cited in restriction requirement mailed June 18, 2025), Freeling (Freeling, J. P.; et al. AIDS Research and Human Retroviruses 2015, vol. 31, pp. 107-114; cited in PTO-892), and Krūkle-Bērziņa (Krūkle-Bērziņa, K.; et al. Journal of Pharmaceutical and Biomedical Analysis 2015, vol. 107, pp. 168-174; cited in PTO-892).
The present application and ‘074 are each assigned to the University of Washington and include Rodney Ho as an inventor.
Claim 1 of ‘074 claims a pharmaceutical composition, comprising: a hydrophobic therapeutic agent having a log P value of 1 or greater; a hydrophilic therapeutic agent having a log P value of less than 1; and one or more compatibilizers comprising a lipid excipient, a lipid conjugate excipient, or a combination thereof, with the solid powder having a powder X-ray
diffraction pattern as described in the claim, and wherein the solid powder comprises a unified repetitive multi-drug motif structure as measured by its powder X-ray diffraction pattern.
Claim 20 of ‘074 claims the lipid excipient is selected from 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC).
Claim 23 of ‘074 depends from claim 1 and requires a molar ratio of hydrophobic therapeutic agent and hydrophilic therapeutic agent to the one or more compatibilizers of from 30:115 to 71:40
Claim 26 of ‘074 requires the solid powder composition of claim 1 dispersed in an aqueous solvent.
The claims of ‘074 do not claim a composition comprising gemcitabine and paclitaxel, as recited in independent claims 1 and 32.
Zhang, Meng, and Krūkle-Bērziņa teach as described in the above rejections under 35 U.S.C. 102 and 35 U.S.C. 103.
It would therefore have been prima facie obvious to one of ordinary skill in the art to prepare a pharmaceutical formulation of claim 1 of ‘074 with gemcitabine and paclitaxel, in view of Zhang teaching the solubility differences of gemcitabine and paclitaxel and acknowledging the challenges of formulating them together. Accordingly, one of ordinary skill in the art would have contemplated the pharmaceutical composition claimed by ‘074 because it is effective for co-formulating hydrophobic and hydrophilic compounds as a single composition. Moreover, the injectable formulation, as well as the synergistic and sustained activity, required by claims 1 and 32, the aqueous solvent of claim 6, and the change in phase transition temperature required by claim 33, would also have been obvious over the claims of ‘074 in view of Zhang, Meng, Freeling, and Krūkle-Bērziņa.
Regarding the specific LogP values recited in claim 1 of ‘074, because Zhang teaches gemcitabine as hydrophilic and paclitaxel and hydrophobic, one of ordinary skill in the art would have recognized that these compounds may be reasonably included composition claim by ‘074, because claim 1 of ‘074 expressly teaches hydrophobic and hydrophilic therapeutic agents. Therefore, even without specific LogP values for gemcitabine and paclitaxel, one of ordinary skill in the art would have recognized these compounds may be reasonably included in the composition claimed by ‘074.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not been patented.
Conclusion
No claims are allowed.
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/B.M.B./ Examiner, Art Unit 1693
/ERIC OLSON/ Primary Examiner, Art Unit 1693