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 .
Summary
Claims 1-2 and 4-17 are pending in this office action. Claims 16-17 are new. Claim 3 is cancelled. All pending claims are under examination in this application.
Priority
The current application was filed on June 26, 2023. The current application claims foreign priority to EP22181609.3 filed on June 28, 2022.
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 non-obviousness.
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 1-2, 4-11, and 13-17 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (CN102579337A) in view of Singh (WO2004/043363A2) and Hong et al. (Drug Delivery, 2017).
[The Examiner is going to introduce each reference and then combine them where appropriate to reject the instant claims.]
1. Zhang et al.
Zhang et al. is considered the closest prior art as it teaches long circulation lipid nano-suspension containing docetaxel and preparation method thereof (see title). Furthermore, Zhang et al. disclose that the invention discloses a long circulation lipid nano-suspension containing docetaxel. The nano-suspension is prepared from the following components in parts by weight: 0.5-50 parts of water solution, 0.5-50 parts of docetaxel, 0.05-20 parts of lipid-PEG (poly(ethylene glycol)) and 50-90 parts of phospholipid or is prepared from 0.5-50 parts of water solution, 0.5-50 parts of docetaxel, 0.05-20 parts of lipid-PEG, 50-90 parts of phospholipid and 0.01-10 parts of targeting factor with tumor targeting function. A preparation method of the nano-suspension comprises the following steps of: (1) dissolving phospholipid and lipid-PEG into the water solution to obtain solution A, or dissolving phospholipid, lipid-PEG and the targeting factor with tumor targeting function into the water solution to obtain solution A; (2) dispersing docetaxel into the solution A obtained in the step (1) to obtain suspension B; (3) carrying out high speed shearing on the suspension B for 1-3 minutes to obtain colostrum C; and (4) homogenizing the colostrum C by a high pressure homogenization method, thus obtaining the long circulation lipid nano-suspension. The preparation has the effects of increasing the content of docetaxel and reducing the toxic or side effect of docetaxel (see abstract).
2. Singh
Singh teaches protein-stabilized liposomal formulations of pharmaceutical agents (see title). In addition, Singh discloses that the present invention relates to protein stabilized liposomes. Specifically, the present invention discloses compositions and methods for protein stabilized liposomes, the creation of protein stabilized liposomes, and the administration of protein stabilized liposomes (see abstract).
3. Hong et al.
Hong et al. teach high drug payload curcumin nanosuspensions
stabilized by mPEG-DSPE and SPC: in vitro and in vivo evaluation (see title). Additionally, Hong et al. disclose the following abstract:
Context: Curcumin (CUR) is a promising drug candidate based on its broad bioactivities and good antitumor effect, but the application of CUR is potentially restricted because of its poor solubility and bioavailability.
Objective: This study aims at developing a simple and effective drug delivery system for CUR to enhance its solubility and bioavailability thus to improve its antitumor efficacy.
Materials and methods: Curcumin nanosuspensions (CUR-NSps) were prepared by precipitation ultrasonication method using mPEG2000-DSPE and soybean lecithin as a combined stabilizer.
Results: CUR-NSps with a high drug payload of 67.07% were successfully prepared. The resultant CUR-NSps had a mean particle size of 186.33 ± 2.73nm with a zeta potential of -19.00 ± 1.31 mV. In vitro cytotoxicity assay showed that CUR-NSps exhibited enhanced cytotoxicity compared to CUR solution. The pharmacokinetics results demonstrated that CUR-NSps exhibited a significantly greater AUC0–24 and prolonged MRT compared to CUR injections after intravenous administration. In the biodistribution study, CUR-NSps demonstrated enhanced biodistribution compared with CUR injections in liver, spleen, kidney, brain, and tumor. The CUR-NSps also showed improved antitumor therapeutic efficacy over the injections (70.34% versus 40.03%, p50.01).
Conclusions: These results suggest that CUR-NSps might represent a promising drug
formulation for intravenous administration of CUR for the treatment of cancer (see abstract).
Combination of Zhang et al., Singh, and Hong et al.
Regarding instant claim 1, Zhang et al., Singh, and Hong et al. teach a method for preparing an aqueous nanocrystalline suspension of API. The necessary citations of Zhang et al., Singh, and Hong et al. that pertain to instant claim 1 are presented in Table I.
Table I
Instant Claim 1
Zhang et al., Singh, and Hong et al. Citations
A method for preparing an aqueous nanocrystalline suspension of API, comprising the following steps: (a) preparing an aqueous suspension comprising a crystalline API, selected from the group consisting of API having intrinsic solubility in water at most 50 mg/L, and having log P at least 4; and a combination of at least two stabilizing agents, selected from the group of phospholipids containing lipophilic carbohydrate chains consisting of from 6 to 20 carbon atoms; wherein at least one of the stabilizing agents is selected from the group of PEG-coupled phospholipids of general formula (I),
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Zhang et al. disclose a nanosuspension comprising 30 mg of water insoluble docetaxel (see paragraphs [0077], [0083], and [0089] within Zhang et al.; a crystalline API can be either commercially available or prepared by a skilled artisan) having log P of 4.1 (see PTO-892 NPL X section 1.1) and intrinsic solubility in water of less than 50 mg/ L (0.025 µg/ml; see PTO-892 NPL X section 1.1), said nanosuspension comprising a mixture of phospholipids SPC (soybean lecithin) : DSPE-PEG at the ratio of 300:9 (mg) (see paragraphs [0067] and [0071] within Zhang et al.) or 300:15 (see paragraph [0077] within Zhang et al.) 300:21 (see paragraph [0083] within Zhang et al.) or 300:27(see paragraph [0089] within Zhang et al.). The size of nanoparticle is around 200-220 nm (see paragraphs [0111] and [0046] within Zhang et al.). The weight ratio of API to the combination of stabilizing agents is ~1:10 (this ratio does not meet the claim limitation), [DSPE-PEG (DSPE-PEG2000 = 2780 g/mol) to SPC (~758 g/mol)].
A skilled artisan (POSITA; person having ordinary skill in the art) would use the appropriate measuring device to determine the nanoparticle diameter.
Singh discloses an aqueous nanosuspension comprising a particle size of 30-220 nm, said nanosuspension comprising a lipid mixture of DSPC (600mg) and PEG-2000-DSPE (100mg). Here the API to phospholipid weight ratio is similar to Zhang et al. and said nanosuspension comprises paclitaxel (known as having logP of more than 4 and intrinsic solubility in water of less than 50 mg/L). The nanosuspension was prepared by high-presser homogenisation.
Regarding the Zhang et al. reference and the first stabilizing phospholipid, the main component of SPC is phosphatidylcholine (see PTO-892 NPL V). This phospholipid meets the claim limitation criteria.
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where the two fatty acid chains are C17 and C15, respectively.
wherein R is independently selected from (C6 to C20)alkyl and (C6 to C20)alkenyl; R1 is
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Regarding the Zhang et al. reference and the second stabilizing phospholipid DSPE-PEG meets the criteria of formula I:
where R = C17 alkyl
n is an integer in the range of from 8 to 125;
A is selected from the group consisting of -OH, -OCH3, -NH2, -NH-(C=O)-CH2-CH2-COOH, -NH-(C=O)-CH2-CH2-SH; -CH2COOH, -N3, -O-CH2COOH, -CH2CH(=O);
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n = 9 for PEG 400; n = 22 for PEG 1000; and n = 45 for PEG 2000 (all PEG variations shown are commercial).
A = -OH
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wherein the weight ratio of API to the combination of stabilizing agents is in the range of from 20:1 to 1:1;
and wherein the concentration of crystalline API in the aqueous suspension in step (a) is in the range of from 10 mg/mL to 100 mg/mL;
(b) placing milling balls into the aqueous suspension from step (a), and
(c) milling the aqueous suspension of step (b) to obtain nanocrystalline API suspension, wherein the size of the API nanocrystals is at most 300 nm, determined using dynamic light scattering in demineralized water at 20 °C.
A preparation method of the nano-suspension comprises the following steps of: (1) dissolving phospholipid and lipid-PEG into the water solution to obtain solution A, or dissolving phospholipid, lipid-PEG and the targeting factor with tumor targeting function into the water solution to obtain solution A; (2) dispersing docetaxel into the solution A obtained in the step (1) to obtain suspension B; (3) carrying out high speed shearing on the suspension B for 1-3 minutes to obtain colostrum C; and (4) homogenizing the colostrum C by a high pressure homogenization method, thus obtaining the long circulation lipid nano-suspension (see abstract and paragraphs [0104] and [0108] within Zhang et al.). The obtained nanoemulsion was then further mixed with mannitol and freeze dried (see paragraphs [0096] and [0105] within Zhang et al.).
Zhang et al. disclose within claim 1, “A long-circulating lipid nanosuspension containing docetaxel, characterized in that it is made
from the following components in parts by weight: 0.5-50 parts of an aqueous solution, 0.5-50 parts of docetaxel, 0.05-20 parts of lipid-PEG, and 50-90 parts of a phospholipid…” (see claim 1 within Zhang et al.). Although the Example within Zhang et al. supplies only a 0.5 mg/mL aqueous suspension of docetaxel (see paragraph [0077] within Zhang et al.), claim 1 allows for a much more concentrated mixture. Hypothetically, one could be at a greater than 10 mg/mL aqueous suspension of docetaxel [30 mg docetaxel in 3 mL distilled water; 10 mg/mL] which is within the disclosed range.
However, the weight ratio of drug (API) to lipid is met by Hong et al. Hong et al. disclose a mixture of curcumin 15 mg, mPEG2000-DSPE 3 mg, and SPC 1.5 mg. This translates to a ratio of (15 mg API / 4.5 mg phospholipids) = 3.33:1 (see Preparation of CUR-NSps, page 111; within Hong et al.).
Hong et al. teach high drug payload curcumin nanosuspensions
stabilized by mPEG-DSPE and SPC: in vitro and in vivo evaluation (see title and abstract within Hong et al.
mPEG2000-DSPE (A = OCH3)
Therefore, a skilled artisan (POSITA) would incorporate the API to phospholipid ratio based on the positive pharmacokinetic, tissue biodistribution, and antitumor data (see Conclusions, page 119; within Hong et al.) with the curcumin loaded phospholipids disclosed by Hong et al., into the docetaxel nanosuspension disclosed by Zhang et al. or the paclitaxel loaded nanosuspension disclosed by Singh.
Therefore, a skilled artisan (POSITA) would use the Zhang et al., Singh, and Hong et al. references to teach every element of instant claim 1.
The remaining instant claims within this 35 U.S.C. § 103 section are directly dependent (claims 2-8) on instant claim 1 and are taught in full by the combination of Zhang et al., Singh, and Hong et al.
Regarding instant claim 2, Zhang et al., Singh, and Hong et al. teach wherein step (c) is followed by a step (d), wherein the resulting suspension from step (c) is sterile-filtered with a filter of the average pore size of 200 nm, resulting in the size of the API nanocrystals of at most 200 nm, determined using dynamic light scattering in demineralized water at 20 0C. Zhang et al. disclose filtering the obtained nanoparticles through a microporous filter membrane (see paragraph [0110] within Zhang et al.) to obtain API nanocrystals between 50 and 250 nm (see paragraph [0041] within Zhang et al.). A skilled artisan (POSITA) would use the appropriate measuring device to determine the nanoparticle diameter.
Regarding instant claim 10, Zhang et al., Singh, and Hong et al. teach wherein the concentration of crystalline API in the aqueous suspension in step (a) is in the range of from 10 mg/mL to 100 mg/mL. Zhang et al. disclose that 30 mg of docetaxel was added and dispersed evenly by ultrasonication to obtain suspension B (see paragraph [0077] within Zhang et al.). Claim 1 within Zhang et al. supports a much more concentrated nanosuspension (see instant claim 1 discussion). Therefore, a skilled artisan (POSITA) would modify the concentration within the claimed range under routine experimentation.
Regarding instant claim 4, Zhang et al., Singh, and Hong et al. teach wherein the molar ratio of the PEG-coupled phospholipids of general formula (I) to the non-PEG-coupled phospholipids is in the range of from 1:49 to 1:4. Zhang et al. disclose a range of the PEG-coupled phospholipids of general formula (I) to the non-PEG-coupled phospholipids by mass (mg) of 9:300 to 27:300 which translates to a overlapping molar ratio of 1:124 to 1:41. [For purposes of this calculation PEG2000 was used; additional overlapping ranges could be obtained with PEG400 or PEG1000.] Please see Table I above for the necessary discussion and citations.
Regarding instant claim 5, Zhang et al., Singh, and Hong et al. teach wherein API is selected from the group consisting of curcumin, abiraterone acetate, ivacaftor, atorvastatin, candesartan cilexetil, and telmisartan. Hong et al. disclose use of the API curcumin (see title and abstract within Hong et al.; also see Table I).
Regarding instant claim 6, Zhang et al., Singh, and Hong et al. teach wherein the PEG-coupled phospholipid has general formula (I), wherein R is independently selected from linear (C6 to C20)alkyl and linear (C6 to C20)alkenyl. Zhang et al. disclose the use of DSPE-PEG where R is a C17 alkyl (see Table I structure and discussion regarding DSPE-PEG).
Regarding instant claim 7, Zhang et al., Singh, and Hong et al. teach wherein the non-PEG-coupled phospholipidic stabilizing agent has the general formula (II)
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wherein n is an integer from 1 to 3; R1 is selected from the group consisting of H; -(CH2)m-NH2; -(CH2)m-CH(OH)-CH2(OH); -(CH2)-CH(COOH)-NH2
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wherein m is an integer from 1 to 3; R2 is selected from -OH; -O-C(=O)-R; R is independently selected from (C6 to C20)alkyl and (C6 to C20)alkenyl.
Zhang et al. disclose the non-PEG-coupled phospholipidic stabilizing agent dioleoyl phosphatidylethanolamine (see claim 5 within Zhang et al.) which meets the claim limitation of instant claim 7. The structure of dioleoyl phosphatidylethanolamine is shown in Figure I.
Figure I
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Regarding instant claim 8, Zhang et al., Singh, and Hong et al. teach wherein the combination of stabilizing agents in step (a) comprises from 2 to 20 mol. %, based on the total phospholipid contents, of the PEG-coupled phospholipid of general formula (I), from 0 to 20 mol. % of an anionic phospholipid, selected from the group consisting of phospholipids with hydrophilic headgroup selected from phosphatidic acid, lysophosphatidic acid, phosphatidylglycerol, lysophosphatidylglycerol, phosphoinositide, lysophosphoinositide, phosphatidylserine, lysophosphatidylserine; and with lipophilic carbohydrate chains containing from 6 to 20 carbon atoms; and from 60 to 98 mol. %, based on the total phospholipid contents, of a phospholipid, selected from the group consisting of phospholipids with hydrophilic headgroup selected from phosphatidylethanolamine, lysophosphatidylethanolamine, phosphatidylcholine, lysophosphatidylcholine, and with lipophilic carbohydrate chains containing from 6 to 20 carbon atoms. Zhang et al. disclose the use of 300:27 (mg) of SPC:DSPE-PEG (see paragraph [0089] within Zhang et al.). First, if we assume PEG2000, then that translates to 2.3 mol% DSPE-PEG [(0.000396 SPC mol + 0.0000097 DSPE-PEG mol)=0.000405 mol; 0.0000097 DSPE-PEG mol/0.000405 total lipid mol= 0.023x100%= 2.3%]. Second, if we select 0 mol% of an anionic phospholipid, then there is no anionic phospholipid. Finally, a phospholipid such as DSPC (see paragraph [0024] within Zhang et al.) can be used in place of SPC (in order to have all the material be associated with PC) within Zhang et al. translates to 97.6 mol% [(0.000380 DSPC mol+0.0000097 DSPE-PEG)=0.000389 total lipid mol; 0.0000097 DSPE-PEG mol/0.000405 total lipid mol=0.024x100%=2.4% DSPE-PEG mol; 100%-2.4%=97.6% DSPC mol]. Additionally, DSPE-PEG and DSPC have lipophilic carbohydrate chains of C17.
Regarding instant claim 9, Zhang et al., Singh, and Hong et al. teach an aqueous pharmaceutical nanocrystalline suspension of API, consisting of nanocrystalline API selected from the group consisting of API, which have their intrinsic solubility in water of at most 50 mg/L, and having log P of at least 4; and a combination of at least two stabilizing agents, selected from the group of phospholipids containing lipophilic carbohydrate chains consisting of from 6 to 20 carbon atoms; wherein at least one of the stabilizing agents is selected from the group of PEG-coupled phospholipids of general formula (I) as defined in claim 1; wherein the weight ratio of API to the combination of stabilizing agents is in the range of from 20:1 to 1:1, wherein the molar ratio of the PEG-coupled phospholipids of general formula (I) to the non-PEG-coupled phospholipids is in the range of from 1:49 to 1:4, and wherein the nanoparticle size is at most 300 nm, measured by DLS in demineralized water at 20 °C. Please see the necessary citations and discussion within instant claims 1 and 4.
Regarding instant claim 11, Zhang et al., Singh, and Hong et al. teach wherein the combination of phospholipidic stabilizing agents comprises from 2 to 20 mol. % of PEG-coupled phospholipid of general formula (I) according to claim 1, from 60 to 98 mol. %, based on the total phospholipid contents, of phosphatidylcholine, and from 0 to 20 mol. %, based on the total phospholipid contents, of phosphatidylglycerol, wherein the lipophilic carbohydrate chains of all the phospholipids contain from 14 to 18 carbon atoms. Please see the necessary citations and discussion within instant claim 8.
Regarding instant claim 13, Zhang et al., Singh, and Hong et al. teach A pharmaceutical composition, containing the aqueous pharmaceutical nanocrystalline suspension of API according to claim 9, further comprising at least one pharmaceutically acceptable excipient. Hong et al. disclose the use of excipients in the DSC thermogram analysis (see Figure 2 within Hong et al.). Furthermore, the use of excipients is common within the pharmaceutical industry. Therefore, a skilled artisan (POSITA) would look to add an excipient to the aqueous pharmaceutical nanocrystalline suspension as part of the formulation of the API.
Regarding instant claim 14, Zhang et al., Singh, and Hong et al. teach a method for in vitro development, screening and bioactivity testing of new natural or synthetic drugs or new drug forms of API, comprising the step of providing the aqueous pharmaceutical nanocrystalline suspension of API according to instant claim 9. Zhang et al. disclose the in vitro release of docetaxel nanosuspension lyophilized formulation (see Example 12 within Zhang et al.).
Regarding instant claim 15, Zhang et al., Singh, and Hong et al. teach a method for stabilizing aqueous nanocrystalline suspensions of low water soluble nanocrystalline compounds, comprising the step of providing a nanocrystalline compound having intrinsic solubility in water of at most 50 mg/L and having log P of at least 4, and the step of providing stabilizing agents selected from the group of phospholipids containing lipophilic carbohydrate chains comprising from 6 to 20 carbon atoms; wherein at least one of the stabilizing agents is selected from the group of PEG-coupled phospholipids of general formula (I), as defined in claim 1; and wherein the content of the PEG-coupled phospholipids of general formula (I) is in the range of from 2 to 20 mol. %, related to the overall content of phospholipidic stabilizing agents in the combination. Please see the necessary discussion and citations within instant claim 1 and 8.
Regarding instant claim 16, Zhang et al., Singh, and Hong et al. teach the method for stabilizing aqueous nanocrystalline suspensions of low water soluble nanocrystalline compounds according to instant claim 15, wherein the lipophilic carbohydrate chains are independently selected from -(CH2)14-CH3; -(CH2)16-CH3; -(CH2)3-(CH=CH-CH2)4-(CH2)3-CH3; and -(CH2)7-CH=CH-(CH2)7-CH3. Please see the discussion and citations within instant claim 1 wherein the lipophilic carbohydrate chains are -(CH2)7-CH=CH-(CH2)7-CH3 (unsaturated), C15 (saturated), and C17 (saturated) for both the non-PEG-coupled and PEG-coupled phospholipids, respectively.
Regarding instant claim 17, Zhang et al., Singh, and Hong et al. teach the method according to instant claim 6, wherein R is independently selected from the group consisting of-(CH2)z-CH3, wherein z is an integer in the range of from 10 to 17; -(CH2)p(CH=CH-CH2)q-(CH2)r-CH3, wherein p and r are independently an integer from 1 to 8; and q is an integer from 1 to 5. Please see the discussion and citations within instant claim 16 wherein the lipophilic carbohydrate chains meet the above limitations.
Analogous Art
The Zhang et al., Singh, and Hong et al. references are directed to the same field of endeavor as the instant claims, that is, a method for preparing an aqueous nanocrystalline suspension of API.
Obviousness
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method for preparing an aqueous nanocrystalline suspension of API disclosed by Zhang et al., using the teachings of Singh, and Hong et al. to incorporate the necessary claim limitations. Starting with Zhang et al., the skilled person only had to try the necessary claim limitations disclosed by Singh, and Hong et al. The combination of Zhang et al., Singh, and Hong et al. would allow one to arrive at the present application without employing inventive skill. This combination of the method for preparing an aqueous nanocrystalline suspension of API taught by Zhang et al. along with the use of the necessary claim limitations taught by Singh, and Hong et al. would allow a research and development scientist (POSITA) to develop the invention taught in the instant application. It would have only required routine experimentation to modify the method for preparing an aqueous nanocrystalline suspension of API disclosed by Zhang et al. with the use of the necessary claim limitations taught by Singh, and Hong et al. This combined modification would have led to an enhanced method for preparing an aqueous nanocrystalline suspension of API that would be beneficial for patients.
In the context of instant method claims 1-8 the desired purpose defines an effect that arises from and is implicit in the method step(s). Thus, where the purpose is limited to stating a technical effect that inevitably occurs during the performance of the claimed method step(s), and is therefore inherent in that/those step(s), that technical effect is not limiting to the subject-matter of the claim. Thus, the present method claim, defining the application/use of the composition according to the prior art, and defining its purpose as "use", is anticipated by any document of the state of the art describing a method of application/use although not mentioning this specific use.
Allowable Subject Matter
Claim 12 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claim 12 is allowable because the specific lipid ratio of 85:10:5 of DPPC:DPPG:MPEG2000-DMPE affords enhanced stabilization of the pharmaceutical nanocrystalline suspension as disclosed within the instant specification (see Example 5). Motivation is lacking to choose this lipid ratio and apply it to the closest prior art of Zhang et al.
Response to Arguments
Applicant's arguments filed November 17, 2025 have been fully considered but they are not persuasive.
The Applicant’s claim amendments were sufficient to address the claim objections and the 35 U.S.C. §112 rejections. Therefore, the claim objections and the 35 U.S.C. §112 rejections from the Non-Final Rejection dated August 22, 2025 are withdrawn from the record.
The Applicant’s claim amendments did not necessitate a new ground of rejection.
Applicant Argument: The Applicant argues that the Zhang et al. reference does not teach an aqueous nanosuspension concentration within 10 mg/mL to 100 mg/mL.
Examiner’s Rebuttal: Zhang et al. disclose within claim 1, “A long-circulating lipid nanosuspension containing docetaxel, characterized in that it is made
from the following components in parts by weight: 0.5-50 parts of an aqueous solution, 0.5-50 parts of docetaxel, 0.05-20 parts of lipid-PEG, and 50-90 parts of a phospholipid…” (see claim 1 within Zhang et al.). Although the Example within Zhang et al. supplies only a 0.5 mg/mL aqueous suspension of docetaxel (see paragraph [0077] within Zhang et al.), claim 1 allows for a much more concentrated mixture. Hypothetically, one could be at a greater than 10 mg/mL aqueous suspension of docetaxel [30 mg docetaxel in 3 mL distilled water; 10 mg/mL].
Applicant Argument: The Applicant argues that the deficiencies within the Zhang et al. reference, the Singh et al. reference, and the Hong et al. reference make a strong argument for patentability.
Examiner’s Rebuttal: The Examiner respectfully disagrees. It is the combination of Zhang et al., Singh et al., and Hong et al. that make this 35 U.S.C. §103 rejection plausible. As shown within instant claim 1, the citations meet every claim limitation. Furthermore, the broad range of all components within the nanosuspension of Zhang et al. disclosed within claim 1 allow a skilled artisan (POSITA) to adjust the ratios accordingly to meet all of the instant claim limitations.
Applicant Argument: The Applicant argues that none of the references of record teach the wet-milling technique.
Examiner’s Rebuttal: This technique is common in the art (see PTO-892 NPL U -V). Yes, none of the references of record disclose this procedure. However, the ability of a skilled artisan (POSITA) to pursue and master this process within the nanosuspension arts would be routine and non-inventive.
Applicant Argument: The Applicant argues that there is little or no motivation to combine the references of record.
Examiner’s Rebuttal: The Examiner respectfully disagrees.
The Zhang et al., the Singh et al., and Hong et al. references all have considerable overlap with the preparation of drug nanosuspensions. In this instance, both Zhang et al. and Singh et al. supply the preparation of the nanosuspension with poorly soluble drugs, while Hong et al. supplies a claim-specific ratio of drug to lipid. All references are directed to the preparation of drug nanosuspensions and therefore constitute analogous art under MPEP §2141.01(a). A POSITA would have reasonably consulted the three references when seeking to improve or adapt a preparation for a drug nanosuspension.
Additionally, incorporating the disclosure of Zhang et al. into the nanosuspensions presented by Singh et al. and Hong et al. represents a predictable use of prior art elements according to their established functions, consistent with MPEP §2143 and KSR.
Furthermore, the additional claim limitations taught by Singh et al. and Hong et al. would have been viewed by a POSITA as routine design optimizations or known modifications to expand upon drug nanosuspensions within the prior art. Implementing these features in Zhang et al. would not require more than ordinary skill or routine experimentation.
Accordingly, the combination of Zhang et al., supplemented by Singh et al. and Hong et al. provides all the elements of the claimed invention. The resulting poorly soluble drug nanosuspension constitutes no more than the predictable outcome of combining familiar prior art components, and therefore the claimed subject matter would have been obvious to a POSITA prior to the effective filing date of the invention.
[Examiner’s Comment: The Examiner respectfully submits that the conclusion of obviousness is based upon proper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).]
Therefore, the 35 U.S.C. §103 rejection is maintained for instant claims 1-2, 4-11, and 13-17.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert A Wax can be reached on 571-272-0623. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JOHN W LIPPERT III/Examiner, Art Unit 1615 /Robert A Wax/Supervisory Patent Examiner, Art Unit 1615