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
Receipt of Applicant’s Remarks/Amendments filed 01/02/2026 is acknowledged. Claims 1-20 are pending.
Claims 1, 3,12, 16 and (Withdrawn) 17-19 are amended.
Claims 2, 4-11, 13-14 and 20 are canceled.
Claims 17-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1, 3,12, 15 and 16 are pending and under examination in this application.
Priority
Acknowledgment is made of applicant’s claim for priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application IN202241056432, filed on 09/30/2022.
Modified Rejections
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(s) 1, 3,12, 15 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Nose-to-brain transport pathways an overview: potential of nanostructured lipid carriers in nose to brain targeting (hereinafter the article is referred as Selvaraj) in view of Development of phenytoin intranasal microemulsion for treatment of epilepsy (hereinafter the article is referred as Acharya), and further in view of Recent strategies and advances in the fabrication of nano lipid carriers and their application towards brain targeting (hereinafter the article is referred as Agrawal).
Selvaraj teaches brain targeting formulation of therapeutics in combination with nasal drug delivery comprising pathways of drug transport from nose to brain and nanostructured lipid carriers (NLCs) (abstract).
Regarding claims 1 and 3, as noted above, Selvaraj teaches intranasal formulation comprising NLCs, and there are different types of nanocarriers (polymeric, lipid and inorganic nanoparticles), particularly lipid-based nanocarriers comprising mono-, di-, triglycerides, fatty acids, and waxes, and the NLCs reduce the toxicity and allows controlled or sustained release of the drug, encapsulate both hydrophilic and lipophilic therapeutic agents and they are highly stable when compared to other nanocarriers (page 2092, left column, 2nd ¶). Furthermore, Selvaraj discloses the NLCs were characterized for the particle size, zeta potential, drug loading and entrapment efficiency, for example valproic acid-loaded NLCs with particle size of 154 ± 16 nm and drug loading percentage 47 ± 0.8 % and it was observed that intranasal route of administration of the valproic acid-NLCs resulted in higher plasma concentration ratio, suggesting that the intranasal route provides a better protection for the seizure therapy than intra-peritoneal administration (page 2092, left column, 3rd ¶). Additionally, Selvaraj discloses in the efficacy of temozolmide nanostructured lipid carriers (TMZ-NLCs) to enhance brain targeting via nasal administration and the formulation was optimized by using four factor, optimized TMZ-NLCs formulations were evaluated for their surface morphology as well as ex vivo permeation and in vivo studies, and all formulations showed sizes in the nanometer range, with high drug loading and prolonged drug release, and the optimized TMZ-NLCs formulations displayed an entrapment efficiency of 81.64 ± 3.7 %, zeta potential of 15.21 ± 3.11 mV (page 2092, right column, 4th ¶), and in Table 2 (page 2093) recent developments of NLCs in brain targeting exemplifies particle size (nm) of NLCs, of particular, curcumin-NLCs showed particle size of 146.8 nm with entrapment efficiency 90.86 % (page 2093, left column, 1st ¶ ) to target these drugs to brain via intranasal administration. Therefore, the scope and subject matter of an intranasal formulation comprising a nano lipid carrier, active pharmaceutical ingredient comprising solid lipid, a liquid lipid and a surfactant with particle size of 100-150 nm are taught, and it would have been reasonably obvious for a person having ordinary skill in the art to experiment and attempt to select various alternative therapeutic agents (i.e., phenytoin or hydantoin derivatives) and include surfactants in methods of making in the NLCs formulation for targeting to brain delivery.
Regarding claim 15, Selvaraj teaches nasal spray formulation (table 1, page 2091).
Selvaraj fails to specifically teach hydantoin derivatives in the NLCs formulation.
Acharya teaches preparation of phenytoin microemulsion for intranasal administration comprising oil, surfactant and cosurfactant and microemulsion that had a smaller globule size of dispersed phase and high level of % drug diffusion was desirable (abstract).
Regarding claim 1, as noted above, Acharya teaches phenytoin intranasal formulation comprising oleic acid (page 376, ¶ Materials), phenytoin concentration of 40 mg/ml for all microemulsion (ME) (page 377, left column 1st ¶), phenytoin microemulsion containing 3.52 mg was administered intranasally to rats and standard solution of phenytoin at concentration of 10, 20, 30, 40, 50, 100 and 200 µg/ml were prepared in methanol (page 378, right column, 1st ¶), and in Table 1 (page 377) displays phenytoin globule size (nm) range from 2 to 256 of samples A1 to A10. A person have skill in the art would have known to adjust the phenytoin concentration of the intranasal formulation based on the weight of the subject to the desired range of 4 mg/ml to 10 mg/ml.
Regarding claim 16, Acharya teaches mono and di-glycerides (page 379, ¶ 3).
Agrawal teaches biocompatible lipid matrix and nanocarrier system for nose-to-brain drug targeting, where the nanocarrier system offers many advantages over other drug carrier systems, including ease of manufacturing and scale-up to industrial level, higher drug targeting, high drug loading, control drug release, compatibility with a wide range of drug substances, non-toxic and non-irritant behavior. Moreover, Agrawal discloses highlights of recent progresses towards the development of NLC for brain targeting of bioactives with particular reference to its surface modifications, formulations
aspects, pharmacokinetic behavior and efficacy (abstract).
Regarding claim 1, Agrawal teaches particle size of the NLCs formulation from 30 nm to 80 nm (page 386, ¶ 2).
Regarding claim 12, Agrawal teaches commonly used solid lipids for NLC formulation are stearic acid, stearyl alcohol, glycerol monostearate, mono-stearin, Compritol® 888 ATO, Precirol® ATO5, cetyl palmitate, Gelucire®, Witepsol® etc., and common examples of liquid lipids involve the use of olive oil, sesame oil, almond oil, peanut oil, soyabean oil, oleic acid, corn oil, soy lecithin, phosphatidyl choline, cetiol, Mygliol®, Capmul® MCM, isopropyl myristate, vitamin E etc. Besides, the surfactants used for NLC preparation are Poloxamer 188, Tween® 80, Tween® 20, SDS,19 SDC,20 PVA,21 Solutol® HS15, Cremophor® EL, Cremophor® RH, Lutrol® F68, Tego Care 450, Span® 85 and many more, wherein the choice of a lipid blend and method of preparation may affect the types and features of NLC, which is further classified into i) imperfect, ii) amorphous, and iii) multiple types; O/F/W type NLC (Fig. 1) (page 374, right column, ¶ 2). Moreover, Agrawal discloses the NLC comprises of solid and liquid lipid blend stabilized by a suitable surfactant, wherein the ratio of solid and liquid lipids depends on the type and nature of the excipient used, and it may vary from 30:70 to 0.1:99.90 for liquid lipid and solid lipid, respectively, and the amount of surfactant is also ranging from 5% to 0.5%, depending on the type of lipid used, the desired property of NLC, and drug-loaded in the system, further, using these ingredients number of fabrication techniques are applied for the development of NLC (page 375, ¶ 2.3). Additionally, Agrawal discloses in Table 1, application of NL for brain targeting of anti-Alzheimer drugs with carrier, route of administration, surfactant/co-surfactant, particle size and characteristics (page 380-383). Furthermore, Agrawal discloses fabrication of NLC used cholesterol (solid lipid) , triolein (liquid lipid) (page 390, last ¶), oleic acid as liquid lipid (page 390, ¶ 2), poloxamer as surfactant (page 374, ¶ 2), triglyceride as liquid lipid and Pluronic F68 (known as poloxamer 188) as surfactant (page 404, ¶ 4). It would have been obvious to one skilled in the art to fabricate lipid nanocarrier systems comprising solid and liquid lipid blend stabilized by a suitable surfactant, adjust the ratio of solid and liquid lipids depending on the type and nature of the excipient used, comprising solid lipid of 15 to 20 %, liquid lipid of 80 to 85 %, and surfactant 1 to 1.5 %. Further, using these ingredients, a number of fabrication techniques are applied for the development of NLC, for example, High-pressure homogenization is the well-established and most popular technique among all the methods which is already used in the industries for the production of lipid drug carriers like microemulsion, nanoemulsion, SLN, and for NLC fabrication (page 375, last ¶ left column to top of right column).
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 fabricate an intranasal formulation comprising a nano lipid carrier, with solid lipid, liquid lipid and a surfactant with claimed particle size (≤ 50 nm), (50, 100 nm), (100, 150 nm) in the NLCs as taught by Selvaraj and incorporate the API phenytoin as taught by Acharya, and further in view of Agrawal in order to fabricate a nose-to-brain drug target delivery system.
One would have been motivated to do so because the combined teachings of Selvaraj in view of Acharya, and further in view of Agrawal discloses nose-to-brain delivery systems comprising intranasal lipid carriers (NLCs), API phenytoin, solid and liquid lipid, surfactants in the formulation and fabrication techniques for improving drug bioavailability, increasing drug solubility and permeation, extending drug action and reducing enzymatic degradation in the drug targeting nose-to-brain delivery.
One of ordinary skill in the art would have been motivated to do this because all the references are drawn to intranasal formulation NLCs formulations and fabrication methods of nanostructured lipid carriers for nose-to-brain delivery with phenytoin as the API.
One of ordinary skill in the art would have found it obvious to apply the different amounts of solid lipid, liquid lipid, surfactant in the NCLs to improve the drug bioavailability, solubility, permeation, encapsulation efficiency and drug loading as taught by Selvaraj in view of Acharya, and further in view of Agrawal. From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention.
It is obvious to combine prior art elements according to the known methods to yield predictable results. Please see MPEP 2141 (III)(A)-(G).
Response to Arguments
In response to applicant’s argument based upon Nguyen’s reference 36 are the inventors of the present application, published on October 8, 2021, which is less than a year from the effective filing date of the present application of September 30, 2022.
Examiner has removed prior art Nguyen reference. However, the subject matter and rejections under 35 U.S.C § 103 still applies despite the amendments, and a prima facie case of obviousness is maintained.
Applicant's arguments filed 1/02/2026 have been fully considered but they are not persuasive. Applicant argues that prior art references do not teach or suggest the unexpected anticonvulsant efficacy, rapid brain uptake within 10 minutes, preferential accumulation in rostral brain regions, olfactory bulb and frontal cortex, nor its therapeutic implications for acute seizure control, and that a PHOSITA would not be able to expect or predict such region-targeted, rapid nose-to-brain delivery of phenytoin sodium, nor its therapeutic for acute seizure control. Applicant asserts of unexpected results and therapeutic effects.
This is not persuasive. The combination of Selvaraj, Acharya and Agrawal teaches the same subject matter (intranasal formulations) NLCs and components comprising phenytoin (API), lipid-based nanocarriers comprising mono-, di-, triglycerides, fatty acids, and waxes, surfactant (poloxamer 188), entrapment efficiency and drug loading for targeting nose-to-brain delivery the purpose of seizure therapy.
It would have been obvious to a PHOSITA before the effective filing date of the claimed invention to formulate an intranasal NLC comprising phenytoin at about 4-10 mg/ml, poloxamer (surfactant) at about 1-1.5%, cholesterol at about 15-20%, oleic acid at about 80-85%, and a resultant surfactant particle size of about 10-45 nm with high entrapment efficiency and drug loading, as such variations in concentration, surfactant levels, lipid composition and particle size represent routine optimization of known drug (phenytoin) delivery systems. Agrawal teaches use of NLCs as a well-established means to enhance drug delivery to the brain via intranasal and blood-brain barrier (BBB) routes and highlights the general formulation elements (solid lipid, liquid lipid, surfactants) that influence encapsulating efficiency, particle size, and brain targeting properties, particularly for CNS-active agents. Furthermore, Selvaraj discloses the potential of intranasal lipid-based nanocarriers (including NLCs) for direct nose-to-brain transport and indicates the general advantages of small particle size and appropriate surfactant selection for permeation through nasal mucosa pathways. Although prior art references does not expressly disclose each precise numerical claimed ranges, selecting these ranges to achieve desirable properties such as small nanometer scale particles, high drug encapsulation and loading are predictable and fall with routine formulation strategies that a PHOSITA would pursue to improve delivery and stability. Optimization of surfactant level, lipid matrix composition (cholesterol and oleic acid), and drug concentration to yield stable NLCs with targeted particle size and encapsulation efficiency is a result-effective variable adjustment within a PHOSITA. Furthermore, Acharya in view of Selvaraj and Agrawal establishes fundamental principles of nano lipid carrier fabrication and performance that would motivate such optimization to enhance permeation and CNS delivery.
Applicant’s arguments regarding unexpected immediate or rapid nose-to-brain onset, enhanced anticonvulsant efficacy, and specific regional brain accumulation do not rebut obviousness because the general concept that intranasal nano lipid carriers improve brain uptake and bypass the BBB was already established in the art, and small particle size and appropriate surfactant/lipid combinations were known to improve mucosal permeation and CNS entry.
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).
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANDRE MACH whose telephone number is (571)272-2755. The examiner can normally be reached 0800 - 1700 M-F.
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/ANDRE MACH/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615