DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-17 have been presented for examination on the merits.
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 1-17 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.
Claims 1, 3 and 6 recite the limitation "wherein the at least two surfactants polysorbate 80 and Carbowax® polyethylene glycol 3350" in line 6 of each claim. There is insufficient antecedent basis for this limitation in the claim. The recitation of two surfactants is not provided preceding this recitation. As such the claim lacks support for these recitations.
Claim 2 recites the limitation "of nanosalsalate suspension" in lines 3-4. There is insufficient antecedent basis for this limitation in the claim. Neither claim 2 nor its parent claim 1 disclose a nanosalsalate suspension, but rather a salsalate nanosuspension.
Claim 2 is also indefinite for reciting “the salsalate nanosuspension comprising about 250 mg to about 2000 mg of nanosalsalate suspension”. As stated above, the term nanosalsalate suspension lacks antecedent basis. Thus, it will be interpreted as salsalate nanosuspension. That is, the claim recites that a nanosuspension comprises …. mg of a nanosuspension. This renders the claim indefinite as it is not clear how a nanosuspension comprises a nanosuspension.
Claim 2 is further indefinite for reciting that the administration is oral or parenteral and that following the administration, the plasma concentration is from about 120 to 200 µg/ml over a period of 12 to 24 hours. This is indefinite because it is known that oral and parenteral administrations need different dosages and achieve different plasma concentrations over a given period of time.
Claims 6-9 recite the limitation "the method or use…" in various lines. There is insufficient antecedent basis for this limitation in the claim. None of the instant claims or their parent claims recite or support the term “or use”.
Also, the recitation of “use” of a composition is not a specific and substantial asserted utility.
Claim 7 is indefinite for reciting “NFKB” and “IKKB”. The claim does not indicate what these abbreviations are referring to.
Claim 9 is indefinite for reciting “a disease”. The recitation of a disease does not provide sufficient disclosure to one of ordinary skill in the art to readily be apprised of what is encompassed by a disease.
Claim 9 is indefinite for reciting “CAR-T therapy”. The claim does not indicate what this abbreviation is referring to.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 7-9 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. The limitations regarding the production of inflammatory cytokines and/or chemokines and the prevention of NFKB activation via IKKB enzyme inhibition are all related to the mechanism of action of salsalate and fail to further limit the parent claim 6. This is evident from the Specification (See at least [0071 of the published version). Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim interpretation:
Claims are directed to a method of treating a subject in need with a salsalate nanosuspension. The conditions that are encompassed by the claimed methods are limited to those listed in the Speciation (See [0022] of the published version).
Claim 2 recites “the salsalate nanosuspension comprising about 250 mg to about 2000 mg of nanosalsalate suspension”. The salsalate nanosuspenion comprises salsalate dispersion, at least two surfactants and citric acid. Thus, the 250 to 2000 mg of a nanosalsalate is the amount of the suspension and not the salsalate alone.
The limitations regarding the production of inflammatory cytokines and/or chemokines and the prevention of NFKB activation via IKKB enzyme inhibition in claims 6-9 are all related to the mechanism of action of salsalate and do not impart a structural or functional limitation on the claimed method.
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 1-17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 11-15 of U.S. Patent No. 11,819,488. Although the claims at issue are not identical, they are not patentably distinct from each other because the examined claims would have been obvious over the reference claims.
In particular, examined claim 1 is directed to a method of treating a subject in need with a salsalate nanosuspension comprising administering to the subject a therapeutically effective amount of the salsalate nanosuspension, wherein the salsalate nanosuspension comprises: a. an aqueous dispersion of salsalate or a salt thereof, wherein the salsalate has an effective average particle size of less than 1 micron; b. at least two surfactants, wherein the at least two surfactants polysorbate 80 and Carbowax® polyethylene glycol 3350; and c. citric acid, wherein the administration comprises: i. orally, parenterally, topical, ophthalmic or nasal administration; and/or ii. a 3 times a day, 4 times a day, every 6 hours, every 8 hours or every 12 hours administration.
The reference claim 11 is directed to a method of treating pain in a subject, the method comprising administering to the subject a therapeutically effective amount of the salsalate nanosuspension, wherein the salsalate nanosuspension comprises: (a) an aqueous dispersion of salsalate or a salt thereof, wherein the salsalate has an effective average particle size of less than 1 micron; (b) at least two surfactants, wherein the at least two surfactants polysorbate 80 and Carbowax® polyethylene glycol 3350; and (c) citric acid. Claims 12-15 recite other limitations including the dosage amount, route of administration, etc.
The differences include the preamble, where examined claims are broadly directed to a method of treating a subject in need, whereas the reference claim 11 is to a method of treating pain. However, pain is encompassed by a subject in need and is considered within the scope of examined claim 1. Also examined claims 3-9 recite treating an inflammatory disease, which is obvious over treating pain because it is well known that salsalate like other NSAIDs are both analgesic and anti-inflammatory agents (See Specification’s definition of salsalate at [0003]).
The claims are obvious because, the recited claims of the instant application are not mutually exclusive since the method of the instant application fully encompasses and overlaps the method of reference claims.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Gan et al (WO 2016115520 or US 20170368080).
Gan et al teach methods of reducing the level of acetylated Tau in a neuron or a glial cell in an individual, the methods involving administering to the individual a prodrug that is converted in the individual to salicylate (See abstract). The prodrug is preferably salsalate (See [0084], [0105]-[0107] and claim 4).
Pharmaceutical compositions can be designed for administration to subjects or patients in need thereof via a number of different routes of administration including oral, buccal, rectal, parenteral, intraperitoneal, etc, (See [0078] and [0132]-[0133]).
The prodrug is in a nanoparticle form (See [0122]-[0124]). Unit dosage forms for oral administration include syrups, and suspensions (See [0146] and [0150]). The said formulation may be dissolved, suspended or emulsified the active agent in an aqueous solvent. Suitable solvents for an active agent include aqueous solvents (See [0143], [0149] and [0155]).
Gan et al disclose that examples of carriers useful in solid dispersions include, water-soluble polymers such as polyethylene glycol (See [0171]).
In some cases, the prodrug is conjugated to, or adsorbed onto, a polysorbate 80-coated nanoparticle. Other suitable nanoparticles include solid lipid nanoparticles (SLN). Solid lipid nanoparticles can optionally include other components, including surfactants, such as polysorbate 80 (Tween 80) (See [0122]-[0123]).
In suppositories, suitable carriers include carbowaxes and polyethylene glycols (See [0145]).
Baumstuemmler et al (8,852,644).
Baumstuemmler et al teach a method for producing microparticles or nanoparticles of water-soluble and water-insoluble substances by controlled precipitation, co-precipitation and self-organization processes (See abstract).
It is stated that the said method is being used to enhance the bioavailability of active ingredients or to deliver one or more active ingredients to a targeted site of action. Another method of enhancing bioavailability is via drug targeting or drug delivery, whereby particles are distributed in the target tissue according to their size or are engineered such as to have suitable surface modifications enabling them to reach the targeted site of absorption or action (See col. 1, lines 42-58).
Baumstuemmler et al disclose producing particles of water-soluble and water-insoluble substances in a microjet reactor and simultaneously stabilizing these either with one or more auxiliary agents or surface modifiers, the resulting particles having particle sizes of up to 2,000 nm, preferably less than 1,000 nm, more preferably less than 500 nm and best of all less than 200 nm, with polydispersion indices generally below 1.0 and preferably below 0.4 (See col. 7, lines 20-27).
The process results in co-precipitate one or more active target substances with one or more auxiliary agents (See Col. 7, lines 38-40). The said active target substances include biologically useful substances, imaging substances, pharmaceutically useful substances, etc. suitable active target material/ medicinal targets include anti-inflammatory substances, antibiotics, corticosteroids, etc. It is also disclosed that the solvent may be an aqueous suspension (See col. 7, lines 48-67).
The said active ingredients may be processed to enable their use in numerous different pharmaceutical compositions including for oral administration or parenteral administration as suspensions, etc, (See col. 8, lines 25-31).
Baumstuemmler et al state that suitable auxiliary agents include adjuvants, diluents, suspending agents and surfactants including polyethylene glycol (e.g. Carbowax 3350®) and polyoxyethylene sorbitol fatty acid esters (e.g. Tweens®) (See col. 8, lines 32-67).
Vaughn (US 20110064813).
Vaughn teaches a compound and administration of the compound to mammals containing salsalate in a nanofied form to reduce inflammation. This compound and administration may be combined with caffeine, omega 3 fatty acids, sodium bicarbonate, and/or simvastatin to further benefit that administration (See abstract).
Vaughn discloses and claims a pharmaceutical composition comprising: a delivery agent, salsalate particles, wherein the salsalate particles have a median particle size of about 1 nanometer to about 300 nanometers (See claims 1-6).
It is disclosed that delivering these products via nanotechnology provide more affordable treatments for chronic disorders while using nanotechnology reduces the number of side effects when these products are administered in a tablet, capsule or injectable form (See [0012] and [0017]).
In one embodiment, Vaughn discloses the formulation as a dispersion of the nano-particles, i.e. a nano-dispersion (See [0014] and [0025]).
Straub et al (8,821,938).
Straub et al teach drugs, especially low aqueous solubility drugs, in a porous matrix form, preferably microparticles (See abstract).
It is further object of the present invention to provide compositions for administration as a bolus injection instead of by infusion. (See Col. 2, Lines 24-26).
Straub et al disclose that the porous drug matrix is at least 1 to 95%, preferably between about 10 and 60%, drug by weight. The matrices also may contain hydrophilic or hydrophobic excipients such as water-soluble polymers, surfactants, tonicity agents, etc. (See Col. 4, Lines 6-11).
The matrix must contain microparticles of drug, which preferably have a diameter between about 100 nm and 5 μm, more preferably between about 500 nm and 5 μm (See Col. 4, Lines 12-16).
The drug may be salsalate and the excipients/surfactants may be PEG 3350, PEG 8000, lecithin, TWEEN™ 80, etc, (See Col. 5, Line 54 and Col. 15, Lines 23-27).
Example 5 discloses the production of a porous griseofulvin matrix using PEG 3350, TWEEN™ 80, and Lecithin (See Col. 16).
The said composition may be in the form of an aqueous suspension (See claims 17-18).
Berkland et al (US 20070172653).
Berkland et al teach a nano-cluster for drug delivery including a plurality of nano-particles, wherein the nano-particles can disperse in response to an environmental cue (See title and abstract).
The said nano-cluster can include an active ingredient, for example vaccines, diagnostic agents, therapeutic agents, drugs, peptides, etc, and combinations of these classes. The nano-cluster or nano-particles, or both, can include at least one, two, three, or more different active ingredients (See [0011]-[0012]).
The said nano-clusters can include a dispersing material that holds the plurality of nano-particles together and/or disperses the nano-particles in response to an environmental cue. The dispersing materials that can be used include surfactants (See [0013]).
Berkland et al further disclose that the said nano-cluster can include from about 1% to about 99% by weight or volume of the nano-particles or dispersing materials. In preferred embodiments, the nano-cluster includes from about 10% to about 90%, 15% to about 80%, 20% to about 70%, 30% to about 60%, and about 40% to about 50% of nano-particles or dispersing materials. In one embodiment, the nano-cluster includes at least 50% of the nano-particles or dispersing material (See [0014]-[0015]).
Also disclosed is a method of preparing a nano-cluster comprising: obtaining a plurality of nano-particles; obtaining a dispersion material and admixing them, wherein the admixture is formulated into a nano-cluster. In certain aspects, obtaining a plurality of nano-particles comprises, obtaining an aqueous suspension of nano-particles; allowing the nano-particles to aggregate together; and retrieving the aggregated nano-particles (See [0019]).
The said nano-particles have a size of from about 1 to about 3000 nanometers. In particular, the said nano-particle has a size of 2, 30, 80, 150, 200, 300, 325, 450, 600, 850, 900, 950, 1000 nanometers (see [0052]).
Berkland et al further disclose that suitable dispersing materials include surfactants such as polysorbate 80, polysorbate 20 and polyethylene glycol and mixtures thereof (See [0058]).
The said nano-clusters can include an active ingredient, including NSAIDs such as salsalate. The nano-clusters can also contain other/additional active agents (See [0061]-[0062], [0066] and [0071]-[0072]).
In certain embodiments, an oral composition may comprise one or more binders, excipients, disintegration agents, flavoring agents, and combinations thereof, including mannitol, lactose, etc (See [0088]).
Berkland et al also disclose pharmaceutical compositions comprising the said nano-clusters which may be in a dosage form for injection (See [0083] and [0093]). Combination therapies are also disclosed (See [0094]-[0096]).
Berkland et al further disclose that the said nano-cluster can include a plurality of nano-particles with a dispersing material that holds the plurality of nano-particles together. This delivery system provides the advantage of particle clusters appropriately sized for delivery with the benefits of nano-particles, such as improvements in drug solubility, bioavailability, transport through biological barriers, intracellular delivery, etc. Changing the nature of the dispersing material allows for the development of an environmentally responsive nano-particle delivery system and/or biosensors. In addition, the special arrangement of nano-particles within the cluster can allow discrete control over the duration and concentration of an active ingredient, a concept that can also be facilitated by the independent formulation of each nano-particle type before cluster formation (See [0048]).
Subramanian et al (Enhancement of anti-inflammatory property of aspirin in mice by a nano-emulsion preparation).
Subramanian et al teach evaluating nano-emulsion preparations of aspirin (acetylsalicylic acid) prepared with a Microfluidizer® Processor in the croton-oil-induced ear edema CD-1 mouse model using ear lobe thickness and the accumulation of specific in situ cytokines as biomarkers of inflammation. The results showed that particle size (90 nm) populations of nano-emulsion preparations of aspirin compared to an aspirin suspension (363 nm), significantly decreased ear lobe thickness approximately 2 fold greater than the aspirin suspension (See abstract and page 1534, 1.).
It is disclosed that nano-emulsions, defined as oil-in-water or water-in-oil emulsions, can be prepared with a Microfluidizer® Processor or with a conventional high-speed homogenizer, with particle sizes averaging ≤100 nm (See page 1534, 1st col, 2nd para). Described is a nano-emulsion preparation produced with a Microfluidizer® Processor which contains the surfactant polysorbate 80, soybean oil and HPLC-grade water as a drug delivery formulation for aspirin (See page 1534, 1st col, 4th para).
The said formulations comprising 800 µg of aspirin mixed in a vanishing cream in a 1:1 ratio was applied to animals (rubbed onto the ear) (See page 1534, 2nd col, 2nd para).
In referencing Fig 1, Subramanian et al disclose that “Dynamic laser light scattering particle size analysis of nano-emulsion of aspirin. As shown in the figure micro fluidized preparation of nano-emulsion of aspirin was a homogeneous distribution with a Z-average size of 90.1 nm” (See Page 1535, Fig. 1), and that “Further, the examination of morphology using transmission electron microscope showed that the nano-emulsion of aspirin was comprised of spherical particles ranging <100 nm (Fig. 4)” (See Page 1537, 3.1 and Fig. 4).
Subramanian et al conclude that the formulations produced preparations with mean particle sizes of 88 nm for blank nano-emulsion, 90 nm for nano-emulsion of aspirin and 363 nm for the aspirin suspension. Our findings regarding enhanced nano-emulsion efficacy might be related to increased bioavailability as has been reported for nano-emulsion preparations of other drugs. More evidence of increased bioavailability is supported by the transdermal delivery studies of paclitaxel, which demonstrated increased bioavailability by pharmacokinetic analysis. Although speculative, in this study the smaller particle size of the nano-emulsions of aspirin (90 nm) compared to the aspirin suspension (363 nm) could have increased the surface to volume ratio and thus the bioavailability of the drug (See Page 1538, conclusion).
Claims 1-17 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Mina Haghighatian whose telephone number is (571)272-0615. The examiner can normally be reached M-F, 7-5 EST.
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/Mina Haghighatian/
Mina Haghighatian
Primary Examiner
Art Unit 1616