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 .
Claim Status
Claims 1, 3-11 and 14-15 are pending.
Claims 1, 3-8, 10 and 14 are currently amended.
Claims 2 and 12-13 have been canceled.
Claims 10-11 and 14-15 are withdrawn.
Claims 1 and 3-9 are currently under consideration.
Claims 1 and 3-9 are rejected.
Acknowledgement of Receipt
Applicants’ election of Group I., claims 1 and 3-9, drawn to a transdermal patch in the reply filed on 01/16/2026, is acknowledged. This Office Action is in response to Applicants’ elections, amendments and remarks filed 01/16/2026.
Priority
This application is a 371 of PCT/CN2022/113953 filed 08/22/2022. Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in Chinese Application No. CN202110969146.7 filed 08/23/2021. Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e). Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Information Disclosure Statement
The Information Disclosure Statement (IDS) submitted on 01/30/2024, 01/30/2025, and 01/16/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, these IDSs have been considered by the Examiner.
Election/Restrictions
Applicants’ election with traverse of Group II (claims 1 and 3-9) in the reply filed on 01/16/2026 is acknowledged. The traversal is on the ground(s) that Yamazaki does not teach the specifically defined mass ratio of propylene glycol to dexmedetomidine and the metal chelate crosslinking agent and a pressure sensitive adhesive as a skeleton structure for dexmedetomidine; amended claim is nonobvious (see Remarks, bridging pgs. 6 and 7). Applicants argue that the Groups (I-IV) share at least the aforementioned distinguishing features as common technical features which constitute the same special technical features (Remarks, pg. 7, para. 2).
These arguments are not found to be persuasive because as per PCT Rule 13.1, the international application shall relate to a group of inventions so linked as to form a single general inventive concept or a “unity of invention.” See MPEP §1850. PCT Rule 13.2 states that said “unity of invention” is fulfilled by defining a special technical feature that is shared amidst the claimed inventions. The Rule further specifies that “[t]he expression “special technical features” shall mean those technical features that define a contribution which each of the claimed inventions, considered as a whole, makes over the prior art.”
The recitation of generic subject matter in the base claims (i.e., technical feature of a composition comprising dexmedetomidine, propylene glycol, a metal chelate crosslinking agent, and a pressure-sensitive adhesive) is sufficient enough to demonstrate a lack of unity amidst the groups set forth in the previous Office Action, as evidenced by Yamazaki (US 9974754 B2, equivalent to WO 2015093503 A1 cited on the IDS). As such, the instantly alleged special technical feature, respectfully, is NOT considered to provide a contribution over the prior art as required above.
The requirement is still deemed proper and is therefore made FINAL.
Claims 10-11 and 14-15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected Groups (I and/or III), there being no allowable generic or linking claim. Applicants’ timely traversed the restriction (election) requirement in the reply filed on 01/16/2026.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. § 103 (a) are summarized as follows:
Determining the scope and contents of the prior art.
Ascertaining the differences between the prior art and the claims at issue.
Resolving the level of ordinary skill in the pertinent art.
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. Applicants are 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.
Applicant Claims
The instant claims are directed to a dexmedetomidine transdermal patch, wherein the dexmedetomidine transdermal patch comprises an adhesive layer formed by a dexmedetomidine transdermal composition, wherein the composition comprises dexmedetomidine, propylene glycol, a metal chelate crosslinking agent, and a pressure-sensitive adhesive, and wherein in parts by weight, in the composition, dexmedetomidine 0.30-3.00 parts; propylene glycol 0.40-8.00 parts; the metal chelate crosslinking agent 0.30-1.25 parts; the pressure-sensitive adhesive 50.00-99.00 parts; and the mass ratio of propylene glycol to dexmedetomidine is (4:3)-(8:3) (instant claim 1); wherein the mass ratio of propylene glycol to dexmedetomidine in the composition is (5:3)-(7:3); or the mass ratio of propylene glycol to dexmedetomidine in the composition is 5:3 (instant claim 3); wherein the mass ratio of the pressure-sensitive adhesive to the metal chelate crosslinking agent is (70:1)-(310:1) (instant claim 4); wherein the mass ratio of the pressure-sensitive adhesive to the metal chelate crosslinking agent is (70:1)-(160:1), (160:1)-(220:1), or (220:1)-(310:1); or (160:1)-(220:1), (160:1)-(210:1), (160:1)-(200:1), or (190:1)-(220:1); or 160:1, 170:1, 180:1, 190:1, 200:1, 210:1, or 220:1 (instant claim 5); wherein the metal chelate crosslinking agent is selected from one or more of aluminum acetylacetonate, zirconium acetylacetonate, titanium acetylacetonate, and poly butyl titanate (instant claim 6); wherein the pressure-sensitive adhesive is selected from one or more of an acrylate pressure-sensitive adhesive, a polyisobutylene pressure-sensitive adhesive, a silicone pressure-sensitive adhesive, a styrene-isoprene-styrene hot melt pressure-sensitive adhesive, and a vinyl acetate copolymer (instant claim 7); wherein the dexmedetomidine transdermal patch comprises in the following order a backing layer, the adhesive layer, and an anti-adhesion release film layer (instant claim 8), further claiming wherein the adhesive layer has a thickness of 25 µm-100 µm (instant claim 9).
Claims 1 and 3-9 are rejected under 35 U.S.C. 103 as being unpatentable over Colley et al. (WO 9102505 A1, pub. 07/03/1991) in view of Pongpeerapat et al. (US 20150098997 A1, pub. 04/09/2015) and Foreman et al. (US 20090130188 A9, pub. 05/21/2009) evidenced by Srivastava et al. (Indian Journal of Critical Care Medicine July 2014 Vol 18 Issue 7, 431-436), herein referenced Colley, Pong, Foreman, and Sriva.
Colley provides a transdermal system for administering dexmedetomidine (DMT) that uses skin permeation enhancers (pg. 3, line 25, claim 7) to enhance the permeability of the skin thereto and achieve more rapid delivery (pg. 4, line 11). Propylene glycol monolaurate (PGML) is a preferred skin permeation enhancer which is taught by Colley as typically being a mixture comprising propylene glycol (pg. 7, line 26, 30; claim 9).
Colley discloses (see figure below) on line 22 of page 8 through line 2 of page 9: “The device (1) comprises: (a) a backing layer (10) which serves as the upper surface of the device; (b) an optional anchor adhesive layer (11) adjacent the backing layer; and (c) a contact adhesive layer (12) which defines the basal surface of the device and which contacts and adheres to the skin during use (claims 3-4). The composite also preferably contains (d) an optional porous intermediate layer (13) between the anchor and contact adhesive layer where an anchor layer is included, typically of an adsorbent, nonwoven fabric (claim 5). After lamination, the anchor adhesive and contact adhesive soak into the intermediate layer to form a composite layer (14) having an upper portion (15) comprising intermediate layer and anchor adhesive, and a lower portion (16) comprising intermediate layer and contact adhesive. When packaged, prior to administration, the device will also preferably comprise a release liner (17), laminated to the exposed contact layer surface.” The release liner is a disposable element which serves only to protect the device prior to application (pg. 12, line 1).
PNG
media_image1.png
348
459
media_image1.png
Greyscale
Colley teaches that the backing layer (10) is made of a sheet or film of a preferably flexible elastomeric material substantially impermeable to DMT and may be made of styrene-isoprene copolymers (pg. 9, line 32). The anchor adhesive layer (11) adheres to the backing layer (10) and to the contact layer (12) is preferred when the device employs permeation enhancers (pg. 10, line 12).
The contact adhesive (12) is a pressure-sensitive adhesive suitable for long-term skin contact (pg. 11, line 1). The drug must be somewhat soluble in the adhesive so that the drug does not partition into the anchor layer (away from the skin) but partitions into the skin (pg. 11, lines 5-7). The material should also have a high diffusivity for dexmedetomidine (pg. 11, lines 8-9).
Colley teaches acrylates, polyisobutylenes, silicones, and polyisobutylenes are preferred while plasticized ethylene-vinyl acetate copolymers, polystyrene-isoprene copolymers are suitable adhesives (pg. 10, line 23, claims 11-12). Colley provides patch preparations (see A-E silicone or acrylic contact adhesives) that teach dexmedetomidine base at 1.8 – 2.2% (dry loading range = 0.5-3.0%); PGML: 8% (pg. 16, lines 2-4).
While Colley teaches and suggests that propylene glycol is present in PGML, this known in the art as not a simple mixture. Pong is provided to teach propylene glycol and crosslinking.
Pong a transdermal delivery device containing a dexmedetomidine (DMT) composition formulated to deliver an amount of DMT to a subject ([0050], claim 1). Pong is focused on flux profiles and therapeutic concentrations in the body ([0067], consider figures, claim 13).
Pong teaches that the dexmedetomidine composition consists of DMT and the pressure sensitive adhesive (claim 34). The transdermal delivery device comprises a single layer matrix comprising the DMT composition (claim 35). The thickness of single layer matrices of interest may vary, in some instances ranging in thickness from 10 to 260 microns ([0115]). The pressure sensitive adhesive may include polyisobutene adhesives, polyisobutylene adhesives ([0103]), crosslinked polyvinylpyrrolidone (PVP) or crosslinked polyacrylic acid, acrylate-vinyl acetate copolymer ([0105-106], claims 17, 33).
The amount of DMT in the transdermal composition ranges from 0.1% to 20% w/w ([0100]) and the DMT solubilization enhancer is incorporated into the DMT composition and is in an amount from 0.01% to 20% (w/w) ([0112]). Similar to Colley, Pong adds propylene glycol monolaurate (PGML) to the adhesive ([0134], Fig. 13, Table 12) but Pong teaches that propylene glycol is also a solubility enhancer ([0113], lines 6-5 from the bottom).
Notably, Pong discloses that the pressure sensitive adhesive may include a composition that is, or is substantially the same as, the composition of Duro-Tak® 87-2510 and Duro-Tak®87-2287 ([0106]). Looking to the instant specification, Applicants disclose these same Duro-Tak (DT) products (see Spec., pg. 8, para. 2). Pong teaches that the amount of pressure sensitive adhesive in the DMT composition ranges may range from 0.1 mg to 2000 mg; from 1% to 99% w/w ([0107]). Pong teaches that the weight ratio of pressure sensitive adhesive to dexmedetomidine in the subject compositions may range from 1:2 and 1:2.5; 1:2.5 and 1:3; 1:3 and 1:3.5 1:3.5 and 1:4: 1:4 and 1:4.5; 1:4.5 and 1:5; 1:5 and 1:10; 1:10 and 1:25; 1:25 and 1:50: 1:50 and 1:75; and 1:75 and 1:99 ([0108]). Pong teaches that the amount of crosslinked polymer in the DMT compositions may range from 0.1 mg to 500 mg; from 2% to 30% w/w ([0111]). Table 6 shows the dexmedetomidine transdermal composition formulations containing 1% dexmedetomidine (e.g., 1% DMT/ DT2287) in another hydroxyl functionalized acrylate polymers containing vinyl acetate, e.g., Duro-Tak® 87-2287 (i.e., DT 2287) (no crosslinker added polymer); Duro-Tak® 87-2516 (crosslinker added polymer). Pong teaches the solubility of DMT in acid (-COOH) functionalized acrylate adhesive, Duro-Tak® 387/87-2353 (no crosslinker added acrylate polymer) is about 10-15%, whereas that in the acid/hydroxyl (-COOH/OH) functionalized acrylate adhesive, Duro-Tak® 87-2979 (crosslinker added acrylate-vinyl acetate polymer), was found to be less than 2% ([0144]). Pong states, “The solubility of drug in acid functionalized acrylate adhesives was greater than that in non-functionalized or hydroxyl functionalized acrylate adhesives,” ([0145]).
It would have been prima facie obvious to a person of ordinary skill in the art, ahead of the effective filing date of the claimed invention, to substitute one known solubility enhancer, i.e., PGML, of Colley with the propylene glycol taught by Pong for a similar purpose of administering drug transdermally. Simple substitution of one permeation enhancer for another is within the purview of the skilled artisan and would yield predictable results.
Pong does not teach metal chelate.
Foreman addresses the challenges of flux decreasing over time, which Pong discovers (Foreman [0003], Pong [0165]). Foreman discloses an acrylic pressure sensitive adhesive (PSA) in an organic solution in which the active ingredient (e.g., drugs) are dispersed rather than fully dissolved ([0006]). When the active remains at least partially dispersed during the drying process, supersaturation is avoided ([0006]). Foreman teaches that a typical conventional acrylic solution PSA may also contain hydrocarbon solvents and, if crosslinked with a metal alkoxide or chelate, stabilizing alcohols and ketones ([0017]). Foreman teaches that in addition to the acrylic polymers, or blends thereof, the adhesive compositions of the invention may optionally comprise a compatible tackifier and/or plasticizer and/or skin permeation enhancers to produce the desired properties required for the intended end use ([0028]). The adhesive compositions may if desired be formulated with a crosslinking agent and that using a crosslinker adds to the cohesive strength ([0029]). Crosslinking agents containing aluminum or titanium are preferred and non-limiting examples include aluminum tris(acetylacetonate) and bis(2.4-pentanedionate-0,0') bis(2-propanolato) titanium ([0029]).
Foreman teaches that the adhesives are useful for delivering drugs through the skin (transdermal) or delivering actives to the skin (dermal) and such delivery processes may be aided by including a permeation enhancer in the adhesive composition ([0031]). Enhancer loadings up to about 30% on adhesive polymer solids, more typically from about 5 to about 15% may be employed ([0031]). Treatment areas where the delivery device of the invention finds use include treatment for cardiovascular (nitroglycerin, clonidine) ([0041]). The transdermal delivery devices of the invention can be made in the form of an article such as a tape, a patch, a sheet, a dressing or any other form known to those skilled in the art ([0043]).
Foreman does not teach dexmedetomidine. However, as evidenced by Sriva, while both clonidine and dexmedetomidine are alpha-2 agonists and produce effective sedation; the hemodynamic stability provided by dexmedetomidine gives it an edge over clonidine for short-term sedation of ICU patients (Abstract). It would have been prima facie obvious to a person of ordinary skill in the art, ahead of the effective filing date of the claimed invention, to substitute one known alpha-2 agonist, i.e., clonidine, with the specific dexmedetomidine taught by Colley, Pong and evidenced by Sriva for a similar purpose of producing sedation (see Colley, claim 1; Pong [0050], Foreman [0041] see sedatives, anxiolytic drugs). Simple substitution of one alpha-2 agonist for another is within the purview of the skilled artisan and would yield predictable results.
It would have been prima facie obvious to a person of ordinary skill in the art, ahead of the effective filing date of the claimed invention, to combine the teachings of Pong and Foreman evidenced by Sriva regarding crosslinking agents and specifically metal chelate crosslinking agents and apply them to the therapeutic system in the form of a skin patch of Colley (pg. 16, para. 1) with expected results. One would be motivated to do so with a reasonable expectation of success because Foreman addresses the challenges surrounding flux profiles which are illustrated by Pong and the incorporation of crosslinking agents would support Colley’s goal to control DMT concentrations in the blood particularly over time (see Colley pg. 6, para. 2). And, Pong shows that the solubility enhancer and the functionalization of the pressure sensitive adhesive affect stability and drug loading in DMT transdermal compositions (Pong [0164], claim 33). Foreman improves upon this by teaching that typical conventional acrylic solution pressure sensitive adhesives for use in transdermal drug delivery in effect, can be enhanced in terms of stability if crosslinked with a metal chelate ([0017]).
Regarding instant claim 3, mass ratio of propylene glycol to dexmedetomidine in the composition is (5:3)-(7:3); or the mass ratio of propylene glycol to dexmedetomidine in the composition is 5:3, Pong teaches that the dexmedetomidine solubilization enhancer is incorporated into the dexmedetomidine composition in an amount ranging from 0.01% to 20% (w/w), such as from 0.05% to 15% (w/w), such as from 0.1% to 10% (w/w), such as from 0.5% to 8% (w/w) and including from 1% to 5% (w/w) ([0112]). Pong discloses that where protocols include delivering a predetermined amount of dexmedetomidine to the Subject, the amount of dexmedetomidine in the compositions of interest may range from 0.001 mg to 10 mg, such as 0.005 to 9.5 mg, such as 0.01 mg to 8.5 mg ([0083]). Such as 0.05 to 8 mg. Such as 0.1 mg to 7.5 mg. Such as 0.5 mg to 7 mg and including from 1 mg to 5 mg ([0083]). Pong provides formulation examples where the solubility enhancer i.e., lauryl lactate, is at 3%, 6%, and 9% while the DMT is at 3% ([0150], Example 8, Table 11). Pong provides Example 15 where the enhancer is also present at 5% w/w while the dexmedetomidine base is at 3% w/w ([0164], Table 22) to read on the claimed range(s).
Regarding instant claims 4-5 (i.e., mass ratio PSA to crosslinker), as mentioned above, Foreman teaches that a typical conventional acrylic solution PSA may also contain hydrocarbon solvents and if crosslinked with a metal alkoxide or chelate, stabilizing alcohols and ketones ([0017]). Foreman discloses that aluminum tris(acetylacetonate), is present from about 0.3% to about 2% by weight of the acrylic copolymer ([0029]). MPEP 2144.05 states that a prima facie case of obviousness exists in the case where the claimed ranges overlap or lie inside ranges disclosed by the prior art. Here the prior art teaches amounts of metal chelate crosslinking agent relative to the PSA that falls within the claimed ranges.
Regarding claim 6, Foreman teaches aluminum tris(acetylacetonate) ([0029]).
Regarding claim 7, all of the prior art teaches acrylate PSA (Colley (pg. 10, line 23, claims 11-12; Pong [0105-106], claims 17, 33; Foreman [0028]).
Regarding claim 8, Colley provides a patch (see figure above) that comprises in the following order, backing layer (10), adhesive layer(s) (11, 12) and release film layer (17).
Regarding claim 9, Colley teaches that the contact layer (12) will generally range in 10 thickness from about 10 to about 100 µm, preferably about 75 µm (pg. 11, lines 9-11). Colley discloses that (11) is generally about 10 to about 75 µm in thickness, preferably about 50 µm (about 2 mil) (pg. 10, line 32; pg. 11, lines 11-18). MPEP 2144.05 states that a prima facie case of obviousness exists in the case where the claimed ranges overlap or lie inside ranges disclosed by the prior art.
For the foregoing reasons the instant claims are rendered obvious by the teachings of the prior art.
Conclusion
Claims 1 and 3-9 are rejected; no claims are currently allowable.
The Examiner asks Applicant to provide support for the amendments in the application disclosure by referencing page numbers, paragraphs, figures, etc. for the sake of compact prosecution.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Karen Ketcham whose telephone number is (571)270-5896. The examiner can normally be reached 900-500 ET.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ali Soroush can be reached at 571-272-9925. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) 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.
/Karen Ketcham/Examiner, Art Unit 1614
/ALI SOROUSH/Supervisory Patent Examiner, Art Unit 1614