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 .
DETAILED ACTION
Status of the Claims
Claims 1, 3-5, 8-11 and 14-15 are pending. Claims 2, 6-7 and 12-13 are canceled. Claims 10-11 and 14-15 are withdrawn. Claims 1, 3-5, and 8-9 are in the prosecution.
Acknowledgement of Receipt
The translation of CN202110969146.7 dated May 19, 2026, is acknowledged.
Maintained Rejections
The following rejections are maintained form the previous Office action dated Feb. 24, 2026, since the previously cited art reads on the newly amended limitations.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. § 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries 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.
Claim(s) 1, 3-5, and 8-9 is/are rejected under 35 U.S.C. § 103 as being unpatentable over Colley et al. (WO 91/02505 A1) in view of Pongpeerapat et al. (US 2015/0098997 A1) and Foreman et al. (US 2009/0130188 A9) 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, respectively.
Colley provides a transdermal system for administering dexmedetomidine 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 permeation enhancer comprising propylene glycol (pg. 7, line 26, 30; claim 9). Looking to the figure of Colley (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).
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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. The device comprises a release liner (17), laminated to the exposed contact layer surface (pg. 12, line 1). The backing layer (10) is substantially impermeable to dexmedetomidine 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) 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).
Colley teaches and suggests that the drug must be somewhat soluble in the adhesive, so the drug does not partition into the anchor layer (away from the skin) but goes into the skin (pg. 11, lines 5-7). The material is to have a high diffusivity for dexmedetomidine (pg. 11, lines 8-9).
Colley teaches acrylate, polyisobutylene, silicones, ethylene-vinyl acetate copolymers, and polystyrene-isoprene copolymers as adhesives (pg. 10, line 23, claims 11-12). Patch preparations (see A-E silicone or acrylic contact adhesives) show a dexmedetomidine base at 1.8 to 2.2% (dry loading range = 0.5-3.0%); PGML: 8% (pg. 16, lines 2-4).
Colley teaches and suggests that propylene glycol is present in PGML, which is art-known as not a simple mixture.
Pong is provided to teach propylene glycol and crosslinking.
Pong discloses a transdermal delivery device comprising a dexmedetomidine composition wherein the dexmedetomidine composition comprises dexmedetomidine; and a pressure sensitive adhesive; and a backing layer (claim 1). Pong focuses on flux profiles and therapeutic concentrations in the body ([0067], see figures, claim 13). The dexmedetomidine composition consists of dexmedetomidine and the pressure sensitive adhesive (claim 34). The transdermal delivery device comprises a single layer matrix comprising the dexmedetomidine composition (claim 35). The thickness of single layer matrices of interest may vary, ranging in thickness from 10 to 260 microns ([0115]). The pressure sensitive adhesives may include poly-isobutene/polyisobutylene adhesive mixtures, acrylic or acrylate copolymers, such as carboxylate acrylate copolymers ([0103]), crosslinked polyvinylpyrrolidone (PVP) or crosslinked polyacrylic acid, acrylate-vinyl acetate copolymer ([0105-106], claims 17, 33).
Pong discloses that the amount of dexmedetomidine in the transdermal composition ranges from 0.1% to 20% w/w ([0100]) and the dexmedetomidine solubilization enhancer is present in the dexmedetomidine composition at 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). Pong teaches propylene glycol as a solubility enhancer (bridging lines 17-18 of paragraph [0113]).
Pong teaches a composition of Duro-Tak® 87-2510 and Duro-Tak®87-2287 that is included in the pressure sensitive adhesive ([0106]). Notably these same Duro-Tak (DT) products are disclosed in applicants’ instant disclosure (see Spec., pg. 8, para. 2).
Pong teaches that the amount of pressure sensitive adhesive in the dexmedetomidine composition may range from 0.1 mg to 2000 mg: from 1% to 99% w/w ([0107]). The weight ratio of pressure sensitive adhesive to dexmedetomidine in the 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]). The amount of crosslinked polymer in the dexmedetomidine compositions may range from 0.1 mg to 500 mg: from 2% to 30% w/w ([0111]). Looking at Table 6 dexmedetomidine transdermal composition formulations contain 1% dexmedetomidine (e.g., 1% dexmedetomidine/ 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 that the solubility of dexmedetomidine 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 disclose metal chelate.
However, Foreman addresses the challenges of flux decreasing over time (as mentioned above Pong looks at flux of transdermal dexmedetomidine delivery), in 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) is dispersed rather than fully dissolved ([0006]). When the active remains at least partially dispersed during the drying process, supersaturation is avoided ([0006]). A conventional acrylic solution PSA may contain hydrocarbon solvents and, if crosslinked with a metal alkoxide or chelate, may contain stabilizing alcohols and ketones ([0017]).
Foreman teaches that in addition to the acrylic polymers, or blends thereof, the adhesive compositions may comprise a compatible tackifier and/or plasticizer and/or skin permeation enhancers to produce the properties required for the intended use ([0028]). Adhesive compositions can be formulated with a crosslinking agent to provide 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]).
Regarding the mass ratio of propylene glycol to dexmedetomidine in the composition is (5:3)-(7:3) limitation of instant claim 1; and the mass ratio of propylene glycol to dexmedetomidine in the composition is 5:3 limitation of instant claim 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]). 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, 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 ([0085]). Pong provides formulation examples where the solubility enhancer i.e., lauryl lactate, is at 3%, 6%, and 9% while dexmedetomidine is at 3% ([0150], Example 8, Table 11). Pong provides Example 15 where the enhancer i.e., lauryl lactate, 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 the metal chelate crosslinking agent limitation, Foreman teaches aluminum tris(acetylacetonate) ([0029]) to read on the aluminum acetylacetonate species recited in lines 11-12 of instant claim 1.
Regarding the pressure-sensitive adhesive, Colley, Pong and Foreman all teach acrylate PSA (Colley (pg. 10, line 23, claims 11-12; Pong [0105-106], claims 17, 33; Foreman [0028]) to read on the acrylate pressure-sensitive adhesive species recited in lines 13-14 of instant claim 1.
Although Foreman does not disclose dexmedetomidine, as evidenced by Sriva, clonidine and dexmedetomidine are alpha-2 agonists that 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). One would be motivated to do so because as Foreman addresses the challenges surrounding flux profiles illustrated by Pong the incorporation of crosslinking agents would support Colley’s aim to control dexmedetomidine concentrations in the blood particularly over time (see Colley pg. 6, para. 2). Pong demonstrates how the solubility enhancer and the functionalization of the pressure sensitive adhesive affect stability and drug loading in dexmedetomidine 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 4 (i.e., mass ratio PSA to crosslinker), and claim 5 (i.e., acrylate PSA is 93.00 - 99.00; titanium acetylacetonate 0.50-0.60), 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 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.
Response to Arguments
Applicants’ arguments have been fully considered but they are not persuasive.
Propylene Glycol
Applicants argue that propylene glycol monolaurate (PGML) taught by Colley is an oil-soluble ester which is made by combining lauric acid and propylene glycol (PG) and it is usually used as a surfactant and emulsifier and therefore PGML and PG have different properties and are used for different purposes (Remarks page 11, paragraph 1). Applicants argue Pongpeerapat uses transdermal compositions of dexmedetomidine and propylene glycol monolaurate (see Example 8), not propylene glycol (Remarks page 11, paragraph 1).
The examiner respectfully submits that Example 8 cited by applicants is not a teaching away from the use of propylene glycol. MPEP §2123(II) states that “[d]isclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments.” The intended use of an ingredient does not diminish Pongpeerapat’s teaching of propylene glycol as a solubility enhancer (bridging lines 17-18 paragraph [0113]). A skilled artisan would readily recognize the breadth of ingredients in the art sharing dual purposes and overlapping properties.
Metal chelates crosslinking agent
Applicants argue Colley nor Pongpeerapat teach a metal chelate (Remarks page 11, paragraph 1) and that Foreman does not recite any of the four metal chelate crosslinking agents recited in claim 1 and does not teach dexmedetomidine or propylene glycol (Remarks, page 12, paragraph 1). Applicants argue a combination of dexmedetomidine and propylene glycol with an adhesive agent and a metal chelate crosslinking agent are not mentioned by the cited references, to conclude that there was a long-felt but unmet need for a patch with these elements (Remarks, page 14).
The Examiner respectfully submits that Foreman teaches aluminum acetylacetonate by disclosing aluminum tris(acetylacetonate) ([0029]) because as evidenced by NIST (i.e., National Institute of Standards and Technology) Chemistry Web Book, aluminum tris(acetylacetonate) and aluminum acetylacetonate are synonyms (see highlighted text in the NIST document provided).
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper 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 considers 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).
In response to applicants’ argument of there being an unmet need because Foreman’s application was filed in 2005 as propylene glycol was well-known and dexmedetomidine had been approved for human clinical earlier, i.e., 1999, in order for evidence of secondary considerations to be accorded substantial weight, there must be a nexus, i.e., a legally and factually sufficient connection or correspondence between the submitted evidence and the claimed invention. Once a prima facie case of obviousness is made by the Office through citation of references, the burden is on the applicant to produce sufficient evidence. Lastly, MPEP §2145 VIII. States that "The mere age of the references is not persuasive of the unobviousness of the combination of their teachings, absent evidence that, notwithstanding knowledge of the references, the art tried and failed to solve the problem." In re Wright, 569 F.2d 1124, 1127, 193 USPQ 332, 335 (CCPA 1977).
Dexmedetomidine
Applicants argue Foreman warns that many drugs are too soluble in the adhesive's solvent system to permit easy dispersion and further never mentions dexmedetomidine (Remarks, page 14).
Colley provides a transdermal system for administering dexmedetomidine. In response to applicants’ argument that Foreman by providing the example of phenobarbital (i.e., GABA receptor-binder not a selective alpha-2-adrenergic receptor agonist) teaches away from dexmedetomidine as a sedative (Remarks, page 12, paragraph 2), the MPEP §2123(II) states that “[d]isclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments.”
Applicants argue patients in Srivastava were given alpha-2 agonists drugs (e.g., clonidine, dexmedetomidine) by IV and not transdermal patch, and even though Foreman teaches and suggests clonidine in a transdermal patch in paragraph [0041], Srivastava teaches away from using dexmedetomidine in a transdermal patch because the reference indicates clonidine can cause tissue damage citing noxious stimulus in pages 431-433 of Srivastava (Remarks, page 13) and then concludes that tissue damage may result even from IV use of dexmedetomidine (Remarks, page 14).
In response, one skilled in the art would recognize within the context of the administering (i.e., IV v. transdermal; long-term versus short-term), that an alpha-2 adrenergic agonist would be preferred over another. Srivastava provides evidence of the stability provided by dexmedetomidine gives it an edge over clonidine and as established above the substitution would support the shared purpose of producing sedation.
Applicants argue that the dosing ratio range, the metal chelate crosslinking agent and PSA as the “skeleton structure” of dexmedetomidine, and choosing propylene glycol provided the results detailed in the remarks, and for a skilled artisan to produce the same would require “extensive testing” (Remarks bridging pages 14-15).
As applicants stated in the remarks “propylene glycol was well-known” (Remarks, page 12), MPEP 2144.05(II.)(A.) states "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) Where the claimed and prior art product(s) are identical or substantially identical, the burden of proof is on applicant to establish that the prior art product(s) do not necessarily or inherently possess the characteristics of the instantly claimed product(s), see in re Best, 195 USPQ 430. See MPEP 2112.01.
Applicants argue that propylene glycol is a more efficient solubilizer compared to Pong, i.e., lauryl lactate and dexmedetomidine and as such Pong’s disclosure cannot read on the claimed range(s). Applicants indicate a synergistic advantage to employing the metal chelate crosslinking agent and the pressure-sensitive adhesive; selected for dexmedetomidine citing paragraphs [0171] and [0189] of the instant disclosure (Remarks page 15). Applicants argue that unexpected results provide an answer to the crystallization and stability concerns disclosed in paragraph [0004] of Foreman to further demonstrate the claimed invention’s significant effect on sleep improvement in mice (Remarks, page 15).
The Examiner respectfully submits that applicant is required to provide and show unexpected results to render non-obviousness compared to the closest prior art of record. MPEP 2173.05 states that although a claim should be interpreted in light of the specification disclosure, it is generally considered improper to read limitations contained in the specification into the claims. As such, one cannot rely on the specification to impart limitations to the claim that are not recited in the claim. Importantly the claims do not recite synergistic effects of the metal chelate crosslinking agent and the pressure-sensitive adhesive.
For these reasons, Applicants’ arguments are found unpersuasive.
Conclusion
All claims under consideration remain rejected; no claims are allowed. Applicants’ amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicants are 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 extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no case, 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 Karen Ketcham whose telephone number is (571)270-5896. The examiner can normally be reached 0830-1630.
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/Karen A Ketcham/Examiner, Art Unit 1614
/ALI SOROUSH/Supervisory Patent Examiner, Art Unit 1614
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