Ex Parte WangDownload PDFPatent Trial and Appeal BoardMar 14, 201712844369 (P.T.A.B. Mar. 14, 2017) Copy Citation United States Patent and Trademark Office UNITED STATES DEPARTMENT OF COMMERCE United States Patent and Trademark Office Address: COMMISSIONER FOR PATENTS P.O.Box 1450 Alexandria, Virginia 22313-1450 www.uspto.gov APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO. 12/844,369 07/27/2010 Changjin Wang 392130-0201 7927 88984 7590 03/16/2017 FOT FY Rr T ARDNFR T T P EXAMINER 3000 K STREET N.W. COUGHLIN, DANIEL F SUITE 600 WASHINGTON, DC 20007-5109 ART UNIT PAPER NUMBER 1619 NOTIFICATION DATE DELIVERY MODE 03/16/2017 ELECTRONIC Please find below and/or attached an Office communication concerning this application or proceeding. The time period for reply, if any, is set in the attached communication. Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the following e-mail address(es): ipdocketing @ foley. com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte CHANGJIN WANG Appeal 2015-002237 Application 12/844,369 Technology Center 1600 Before DONALD E. ADAMS, JEFFREY N. FREDMAN, and RYAN H. FLAX, Administrative Patent Judges. FREDMAN, Administrative Patent Judge. DECISION ON APPEAL This is an appeal1 under 35U.S.C. § 134 involving a pharmaceutical transdermal formulation. The Examiner rejected the claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm. 1 Appellant identifies the real party in interest as ABSIZE, INC. (see App. Br. 1). Appeal 2015-002237 Application 12/844,369 Statement of the Case Background “The preparations of this invention have a saturated solution of an active pharmaceutical ingredient in a solvent therefor in intimate combination and contact with a suspension of nanoparticles of the active pharmaceutical ingredient in the solvent, and a pharmaceutically acceptable carrier therefor suitable for topical administration” (Spec. 11). The Claims Claims 1—12 and 16—18 are on appeal.2 Claim 1 is representative and reads as follows: 1. A pharmaceutical transdermal formulation comprising an active pharmaceutical ingredient wherein said formulation contains a saturated aqueous solution of the active pharmaceutical ingredient in intimate combination with a suspension of nanoparticles having a size distribution of from 1 to 100 nm, said formulation, when transdermally administered, provides for a dynamic equilibrium with the amount of said active pharmaceutical ingredient delivered transdermally and the amount in suspension so that the solution retains a saturated concentration of said active pharmaceutical ingredient until the suspension is exhausted, provided that said formulation is maintained in a pharmaceutically acceptable non-nanoparticle carrier. The Issue The Examiner rejected claims 1—12 and 16—18 under 35 U.S.C. § 103(a) as obvious over Bae,3 Murrell,4 and Lee5 (Non-Final Act. (mailed June 17, 2013) 3-8). 2 Claims 13—15 and 19-37 were cancelled (see App. Br. 17—18 (Claims App’x)). 2 Appeal 2015-002237 Application 12/844,369 The Examiner finds Bae teaches “a composition comprising nanoparticles of a sparingly water-soluble drug . . . wherein the particles of the composition display a particle size distribution of 10 to 1000 nm” and where “the sparingly water-soluble drug is . . . piroxicam” (Ans. 4—5). The Examiner acknowledges Bae does not teach “a composition that is a transdermal formulation” (id. at 5). The Examiner finds Murrell teaches “a transdermal patch for the delivery of a nitric oxide-donor, such as nitroglycerin, and a second active agent (see Abstract), wherein the second active agent can be an NS AID, such as piroxicam” (id.). The Examiner finds Lee teaches transdermal delivery compositions where the active ingredient is present in the composition in a combination of a solid microparticulate state and a solubilized state . . . wherein, the composition comprises microreservoirs containing the solid and solubilized forms of the active ingredient, where the drug solids act as a depot and, as the solubilized fraction is depleted by diffusion to and permeation into/across a patient's skin, more drug is drawn into solution from the particulate depot, thus enabling controlled release over time. (Id.) The Examiner finds it obvious to arrive at particle size distributions encompassing the claimed limitations by the express teachings of Bae [’]416 as to the increase in solubility arising from smaller particle sizes . . . and, perhaps more importantly, the increased bioavailability realized from the enhanced solubility ... as well as by the express teachings of Lee [’]349 as to the control of active ingredient 3 Bae et al., WO 2008/013416 Al, published Jan. 31, 2008 (“Bae”). 4 Murrell et al., US 2007/0059351 Al, published Mar. 15, 2007 (“Murrell”). 5 Lee et al., US 2007/0264349 Al, published Nov. 15, 2007 (“Lee”). 3 Appeal 2015-002237 Application 12/844,369 release over time that the equilibrium-controlled depot of solid drug particles provides. (Ans. 7.) The issue with respect to this rejection is: Does the evidence of record support the Examiner’s conclusion that Bae, Murrell, and Lee render claim 1 obvious? Findings of Fact 1. Bae teaches “nanoparticles of a sparingly water-soluble drug, which exhibits enhanced bioavailability and particle size stability of the drug” (Bae 1:7—9). Bae teaches “a powder composition comprising the particles of the sparingly water-soluble drug prepared by the inventive method, which shows a particle size distribution of 10 to 1000 nm for 10 to 90% of the drug particles ... an average particle size of 10 to 400 nm in an aqueous medium” {id. at 3:26-4:3). 2. Bae teaches “examples of the sparingly water-soluble dmg include non-steroidal anti-inflammatory drugs including . . . piroxicam” (id. at 5:23-26). 3. Bae teaches “the process time can be adjusted according to the kind of the active ingredient.... As the process time of step 2) is longer, the particle size of the active ingredient becomes smaller and more homogeneous” (id. at 9:8—15). 4. Murrell teaches “devices for transdermally co-delivering low doses of a nitric oxide-donor with other active agents. The devices can be used for variety of treatment regimens including pain relief’ (Murrell 12). 5. Murrell teaches “[ejxamples of NSAIDS which can be used as the second active agent include . . . piroxicam” (id. 128). 4 Appeal 2015-002237 Application 12/844,369 6. Lee teaches: “Transdermal delivery also creates steady levels of a drug in the bloodstream and helps to improve drug efficacy. Depending on various ingredients that are used to formulate the drug, as well as technical aspects of the patch ... the rate of release of the drug can be precisely manipulated” (Lee 110). 7. Lee teaches: The active pharmaceutical ingredient can be present in (a) a solid nanoparticulate state; (b) a solid microparticulate state; (c) solubilized; or (d) any combination thereof. In another embodiment of the invention, the composition is suitable for transdermal delivery. In yet another embodiment of the invention, the composition which is suitable for transdermal delivery provides for a depot effect. {id. 118.) 8. Lee teaches: By varying different parameters of Route I and Route II, the size and integrity of such globules can be modified. Hence, the stability of globules comprising dissolved API can be altered to enable the release of API, either as a solution or precipitate. This is a microreservoir-dissolution-controlled system, where the drug solids act as depot and, as the solubilized fraction is depleted, more drug is drawn into solution [from] the particulate depot. Thus, the emulsion globules comprising solubilized API enable controlled API release over time. {id. 1107.) 9. Lee teaches “the emulsion globules comprising solubilized API, API nanoparticles, or a combination thereof can be diluted with aqueous solutions without stability loss. . . . The concentration of API, however, depends on the solubility of the actual drug and the amount of solvent used to dissolve it” {id. 1109). 5 Appeal 2015-002237 Application 12/844,369 Principles of Law “Absent an express definition in their specification, the fact that appellants can point to definitions or usages that conform to their interpretation does not make the PTO’s definition unreasonable when the PTO can point to other sources that support its interpretation.” In re Morris, 127 F.3d 1048, 1056 (Fed. Cir. 1997). Analysis We adopt the Examiner’s findings of fact and reasoning regarding the scope and content of the prior art (Non-Final Act. 3—8; FF 1—9) and agree that the claims are obvious over Bae, Murrell, and Lee. We address Appellant’s arguments below. Appellant contends the “structure of Appellant’s recited formulation enables the dynamic equilibriums to remain equal. Appellant’s recited transdermal formulation comprises a ‘saturated aqueous solution’ of API that is ‘transdermally administered’” (App. Br. 8). Appellant contends “[n]o cited reference teaches such a relationship. Moreover, none of the cited references teach a saturated aqueous solution of the API, which retains its saturated concentration upon transdermal application” (id. ). The Examiner responds that Appellant is claiming a well-recognized phenomenon of solution thermodynamics whereby, when solute is present in a solvent medium at levels above the saturation solubility of that solute in the selected solvent, the solute will exist in both a solid state as well as in solution. As would be recognized by one of ordinary skill in the art, in such situations there would be a solution equilibrium in place whereby a constant, balanced interchange between solute particles (molecules or ions) in the solid state and in solution would occur, such phenomenon considered to be a “dynamic equilibrium,” which equilibrium 6 Appeal 2015-002237 Application 12/844,369 would necessarily encompass the “self-replenishing” phenomenon argued by Appellant, all in accord with well- accepted applications of Le Chatelier’s Principle. (Ans. 5.) We find that the Examiner has the better position. Claim 1 recites a formulation that comprises a pharmaceutical ingredient, here elected as piroxicam, in two forms. The first form is a nanoparticle made of the pharmaceutical and the second form is a saturated aqueous solution of the pharmaceutical. As the Examiner points out, as pharmaceutical diffuses from the aqueous solution in the transdermal patch into the patient, reducing the amount of pharmaceutical in the aqueous solution, the dynamic equilibrium between the nanoparticles composed of pharmaceutical and the saturated aqueous solution will result in dissolution of sufficient solid nanoparticle to replace the pharmaceutical that diffused into the patient, until the nanoparticle has fully dissolved (see id.). Lee teaches this process, explaining that “drug solids act as a depot and, as the solubilized fraction is depleted, more drug is drawn into solution [from] the particulate depot” (FF 8). This understanding is also consistent with the Specification, which teaches the nanoparticle “pharmaceutical preparation of the present invention serves as a self-replenishing depot for as long as the active pharmaceutical ingredient remains in suspension and for some time thereafter until all or substantially all of the active pharmaceutical ingredient is depleted” (Spec. 151). Therefore, the broadest reasonable interpretation of claim 1, consistent with the Specification, is that the “saturated aqueous solution” necessarily results in a solution comprising a mixture combining nanoparticles with 7 Appeal 2015-002237 Application 12/844,369 pharmaceutical and an aqueous solution with pharmaceutical in equilibrium. “[DJuring patent prosecution when claims can be amended, ambiguities should be recognized, scope and breadth of language explored, and clarification imposed.” In re Zletz, 893 F.2d 319, 322 (Fed. Cir. 1989). We note: Appellant does not contest that both a solid particulate state and a solubilized state can be present in the emulsion taught by Lee; however, [Appellant contends] in no way does the presence of both a particulate state and a solubilized state necessarily imply that “said formulation contains a saturated aqueous solution of the active pharmaceutical ingredient,” nor does it imply that “said formulation, when transdermally administered, provides for a dynamic equilibrium with the amount of said active pharmaceutical ingredient delivered transdermally and the amount in suspension so that the solution retains a saturated concentration of said active pharmaceutical ingredient,” as required by [c]laim 1. (App. Br. 10.) Similarly, Appellant contends “dynamic equilibrium is not equilibrium per se because the rate of dissolution of the drug is not based on equilibrium constants for the drug but rather on the rate of delivery of the drug to the body” (Reply Br. 7). We find this argument unpersuasive because Appellant has provided no evidence, other than attorney argument, that the obvious combination of Bae, Murrell, and Lee, resulting in a transdermal delivery system with piroxicam nanoparticles and a piroxicam aqueous solution, would not result in a “saturated aqueous solution” or “dynamic equilibrium” as required by claim 1 and expected based on Le Chatelier’s principle as discussed by the Examiner (see Ans. 6—7). See In re Pearson, 494 F.2d 1399, 1405 (CCPA 1974) (“Attorney’s argument in a brief cannot take the place of evidence.”). 8 Appeal 2015-002237 Application 12/844,369 Appellant contends the “processes disclosed in Bae produce nanoparticles with enhanced bioavailability for the purpose of providing a direct and immediate bolus releasethat “Murrell does not remedy the above deficiencies of the teachings of Bae, nor is Murrell cited for this purpose”; and that “Lee provides no discussion of: the solubilized portion being at saturation, a dynamic equilibrium, or Le Chatelier’s Principle” (App. Br. 9, 11). We find these arguments unpersuasive because they do not address the references in combination, nor do these arguments address the knowledge of the skilled artisan of the prior art Le Chatelier’s principle. See In re Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986) (“Non obviousness cannot be established by attacking references individually where the rejection is based upon the teachings of a combination of references.”) A reference “must be read, not in isolation, but for what it fairly teaches in combination with the prior art as a whole.” (Id.) See also Perfect Web Techs., Inc. v. Info USA, Inc., 587 F.3d 1324, 1329 (Fed. Cir. 2009) (explaining that the obviousness analysis “may include recourse to logic, judgment, and common sense available to the person of ordinary skill that do not necessarily require explication in any reference or expert opinion”). Appellant contends: “If the movement of API from particulate form to soluble form is a consequence of a dynamic equilibrium in Lee, such a teaching is not enabled by Lee” (App. Br. 11). Appellant further contends “in various embodiments described in Lee, the solid state is formed through instability of the emulsion and the application of shear forces. Thus, it 9 Appeal 2015-002237 Application 12/844,369 cannot be implied from the presence of both a solid state and a soluble state in Lee that the solution is at a saturated concentration” {id. at 12). We do not find this argument persuasive and agree with the Examiner that in Lee, the equilibrium between solid and solvated fractions must necessarily exist in order for the dosage form to perform as described. Nor is the inherent instability of emulsion systems over time relevant to the obviousness issue. The fact that the emulsion may become unstable is immaterial as long as the emulsion remains stable long enough to perform as taught. In this regard, the invention as claimed recites no limitations directed to time-related factors and, thus, can be read to encompass a system that displays stability even if for only a limited time, a teaching, incidentally, absent from the cited reference. (Ans. 6—7.) We also note that Lee directly contradicts Appellant’s concerns regarding enablement of the composition or the composition’s stability and solubility, teaching that “the emulsion globules comprising solubilized API, API nanoparticles, or a combination thereof can be diluted with aqueous solutions without stability loss. . . . The concentration of API, however, depends on the solubility of the actual drug and the amount of solvent used to dissolve it” (PL 9). Thus, Lee recognizes the emulsion may be in aqueous solution in a stable form, and that the concentration depends solely upon solubility and solvent amounts, supporting the Examiner’s argument that Lee teaches, and Le Chatelier’s principle inherently results, in a solution where the solvent solubilizes pharmaceutical from the nanoparticles until the solvent is saturated, and then remains in equilibrium with the nanoparticles until they completely dissolve (see PL 8). 10 Appeal 2015-002237 Application 12/844,369 Appellant contends “there is no obvious reason a person skilled in the art would combine the elements of each reference in a manner that would have led to Appellant’s recited formulation” (App. Br. 12). Appellant contends that because “Lee, however, already teaches the formation of API nanoparticles within emulsion globules having diameters of about 10 nm to about 1000 nm” then “[a]ny positive impact of using such particle distributions would already be present in the Lee system. Thus, Appellant fails to understand, and the Examiner fails to articulate, why a person skilled in the art would be motivated to combine the cited references” {id. at 13—14). We do not find this argument persuasive because we agree with the Examiner that Bae teaches “the increase in solubility arising from smaller particle sizes, particularly advantageous for sparingly soluble active species, and, perhaps more importantly, the increased bioavailability realized from the enhanced solubility” which provide reasons to use nanoparticles of piroxicam at those sizes in combination with Lee’s teaching of a transdermal delivery formulation for “control of active ingredient release over time that the equilibrium-controlled depot of solid drug particles provides” (Ans. 7). That is, Lee teaches a transdermal delivery system comprising nanoparticles in equilibrium with an aqueous solution so “the rate of release of the drug can be precisely manipulated” (FF 6—9). Murrell teaches that piroxicam, the elected species, may be incorporated into transdermal delivery systems (FF 4—5). The ordinary artisan, interested in increasing ingredient release and bioavailablity of piroxicam in a transdermal delivery system rendered obvious by Lee and Murrell, would have reasonably used nanoparticles as prepared by Bae for a sparingly water soluble drug like piroxicam because Bae teaches “nanoparticles of a sparingly water-soluble 11 Appeal 2015-002237 Application 12/844,369 drug, which exhibits enhanced bioavailability and particle size stability of the drug” (FF 1). See KSR Inti Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (“The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.”) Appellant does not identify any unexpected result. We recognize, but find unpersuasive, Appellant’s contention that the claimed feature of a dynamic equilibrium requires that, as the active ingredient is delivered through the skin, the suspension acts as a reservoir to maintain a steady state system for the sustained release of the active ingredient through the skin. To create a dynamic equilibrium, suspended particles of the active pharmaceutical ingredient replenish the active pharmaceutical ingredient in solution as it is delivered transdermally through the patient’s skin. (Reply Br. 10.) As already discussed, Appellant’s argument fails to explain why the system in Lee, a transdermal delivery system comprised of nanoparticles with active pharmaceutical agent in an aqueous solution also containing active pharmaceutical agent (FF 6—9), does not necessarily and inherently result in the same dynamic equilibrium claimed by Appellant. See In re Best, 562 F.2d 1252, 125^55 (CCPA 1977) (“[W]here the Patent Office has reason to believe that a functional limitation asserted to be critical for establishing novelty in the claimed subject matter may, in fact, be an inherent characteristic of the prior art, it possesses the authority to require the applicant to prove that the subject matter shown to be in the prior art does not possess the characteristic relied on.”) 12 Appeal 2015-002237 Application 12/844,369 SUMMARY In summary, we affirm the rejection of claim 1 under 35 U.S.C. § 103(a) as obvious over Bae, Murrell, and Lee. Claims 2—12 and 16—18 fall with claim 1. No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a). AFFIRMED 13 Copy with citationCopy as parenthetical citation