Corium International, Inc.Download PDFPatent Trials and Appeals BoardFeb 2, 20222021001300 (P.T.A.B. Feb. 2, 2022) 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. 15/660,924 07/26/2017 Eun Soo Lee 091500-0704/8043.US00 2959 108547 7590 02/02/2022 McDermott Will & Emery LLP 500 North Capitol Street NW Washington, DC 20001 EXAMINER LIU, TRACY ART UNIT PAPER NUMBER 1612 NOTIFICATION DATE DELIVERY MODE 02/02/2022 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): mweipdocket@mwe.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte EUN SOO LEE, PARMINDER SINGH, APPALA SAGI, and AMIT K. JAIN Appeal 2021-001300 Application 15/660,924 Technology Center 1600 Before ULRIKE W. JENKS, TAWEN CHANG, and RACHEL H. TOWNSEND, Administrative Patent Judges. TOWNSEND, Administrative Patent Judge. DECISION ON APPEAL Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the Examiner’s decision to reject claims to a composition including an active agent and an amphoteric inorganic base and its use as being obvious. We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. 1 We use the word Appellant to refer to “applicant” as defined in 37 C.F.R. § 1.42. Appellant identifies the real party in interest as Corium, Inc. (Appeal Br. 1.) Appeal 2021-001300 Application 15/660,924 2 STATEMENT OF THE CASE Appellant’s Specification states the following regarding amine drugs and their use in oral formulations and transdermal formulations: Amine drugs exist in two forms, a free base and a salt. The salt form is the conjugated acid salt (i.e., protonated form) of an amine drug, and the free base is the conjugated base (i.e., deprotonated form) of the amine drug. In general, the salt form is more stable, water soluble, and bioavailable than the free base form. As such, most oral formulations of amine drugs include the salt form of the amine drug. In contrast, transdermal formulations typically use a free base form because the free base is much more skin permeable than the salt form. (Spec. ¶ 3.) Appellant’s Specification indicates that there are some “significant drawbacks” with the use of the free base in transdermal formulations. (Id. ¶ 4.) Besides instability of the free base form, another drawback includes difficulty in solubilizing “a sufficient amount” of the free base in a polymer matrix due to recrystallization of the free base during processing or storage prior to use because of low solubility of the free base in the matrix. (Id.) The Specification further states: “[a]dditionally, drug flux is often difficult to control and deliver for multiple days at a constant rate when a drug is very permeable through the skin.” (Id.) Appellant’s invention is directed to a composition of an amine salt form of a drug for transdermal application. (Id. ¶ 2.) Claims 1-31 are on appeal. Claim 1 reproduced below, is illustrative of the claimed subject matter: 1. A composition for transdermal delivery, comprising: a drug reservoir comprising an amine salt form of an active agent and an amphoteric inorganic base compound, wherein the Appeal 2021-001300 Application 15/660,924 3 pKa of the amphoteric inorganic base compound is lower than that of the amine salt form of the active agent. (Appeal Br. 13 (Claims App.).) The prior art relied upon by the Examiner is: Name Reference Date Gale et al. US 5,635,203 June 3, 1997 Hsu et al. US 2002/0192243 A1 Dec. 19, 2002 Song et al. US 2004/0033254 A1 Feb. 19, 2004 Rasmussen et al. US 2010/0121290 A1 May 13, 2010 Cottrell et al. US 2011/0244023 A1 Oct. 6, 2011 Stinchcomb et al. US 2017/0202830 A1 July 20, 2017 The following grounds of rejection by the Examiner are before us on review: Claims 1-6, 8, 14, 16-18, 20, 21, and 24-31 under 35 U.S.C. § 103 as unpatentable over Hsu. Claims 7, 9, and 15 under 35 U.S.C. § 103 as unpatentable over Hsu and Stinchcomb. Claim 10 and 11 under 35 U.S.C. § 103 as unpatentable over Hsu and Cottrell. Claims 12 and 13 under 35 U.S.C. § 103 as unpatentable over Hsu and Song. Claims 19 and 22 under 35 U.S.C. § 103 as unpatentable over Hsu and Rasmussen. Claim 23 under 35 U.S.C. § 103 as unpatentable over Hsu and Gale. Appeal 2021-001300 Application 15/660,924 4 DISCUSSION Obviousness of Claim 1 over Hsu Appellant argues the claims rejected over Hsu alone as a group. We therefore focus our discussion on claim 1. (Appeal Br. 2.) The Examiner found that Hsu discloses a composition for the delivery of a drug to treat Alzheimer’s, such as donepezil HCl, via transdermal delivery. (Final Action 3-4 (citing Hsu ¶ 67).) The Examiner noted that Hsu teaches the composition includes “a pharmaceutically acceptable base to enhance the flux of the drug through the body surface without causing damage thereto.” (Id. at 3.) The Examiner found that Hsu discloses that inorganic salts of weak acids, including sodium bicarbonate, are suitable as the base. (Id. (citing Hsu ¶¶ 11, 40, 48).) The Examiner further found that a number of paragraphs in Hsu support the conclusion that Hsu’s formulations for use in transdermal patches include a salt form of the drug. (Ans. 5 (citing Hsu ¶¶ 19, 43).) The Examiner noted that although “Hsu discloses neutralizing drugs in the form of an acid addition salt, paragraph [0044] of Hsu discloses . . . the enhancer is preferably present in an amount just sufficient to neutralize the salt.” (Id.) The Examiner concluded that “[s]ince Hsu discloses wherein it is only preferable for the enhancer to be in an amount sufficient to neutralize the salt, it would have been obvious to one of ordinary skill in the art that [such] an amount . . . is not absolutely necessary.” (Id.) The Examiner further pointed to Table 2 of Hsu teaching a dried film comprising galanthamine HBr and NaOH as support for the conclusion that Appeal 2021-001300 Application 15/660,924 5 Hsu teaches compositions that include a drug in salt form combined with an inorganic base. (Ans. 6.) According to the Examiner, the dried film in Table 2 comprises galanthamine HBr and not the free base of galanthamine since Table 2 disclose a composition before neutralization has occurred. This is evident by Table 2 disclosing Gala-2 and Gala-3 comprising 1.1% and 2.2% NaOH respectively, and by Table 3 disclosing Gala-2 and Gala-3 comprising 0% and 1% NaOH, respectively, after neutralization. (Id.) The Examiner explained that “[t]he prior art is not anticipatory insofar as this combination must be selected from various lists/locations in the reference.” (Final Action 4.) Nevertheless, the Examiner found that the modification “represents nothing more than ‘the predictable use of prior art elements according to their established functions.’” (Id.) Regarding the pKa requirement, the Examiner explained the composition of Hsu et al. comprise substantially the same amphoteric inorganic base compound (e.g. sodium bicarbonate) and amine salt form of an active agent (e.g. donepezil HCL) as the claimed invention . . . one of ordinary skill in the art would reasonably conclude that the pKa of sodium bicarbonate is lower than that of donepezil HCL. (Id. at 5-6.) We agree with the Examiner’s conclusion of obviousness. Hsu teaches combining a drug and a permeation enhancer together in a single pharmaceutical formulation. (Hsu ¶¶ 13, 76.) Hsu teaches that the drug for use can be an Alzheimer’s drug and identifies donepezil HCl as a pharmaceutically acceptable use of such a drug. (Hsu ¶¶ 11, 67.) Hsu further teaches that the permeation enhancer is selected to provide a pH at the body surface in the range of 8.0-13.0, can be an inorganic base, and that Appeal 2021-001300 Application 15/660,924 6 a preferred inorganic base includes sodium bicarbonate. (Hsu ¶¶ 32, 33, 40.) Consequently, we agree with the Examiner that the claimed composition would have been obvious from the teachings of Hsu. Appellant argues that the Examiner’s rejection is in error because when viewed in its entirety it is clear that Hsu requires an amount of base in the composition sufficient to neutralize the amine salt of the drug and to be present in excess of a neutralizing amount. (Appeal Br. 3-4.) Appellant explains that Hsu requires the base, which is the permeation enhancer for the drug of the composition, to contact the skin so as to provide for the enhanced permeation. (Id. (citing Hsu ¶¶ 10, 33, 36).) According to Appellant, as such, the amount of base added with an amine salt must be in excess of the amount to neutralize the acid, otherwise there would not be any available base to contact the skin so as to provide the enhanced permeation. (Id. (citing Hsu ¶¶ 43, 44, 102).) Thus, argues Appellant, “there is therefore no salt form of the drug present in the composition” of Hsu. (Id.) Appellant argues further that, although Hsu describes an Example of galanthamine HBr added to NaOH and an in vitro example of applying the composition to skin and purports to measure the amount of galanthamine HBr that permeates the skin, it cannot be that galanthamine HBr was measured in the compositions that also contained NaOH. (Id. at 5-6.) Appellant argues this is so because there was either a 0% excess or 1% excess of NaOH added and the reaction that occurred when the two were combined went to completion such that only neutral drug would be left in those compositions applied to the skin. (Id. at 5-6 (citing Hsu ¶¶ 113, 115-117, 102).) We do not find Appellant’s argument persuasive because we agree with the Examiner that complete neutralization of the acid addition salt is Appeal 2021-001300 Application 15/660,924 7 merely a preferred embodiment of Hsu. (See Hsu ¶ 44.) Although paragraph 102 of Hsu describes “a delivery system” “in which the drug is present in nonionized, neutral form along with an excess of base to serve as a permeation enhancer,” it is clear from Hsu’s Example 1 that such a formulation is not necessary to enhance permeation of the acid addition salt of basic drugs. In particular, Table 4 of Hsu demonstrates that even when no excess of base is present, permeation of the acid addition salt of the basic drug is enhanced at all measured time points compared to a composition that does not include any base at all. (See also id. ¶ 119 (“The formulation of Gala-2 provided up to 2-fold more galanthamine HBr flux than in the absence of NaOH (Gala-1).”).) Thus, it cannot be the case, as Appellant argues, that Hsu can only be read as teaching that excess base is required to provide for enhanced permeation. Furthermore, while Example 1 of Hsu does exemplify only formulations in which complete neutralization of the active acid salt galanthamine HBr is neutralized with the base NaOH, such an example is not limiting of the broader disclosure of Hsu. (See Hsu ¶ 44 (noting only that it is “preferabl[e]” to use a neutralizing amount of enhancer), ¶ 108 (noting the examples are not limiting of the scope of the invention), ¶ 121 (noting that the description “in conjunction with the preferred specific embodiments” are illustrative, not limiting).) As noted above, that disclosure includes that an amine salt of the drug, including donepezil HCl, can be combined with inorganic bases, including sodium bicarbonate, that Appeal 2021-001300 Application 15/660,924 8 provide for a pH between 8.0-13.0 at the body surface to which the composition is to be applied. Hsu explains that it is understood that, for all of the inorganic and organic bases described herein, the optimum amount of any such base will depend on the strength or weakness of the base and its molecular weight, and other factors such as the number of ionizable sites in the active agent being administered and whether there are any acidic species present in the formulation or patch. One skilled in the art may readily determine the optimum amount for any particular base such that the degree of enhancement is optimized while the possibility of damage to the body surface is eliminated or at least substantially minimized. (Hsu ¶ 38.) Hsu does not require that for all hydrochloride salts of amine drugs that the drug must be completely neutralized by the inorganic base permeation enhancer, just that the enhancer provide for permeation enhancement above a formulation that does not include the enhancer. Appellant’s arguments to the contrary are premised on an exemplification of the invention, and attorney argument as to how paragraph 102 of Hsu must be interpreted based on an unsupported argument that to enhance permeation across the skin an excess of base must be present. “Attorney’s argument in a brief cannot take the place of evidence.” In re Pearson, 494 F.2d 1399, 1405 (CCPA 1974). Unexpected Results Appellant argues that even assuming a prima facie case of obviousness has been established by the Examiner, there is evidence that “the claimed compositions provide relatively high and constant skin flux of the active drug over several days, whereas comparative compositions do Appeal 2021-001300 Application 15/660,924 9 not.” (Appeal Br. 8.) We agree with the Examiner that Appellant’s data is not persuasive of unexpected results. The composition that Appellant points to as showing the relatively high and constant skin flux of the active drug over several days is one that has memantine HCl and sodium bicarbonate as the amphoteric inorganic base, as well as including octyl dodecanol and glycerine. Octyl dodecanol and glycerine, as the Examiner noted, are solubilizers that help to stabilize the neutral from of the active and the salt form of the active, respectively. (See Ans. 8 (citing Spec. ¶¶ 56, 57).) Appellant’s Specification explains that “[t]he salt form solubilizer helps to solubilize and stabilize” the acid amine ion, its counterion, the bicarbonate ion, and its counterion in the initial ionization reaction that occurs when the amine salt is combined with the sodium bicarbonate. (Spec. ¶ 56.) The neutral form solubilizer helps stabilize the conjugated free base amine that occurs when the acid amine ion reacts with the bicarbonate ion. (Id. ¶ 57.) When the free base diffuses and permeates through to the skin, the prior reactions are driven to produce more of the free base, which again is stabilized by the neutral form solubilizer. Thus, as the Examiner noted, “one of ordinary skill in the art would reasonably expect the salt form and neutral form solubilizers to be critical in the type of skin flux” that Appellant relies on to establish unexpected results. However, claim 1 does not recite such solubilizers. (Ans. 8.) Consequently, the evidence relied upon fails to establish unexpected results because it is not commensurate in scope with the claim. In re Dill, 604 F.2d 1356, 1361 (CCPA 1979) (finding a failure of proof of unexpected results because the affidavit “offers no proof whatsoever pertaining to unexpected results obtained with the invention as set forth in [the] claims . . . , which do not call Appeal 2021-001300 Application 15/660,924 10 for tumbling in a boron carbide medium” and concluding “the evidence is not commensurate in scope with the claims”). In addition, as the Examiner also noted, Appellant’s Specification indicates that a small equilibrium constant ratio of the acid amine and conjugated free amine to the carbonic acid and bicarbonate is important in the system. (Ans. 7; see Spec. ¶¶ 52-55.) As the Specification explains, where the ratios are very small “only a very small amount of amine drug free base product will be formed” and, “[b]ecause of this, conjugated free base amine is not precipitated out as crystals, but instead, remains solubilized in the equilibrium system and ultimately is removed by diffusion and permeation through the skin.” (Spec. ¶ 55.) The Specification further explains that, “[a]s the conjugated free base amine is removed by permeation through the skin, the reaction is continuously driven forward to generate more amine drug free base to maintain equilibrium.” (Id.) Appellant only demonstrates the relatively high and constant skin flux of the active drug over several days with memantine HCl and sodium bicarbonate, which has an equilibrium constant ratio of the acid amine and conjugated free amine to the carbonic acid and bicarbonate of 0.000135. Claim 1 does not recite a particular ratio. Thus, for this additional reason, the evidence is not commensurate in scope with the claim, and consequently fails to establish unexpected results. Id. Finally, Appellant’s single example with memantine HCl and sodium bicarbonate is insufficient to establish unexpected results for the full scope of the claim, which does not require any particular combination of amine salt or amphoteric inorganic base or recite the equilibrium constant ratio of the acid amine and conjugated free amine to the carbonic acid and bicarbonate Appeal 2021-001300 Application 15/660,924 11 that these two components have. One data point is insufficient “to ascertain a trend in the exemplified data which would allow [one having ordinary skill in the art] to reasonably extend the probative value thereof.” In re Kollman, 595 F.2d 48, 56 (Fed. Cir. 1979). This is true even as to the amine salts set forth in claim 3, given the discussion above regarding the importance indicated in Appellant’s Specification of the “very small” equilibrium constant ratio of amine components to base components. (See Spec. ¶ 55.) In light of the foregoing, we affirm the Examiner’s rejection of claim 1 as being obvious from Hsu. Claims 2-6, 8, 14, 16-18, 20, 21, and 24-31 have not been argued separately and therefore fall with claim 1. 37 C.F.R. § 41.37(c)(1)(iv) (2019). Obviousness of Claims over Hsu and secondary references Appellant’s argument against the Examiner’s additional rejections which rely on secondary references to address dependent limitations is that those secondary references “do not cure the deficiencies of Hsu,” i.e., the alleged failure to “show[] or suggest[] a drug reservoir of a transdermal device that comprises an amine salt form of an active agent and an amphoteric inorganic base compound, as claimed.” (Appeal Br. 11-12.) However, for the reasons discussed, we do not find Hsu to be deficient in that regard. Consequently, we affirm the Examiner’s rejection of: claims 7, 9, and 15 under 35 U.S.C. § 103 as unpatentable over Hsu and Stinchcomb; claim 10 and 11 under 35 U.S.C. § 103 as unpatentable over Hsu and Cottrell; Appeal 2021-001300 Application 15/660,924 12 claims 12 and 13 under 35 U.S.C. § 103 as unpatentable over Hsu and Song; claims 19 and 22 under 35 U.S.C. § 103 as unpatentable over Hsu and Rasmussen; and, claim 23 under 35 U.S.C. § 103 as unpatentable over Hsu and Gale. DECISION SUMMARY In summary: Claim(s) Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 1-6, 8, 14, 16-18, 20, 21, 24-31 103 Hsu 1-6, 8, 14, 16-18, 20, 21, 24-31 7, 9, 15 103 Hsu, Stinchcomb 7, 9, 15 10, 11 103 Hsu, Cottrell 10, 11 12, 13 103 Hsu, Song 12, 13 19, 22 103 Hsu, Rasmussen 19, 22 23 103 Hsu, Gale 23 Overall Outcome 1-31 TIME PERIOD FOR RESPONSE No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a). See 37 C.F.R. § 1.136(a)(1)(iv). AFFIRMED Copy with citationCopy as parenthetical citation