Ex Parte Masini-Eteve

Patent Trial and Appeal BoardAug 16, 2016

11249122 (P.T.A.B. Aug. 16, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE FIRST NAMED INVENTOR 111249,122 10/13/2005 Valerie Masini-Eteve 22428 7590 08/18/2016 Foley & Lardner LLP 3000 K STREET N.W. SUITE 600 WASHINGTON, DC 20007-5109 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 ATTORNEY DOCKET NO. CONFIRMATION NO. 088734-1121 1575 EXAMINER WESTERBERG, NISSA M ART UNIT PAPER NUMBER 1618 NOTIFICATION DATE DELIVERY MODE 08/18/2016 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 VALERIE MASINI-ETEVE1 Appeal2014-000820 Application 11/249, 122 Technology Center 1600 Before ERIC B. GRIMES, ULRIKE W. JENKS, and TIMOTHY G. MAJORS, Administrative Patent Judges. MAJORS, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. Â§ 134 involving claims to compositions of 4-hydroxy tamoxifen ("4-0HT") which have been rejected as obvious. We have jurisdiction under 35 U.S.C. Â§ 6(b). We affirm. 1 Appellant identifies the Real Party in Interest as Besins Healthcare Luxembourg SARL. (App. Br. 3.) Appeal2014-000820 Application 11/249, 122 STATEMENT OF THE CASE "The compound 4-hydroxy tamoxifen (hereinafter referred to as 4- 0 HT) ... constitutes an active metabolite of the well characterized anti- estrogen compound, tamoxifen." (Spec. i-f 3.) "The present invention provides 4-0HT-containing pharmaceutical compositions and gels" and particularly formulations "suitable for topical and transdermal application." (Id. at i-f 6.) According to the Specification, such compositions and gels are useful for, among other things, "treating and/or preventing conditions involving dense breast tissue ... [and] treating and/or preventing benign breast diseases." (Id. at i-f 55 (emphasis omitted).) Claims 1---6 and 8-17 are on appeal. 2 Claim 1 is illustrative: 1. A transdermal pharmaceutical composition formulated for topical administration comprising: 0.105 - 0.350 % of 4-hydroxy tamoxifen, 50 - 7 5 % of a [sic] least one C2-C6 alcohol, 0.1- 5.0 % of at least one gelling agent, 0.1 - 5.0 % of isopropyl myristate as a penetration enhancer, and 20 - 50 % of an aqueous vehicle, wherein percentages (%) are weight to weight of the composition. (App. Br. 23 (Claims App'x).) The claims stand rejected as follows: I. Claims 1---6, 8-15, and 17 are rejected under 35 U.S.C. Â§ 103(a) over Bua (US 2004/0138314 Al, published July 15, 2004) ("Bua") 2 Claim 18 is presently withdrawn from consideration. (See Final Act. dated Oct. 22, 2012; Remarks dated Feb. 22, 2013 (and accompanying claim set).) 2 Appeal2014-000820 Application 11/249, 122 optionally further in view of Mauvais-Jarvis et al. (US 4,919,937, issued Apr. 24, 1990) ("Mauvais-Jarvis") and Masini-Eteve et al. (US 2003/0087885 Al, published May 8, 2003) ("Masini-Eteve"). II. Claim 12 is rejected under 35 U.S.C. Â§ 103(a) over Bua, optionally further in view of Mauvais-Jarvis and Masini-Eteve, and further in view of Azamoff et al. (US 2003/0175329 Al, published Sept. 18, 2003) ("Azamoff'). III. Claim 16 is rejected under 35 U.S.C. Â§ 103(a) over Bua, optionally further in view of Mauvais-Jarvis and Masini-Eteve, and further in view of Walters et al. (US 2003/0150876 Al, published Aug. 14, 2003) ("Walters"). IV. Claims 1-6, 8, 9, 12-15, and 17 are rejected under 35 U.S.C. Â§ 103(a) over Mauvais-Jarvis in view of Masini-Eteve. V. Claims 10 and 11 are rejected under 35 U.S.C. Â§ 103(a) over Mauvais-Jarvis and Masini-Eteve, and further in view of Azamoff. VI. Claim 16 is rejected under 35 U.S.C. Â§ 103(a) over Mauvais- Jarvis and Masini-Eteve, and further in view of Walters. With respect to Rejection I and Rejection IV, the Examiner includes claim 7 within the range of claims being rejected. (Id. at 2, 6.) This appears to be incorrect as claim 7 was canceled earlier in prosecution. (See Sept. 7, 2012 Response to Office Action.) REJECTION I Issue The patentability of the pending claims hinges on (i) whether it would have been prima facie obvious through routine optimization to modify the 4- 3 Appeal2014-000820 Application 11/249, 122 OHT concentration in formulations taught or suggested in the prior art; and (ii), if so, whether Appellant's evidence (e.g., of alleged unexpected results) is sufficiently persuasive to outweigh the evidence supporting the Examiner's prima facie case. The Examiner rejected claims 1---6, 8-15, and 17, concluding that those claims would have been obvious over Bua, in further view of Mauvais- J arvis and Masini-Eteve. 3 The Examiner finds that Bua teaches a formulation containing 4-0HT along with the other ingredients (C2---C6 alcohol, isopropyl myristate, etc.) in overlapping ranges/concentrations as recited in claim 1, for example. The Examiner finds that Bua discloses "about 0.001 g- about 1.0 g or about 0.01 to about 0.1 g of [ 4-0HT] in 100 g of gel (about 0.001 %- about 1.0%, about 0.01 % to about 0.1 %, i-f [0046])." (Ans. 2, 11-12.) The Examiner finds that "the amount of 4- 0HT in the gel formulation is a results effective parameter that a person of ordinary skill in the art would routinely optimize" and further that "[i]t would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient to add in order to best achieve the desired results, such as the 0.15% [ 4-0HT] concentration disclosed by Mauvais- Jarvis." (Id. at 4.) Also, according to the Examiner: ranges of these claims lie within the broad range disclosed by Bua and the person of ordinary skill in the art would routinely optimize the amount of the active ingredient depending on the particular condition being treated and dosing frequency, for 3 The Examiner indicates that the teachings of Mauvais-Jarvis and Masini- Eteve are "optionally" combined with Bua. (Ans. 2.) On appeal and in order to consolidate issues where appropriate, we address the rejection based on the combination of Bua, Mauvais-Jarvis, and Masini-Eteve. 4 Appeal2014-000820 Application 11/249, 122 example, with higher concentrations possibly resulting in greater therapeutic effect and/ or less frequent dosing. (Id. at 11-12.) Appellant contends "the Â§ 103 rejections rely on an improper hindsight selection of the recited amounts of 4-0HT from broad disclosures in Bua and/or Mauvais-Jarvis, but the cited references fail to provide any teachings, suggestions or guidance that would have led the skilled artisan to a composition as claimed." (App. Br. 11.) More specifically, Appellant argues "routine optimization" does not apply because the amount of 4-0HT disclosed in Bua is a "broad range [about 0.001 to about 1.0%] ... that spans three orders of magnitude" relative to "the claimed amounts of 4-0HT (0.105 - 0.350%)." (Id. at 12.) Plus, Appellant contends, "other teachings in Bua, such as its narrower, preferred range and specific examples that are outside of the claimed range, would have led the skilled artisan away from compositions with an amount of 4-0HT as recited in the claims." (Id.) Finally, Appellant argues the "rejections are improper because the invention identifies and solves a problem that was not even recognized in the art, and the claimed compositions achieve unexpected results." (Id. at 11-12.) Findings of Fact FF 1. The Examiner's findings of fact and statement of the rejection of claims 1---6, 8-15, and 17 under 35 U.S.C. Â§ 103(a) over Bua, Mauvais- Jarvis, and Masini-Eteve may be found at pages 2-6 and 10-13 of the Examiner's Answer dated August 23, 2013. (See also, Final Act. dated Oct. 5 Appeal2014-000820 Application 11/249, 122 22, 2012 at 4--9.)4 We adopt those findings unless otherwise stated, and provide below certain illustrative disclosures of the prior art. FF 2. Bua teaches "treatment [that] comprises administering 4- hydroxytamoxifen percutaneously to a patient having dense breast tissue." (Bua Abstract.) According to Bua "[t]he concentration of [ 4-0HT] in these formulations may vary, but a dose should result in local [ 4-0HT] concentrations that effectively oppose estrogenic driven effects." (Id. at i-f 15.) Bua discloses "preferred formulations contain [ 4-0 HT] in a hydroalcoholic gel. The amount of [ 4-0HT] per 100 grams of gel may range from about 0.001 gram to about 1.0 gram. Preferably, it ranges from about 0.01 gram to about 0.1 gram." (Id. at i-f 46.) Bua further describes "two highly preferred [ 4-0HT] gel formulations" that include 0.02 g (20 mg) and 0.057 g (57 mg) of 4-0HT per 100 g of gel, as well as various other ingredients such as isopropyl myristate (as a penetration enhancer), hydroxypropylcellulose, and a phosphate buffer. (Id., see also i-f 44.) Hydroxypropylcellulose is a gelling agent. (Spec. i-f 12.) FF 3. Mauvais-Jarvis teaches percutaneous administration of 4-0HT "for the treatment of breast affections [sic, afflictions], particularly benign cancerous affections [sic] of the breast." (Mauvais-Jarvis Abstract.) Mauvais-Jarvis further teaches a formulation of a hydroalcoholic gel that includes 0.15 g of 4-hydroxytamoxifen per 100 g of gel (0.15% by weight), along with other ingredients such as progesterone, CarbopolÂ® 934, and triethanolamine. (Id. at col. 3, 11. 29--42.) 4 We also adopt the Examiner's findings for Rejections II-III (adding the Azamoff and Walters references respectively). (Ans. 5---6, 8-10.) 6 Appeal2014-000820 Application 11/249, 122 FF 4. Masini-Eteve discloses pharmaceutical hydroalcoholic gel compositions for transdermal application. (See, e.g., Masini-Eteve i-fi-122, 25, 31, 32.) Masini-Eteve teaches the gel may contain dihydrotestosterone and isopropyl myristate as a preferred penetration enhancer, along with other ingredients such as a gelling agent (e.g., CarbopolÂ® 980) and triethanolamine as a base. (Id. at i-fi-1 22, 31, 50, 51.) Analysis Claim 1 The concentration range of 4-0HT in claim 1is0.105---0.350%. As discussed above, the Examiner determined that a composition having a concentration within that range would have been prima facie obvious through routine optimization in view of Bua's teaching of a 4-0HT concentration of about 0.001-1 %, preferably about 0.01---0.1 %, and the teaching in Mauvais-Jarvis of a 4-0HT concentration of0.15%. We agree with the Examiner. A prima facie case of obviousness typically exists when claimed ranges overlap with ranges disclosed in the prior art. In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003) ("In cases involving overlapping ranges, we and our predecessor court have consistently held that even a slight overlap in range establishes a prima facie case of obviousness."). The prior art range in Bua "completely encompass[ es]" the 4-0HT concentration range recited in claim 1- meaning the "conclusion [of obviousness] is even more compelling than in cases of mere overlap." Id. at 1330. (FF 2.) Moreover, the Examiner finds that the concentration of 4-0HT in Bua is a results-effective variable, and Appellant does not persuasively show 7 Appeal2014-000820 Application 11/249, 122 otherwise. We thus agree with the Examiner that the skilled artisan would reasonably be expected to modify and optimize the concentration of 4-0HT within the ranges taught in Bua. In re Boesch, 617 F .2d 272, 27 6 (CCP A 1980) ("[D]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art."). As the Examiner correctly points out, the skilled artisan would routinely optimize the concentration of the active drug to improve therapeutic effect and patient compliance (e.g., less frequent dosing). (Ans. 11-12; Final Act. 6.) Bua also teaches that "the initial dose [of 4-0HT] may be optimized in each patient, depending on individual responses." (Bua ,-r 38.) Here, for example, it would have been routine for the person of ordinary skill in the art to increase the 4-0HT concentrations in Bua's examples and so decrease the dosing frequency. Instead of the patient receiving a dose of 1-2 mg/day of the 0.057% concentration in two or four metered doses respectively (Bua ,-r 66, Table 5), it would have been obvious to the skilled artisan to instead administer a single daily dose at 4-0HT concentrations of 0.114% or 0.228% (2--4 times the concentration in Bua), concentrations within the 0.105---0.350% range of claim 1. Appellant counters that the range recited in Bua is too broad compared to the "relatively narrow" concentration range in claim 1 (and other claims) to support the Examiner's obviousness rationale. (Reply Br. 3--4.) Appellant describes the claimed range as a species within a much broader genus disclosed in the prior art, and further points out that Bua's range "spans three orders of magnitude" compared to the claimed range. (App. Br. 10-12.) 8 Appeal2014-000820 Application 11/249, 122 We are not persuaded that the prior-art range of Bua is so large, encompassing so many possibilities, that the Examiner erred in concluding that claim 1 is prima facie obvious. On this point, In re Peterson is instructive. In that case, like here, the patent applicant argued that "a skilled artisan would not have assumed from [the prior art] that using the claimed amounts" would provide the improvements of the invention "because [the prior art] defines very broad ranges." In re Peterson, 315 F.3d at 1328. Nevertheless, the Federal Circuit affirmed the Board's determination that the claims were prima facie obvious. Id. at 1330. Here, Appellant focuses on the broadest range disclosed by Bua (about 0.001 to 1 %) rather than Bua's preferred range of about 0.01 to 0.1 %, where the upper limit of Bua's preferred range differs from the lower end of the claimed range by only 0.005%. We agree with the Examiner that Bua would have made obvious a composition comprising a 4-0HT concentration encompassed by claim 1, particularly in view of its disclosure that preferred 4-0HT concentrations are "about" 0.01---0.1 %. (FF 2.) Appellant's argument that 4-0HT concentrations in certain embodiments of Bua, having concentrations below the ranges claimed, would have "led the skilled artisan away" from the claimed compositions is also unpersuasive. (App. Br. 12.) Bua's teaching is not limited to the example formulations having 4-0HT concentrations of 0.02% and 0.057%, which are cited by Appellant. Merck & Co., Inc. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989) ("[I]n a section 103 inquiry, the fact that a specific [embodiment] is taught to be preferred is not controlling, since all disclosures of the prior art, including unpreferred embodiments, must be 9 Appeal2014-000820 Application 11/249, 122 considered.") (Internal quotation marks omitted). To the contrary, Bua expressly teaches the "amount of [ 4-0HT] per 100 grams of gel may range from about 0.001 to about 1.0 gram" and "[p ]referably" may be "about 0.1 gram," which abuts the range recited in claim 1. (FF 2.) Mauvais-Jarvis further supports the rejection- leading the skilled artisan toward the claimed subject matter - by teaching 0.15% 4-0HT, which is within the range of claim 1. (FF 3.) On this record, Appellant has not persuasively shown that Bua would have led the skilled artisan away from a formulation with a 4-0HT concentration within the scope of the claims. In re Peterson, 315 F.3d at 1332 (rejecting teaching away argument because "[w]hile [the prior art] mentions a preferred alloy that does not contain rhenium, it does not disparage or otherwise discourage the use of alloys containing rhenium. ")5 Appellant also argues the "skilled artisan practicing Bua would have been wary of using a concentration double that of the highest end of Bua's preferred range, or four times to ten times the amounts exemplified in Bua" 5 Appellant also argues "routine optimization" does not apply, citing Ex Parte Whalen II. (Reply Br. 5.) But Whalen II is distinguishable for at least the reason that the Board found "the prior art teaches away from the claimed solution." Ex Parte Whalen II, No. 2007-4423, 2008 WL 2957928, at *9 (BP AI July 23, 2008). The claims in that case related to embolic compositions having "a viscosity of at least about 150 cSt." Id. at *2. Among other things, the Board held that "the [prior art] references teach that low viscosity is a desirable characteristic for embolic compositions" and that prior art compositions with viscosities approaching the claimed amount failed to work appropriately. Id. at *8 (discussing a prior art composition with a viscosity of 145 cSt that was injected into the vascular site only with significant difficulty). 10 Appeal2014-000820 Application 11/249, 122 based on concerns about "avoiding systemic effects and minimizing side effects." (Reply Br. 6.) Yet, as discussed above, Bua discloses a broader range of from 0.001-1%of4-0HT- completely encompassing the claimed ranges -that is suitable for use. (FF 2.) Appellant does not persuasively identify any actual side effects or systemic problems that arose at higher concentrations of the 4-0HT gel in Bua that would have steered the skilled artisan away. Instead, portions of Bua cited by Appellant indicate that systemic and side effects of administering the percutaneous 4-0HT gel formulations did not pose significant problems, including at daily doses of 0.5, 1, and 2 mg. (Bua i-fi-163, 75.) In any event, that a skilled artisan might proceed with care and awareness of potential side effects when increasing 4- 0 HT concentrations does not mean the skilled artisan would forego proceeding at all. For these reasons, we conclude the Examiner established a prima facie case that claim 1 would have been obvious over Bua, in view of Mauvais- J arvis and Masini-Eteve. Claims 2---6, 8-15, and 17 Appellant argues the patentability of these claims because claims 2 and 3 recite narrower 4-0HT ranges than claim 1. In particular, claim 2 includes the range 0.205---0.350% and claim 3 includes the range 0.220- 0.350%. Appellant repeats the arguments concerning claim 1, but notes also that the 4-0HT concentration in Mauvais-Jarvis (0.15%) lies outside the ranges of claims 2 and 3. (App. Br. 14; Reply Br. 4.) For reasons similar to those discussed above, Appellant's arguments are unpersuasive. Bua's range still encompasses the 4-0HT ranges recited 11 Appeal2014-000820 Application 11/249, 122 in claims 2 and 3, and we do not agree that Bua's examples teach away from increasing the concentrations as a matter of routine optimization of a results- eff ective variable. That, plus the Examiner's citation to potential for increased therapeutic effect at lower dosing frequencies when increased concentrations are used (Ans. 11-12) provides reasoning sufficient to support the conclusion that claims 2 and 3 would have been prima facie obvious. We further conclude that the Examiner established a prima facie case that claims 4---6, 8-15, and 17 would have been obvious as these claims are not separately argued, except insofar as they depend (directly or indirectly) from claim 2. Secondary Considerations We tum next to Appellant's attempt to rebut the Examiner's prima facie case with "secondary considerations of non-obviousness." (App. Br. 13, 16-21.) Appellant contends the claims are nonobvious for two reasons. First, according to Appellant, "the claimed compositions address a problem that was not recognized in the prior art." (Id. at 16.) Second, Appellant argues that compositions "having an amount of 4-0HT as recited in the claims, exhibit unexpected results with regard to reduced absorption variability." (Id. at 17.) We address these arguments below. Appellant argues the invention recognizes and addresses a "variability" problem related to administration of topical 4-0HT gel compositions. (App. Br. 16.) Appellant contends "the inventors surprisingly and unexpectedly determined that the amount of drug absorbed from transdermal 4-0HT hydroalcoholic gel compositions ... depends on how much product is applied to a given surface area." (Id.) Because of this, 12 Appeal2014-000820 Application 11/249, 122 Appellant contends, patients applying the same amount of a composition may absorb different amounts of 4-0HT due to differences in breast sizes. (Id.) According to Appellant, "[t]his problem can be clinically significant, because it makes it difficult to ensure that a given patient is absorbing an appropriate amount of 4-0HT." (Id.) And, Appellant's argument goes, "without the teachings provided in the specification, the skilled artisan would have had no reason to formulate compositions having the recited amounts of 4-0HT." (Id. at 17.) Appellant's "unrecognized problem" argument is not persuasive. As an initial matter, we are not persuaded that the skilled artisan would have been unaware that absorption of the active ingredient 4-0HT would vary depending on how much is applied to a given surface area. Bua, for example, teaches that "[t]he effectiveness of percutaneous drug administration depends on many factors, including drug concentration [and] surface area of application" among others, and that "those in the pharmaceutical field can manipulate the various factors and methods to achieve efficacious percutaneous delivery." (Bua i-fi-1 42--43.) It is true, however, that the cited art does not discuss the precise effect that 4-0HT concentration and surface area of administration have on absorption in the same manner as Appellant's Specification. But even assuming Appellant was the first to describe the extent of variability in absorption when different concentrations of otherwise known or obvious 4- 0HT compositions are applied to different surface areas, we are not persuaded the Examiner's prima facie case has been overcome. In re Baxter Travenol Labs., 952 F.2d 388, 392 (Fed. Cir. 1991) ("Mere recognition of 13 Appeal2014-000820 Application 11/249, 122 latent properties in the prior art does not render nonobvious an otherwise known invention.") Indeed, separate and apart from Appellant's disclosure, there is adequate reason to conclude that the skilled artisan would have optimized the 4-0HT concentrations within the range disclosed in Bua. As discussed above, we agree with the Examiner that the skilled artisan would have predictably increased the 4-0HT concentrations from Bua's examples in order to decrease dosing frequency. Also, contrary to Appellant's argument, it is not necessary that the skilled artisan optimize the formulation for the same reasons set forth in the Specification. KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398, 419 (2007) ("In determining whether the subject matter of a patent claim is obvious, neither the particular motivation nor the avowed purpose of the patentee controls. What matters is the objective reach of the claim.") If optimization for conventional reasons (e.g., improving therapeutic effect and decreasing dosing frequency) would have led to the compositions within the scope of the claims, the compositions would be no less obvious. Appellant cites the 2010 KSR Guidelines Update, and particularly its discussion of In re Omeprazole Patent Litigation, 536 F.3d 1361 (Fed. Cir. 2008), from which Appellant contends "an invention that might otherwise appear obvious can be non-obvious when the invention addresses 'a previously unknown problem."' (App. Br. 16 (citations omitted).) Although a patent applicant's solution to an unknown problem is a factor entitled to due consideration, Appellant's evidence does not persuade us that the claims are nonobvious for the reasons discussed above. Moreover, we disagree that the issues in this appeal are analogous to In re Omeprazole. In that case, the 14 Appeal2014-000820 Application 11/249, 122 Federal Circuit affirmed a district court's determination (following a bench trial) that the patent challenger did not establish by "clear and convincing evidence that a person of skill in the art would have appreciated the need to include a subcoating" to a particular drug formulation disclosed in the prior art. Id. at 1380. The district court had further found that, even if the skilled person had recognized the problem the patent owner solved (i.e., the negative interaction between the drug core and the enteric coating causing the drug to degrade), the skilled person would have pursued other solutions and not the one claimed by the patent owner. (Id. at 1380-81.) The record in the present appeal is quite different, involving routine optimization of the active ingredient's concentration within a range disclosed in a single prior art reference. And, based on conventional reasons cited in the record (e.g., to decrease dosing frequency), the skilled person would have predictably arrived at a composition with the 4-0HT concentrations claimed. Appellant's "unexpected results" argument also points to the property of absorption variability. More specifically, Appellant argues that, when 4- 0HT concentrations of 0.114% and 0.228% that are within the scope of the claims are used, there is "reduced variability" compared to the variability seen when compositions having a 4-0HT concentration of 0.057% are used. (App. Br. 18.) To illustrate this "reduced variability," Appellant cites in vitro testing in Example 2 of the Specification and a document identified as "Statistical Analysis of Data Presented in U.S. 11/249,122" (hereafter "Statistical Analysis"). (Id. at 17-20.) Appellant contends the in vitro testing shows, for example, "four times as much of the 0.057% composition (outside the claimed range) results in about 23.5 times as much 4-0HT being 15 Appeal2014-000820 Application 11/249, 122 absorbed" compared to "only 17.7 times as much 4[-]0HT being absorbed" when four times as much of the 0.114% composition is applied. (Id. at 18.) Moreover, Appellant contends that when the same absolute amount of 4- 0HT is applied (e.g., 20ÂµL of0.057%, lOÂµL of0.114%, and 5ÂµL of 0.228% ), the absorption of the 0.114% and 0.228% is "similar" at "34.105 ng vs. 20.300 ng," yet "twice" to "more than three times as much" of the 0.057% composition is absorbed at "74.312 ng." (Id. at 19 (incl. graph).) Citing the "Statistical Analysis," Appellant states "the analysis 'determined with 95% confidence' that absorption of the 0.057 % 4-0HT composition 'varied non-linearly with the volume of gel applied,' while absorption of compositions within the scope of the claims 'did not show much [sic] non- linear variability."' (Reply Br. 7 .) Appellant argues the reduced variability with compositions having 4-0HT concentrations within the scope of the claims "offer significant advantages in the clinical context" and "lends more predictability to dosing decisions." (Id. at 8; App. Br. 20.) The Examiner determined that Appellant's argument and evidence of unexpected results is not sufficiently persuasive to overcome the prima facie case. The Examiner graphically represents the values from Example 2 in the Specification (Ans. 15; Final Act. 7-8) and finds, for example, that "[t]aking into account the standard deviations associated with these values and the variability between the 114-20 and 228-10 compositions that both lie with[ in] the scope of the instant claims, the data show that the differences are a matter of degree rather than kind." (Ans. 15.) Moreover, the Examiner finds that "[ w ]ithout data for a concentration above the claimed range, the criticality of the claimed range cannot be determined." (Id.) The Examiner 16 Appeal2014-000820 Application 11/249, 122 further finds that Appellant did not provide sufficiently persuasive evidence to support other contentions about the alleged unexpected results: "[ w ]hile Appellant[] state[ s] that this [reduced variability] results in a significant advantage in the clinical context, no data to support this statement are of record" (id. at 15-16); "[t]he statements regarding the effect or lack of effect of various alcohols, gelling agents was not presented in a declaration or other forms of evidence" (Final Act. 8). Based on the record before us and the strength of the prima facie case, we agree with the Examiner. Pfizer Inc. v. Apotex Inc., 480 F.3d 1348, 1372 (Fed. Cir. 2007) ("[W]e hold that even if Pfizer showed that amlodipine besylate exhibits unexpectedly superior results, this secondary consideration does not overcome the strong showing of obviousness in this case. Although secondary considerations must be taken into account, they do not necessarily control the obviousness conclusion.") We have considered Appellant's data from Example 2, but like the Examiner, we find that it reflects a difference in degree (extent of absorption variability) not kind and thus is less persuasive in showing unexpected results. Bristol-Myers Squibb Co. v. Teva Pharms. USA, Inc., 752 F.3d 967, 977 (Fed. Cir. 2014). At best, Appellant's evidence and argument show that when 4-0HT concentrations of 0.057% are used, there is a degree of non- linear variability in absorption and, at concentrations of 0.114% and 0.228%, there is less non-linear variability. Yet a substantial degree of variability still exists across all concentrations. (See, e.g., Final Act. 7-8 (graphs).) Moreover, Appellant has not provided sufficiently persuasive evidence to demonstrate the practical and clinical significance of, for example, the 23 .5x 17 Appeal2014-000820 Application 11/249, 122 absorption variability seen when 4 times the amount of 0.057% is applied compared to the 17.7 x absorption variability seen with the 0 .114 % formulation. So too, the data does not consistently show reduced absorption variability at 4-0HT concentrations within the scope of the claims. For example, the Examiner points to "the variability between the 114-20 [20 ÂµL of 0.114%] and 228-10 [10 ÂµL of 0.228%] compositions that both lie within the scope of the claims," which exhibited average absorption of 185. 592 ng versus 56.048 ng respectively-more than three times as much 4-0HT being absorbed at the 0.114% concentration compared to the 0.228% concentration. (Ans. 15; Spec. i-f 110.) Appellant, citing a different subset of data, argues that a 2x and 3x difference in absorption when the same absolute amount of 4-0HT is applied unexpectedly and surprisingly distinguishes the claimed compositions from the prior art. (App. Br. 19-20.) Appellant states that "applying the same absolute amount of 4-0HT by applying equivalent doses of two compositions [10 ÂµL of0.114% and 5 ÂµL of 0.228%] within the scope of the claims ... results in a similar amount of 4-0HT being absorbed." (App. Br. 19.) Yet, according to Appellant, when the same absolute amount of the 0.057% (20 ÂµL) formulation that is outside the claimed range is applied, "twice" to "more than three times as much" 4- OHT is absorbed. (App. Br. 19.) From this, Appellant argues: That a patient could effectively experience double or triple the amount of drug from a composition outside the scope of the claims as compared with the same absolute dose of a composition within the scope of the claims certainly makes the claimed compositions surprisingly and unexpectedly 18 Appeal2014-000820 Application 11/249, 122 advantageous with regard to improved reproducibility and reduced variability. (App. Br. 20.) But, as the data cited by the Examiner makes clear, the same 3x absorption variability is seen even among compositions with concentrations that are claimed. (Ans. 15; Spec. i-f 110.) Appellant's argument and evidence is also unpersuasive because it does not show unexpected results commensurate in scope with the claims, nor does it demonstrate the criticality of the particular 4-0HT concentration range that is claimed. In re Peterson, 315 F.3d at 1330-31 ("[T]he applicant's showing of unexpected results must be commensurate in scope with the claimed range. . . . Although those data [showing results for 1 % and 2% rhenium] show that alloy strength improved with the addition of rhenium, they do not evidence unexpected results for the entire claimed range of about 1-3% rhenium.") The upper limit of 4-0HT concentration in all the claims is 0.350%. Appellant, however, does not provide data for concentrations above 0.228%. Nor does Appellant provide data for concentrations above 0.350% such that "the criticality of the claimed range cannot be determined." (Ans. 15.) Without this evidence, and given the closeness of the prior art and the strength of the prima facie case, we are not persuaded that the claimed compositions would have been nonobvious. Conclusion of Law We conclude the Examiner established by a preponderance of the evidence that claims 1---6, 8-15, and 17 would have been obvious over Bua, in view of Mauvais-Jarvis and Masini-Eteve. Appellant's argument and 19 Appeal2014-000820 Application 11/249, 122 evidence of secondary considerations is not sufficiently persuasive to overcome the Examiner's prima facie case. REJECTIONS II & III The Examiner rejected claim 12 over Bua, Mauvais-Jarvis, and Masini-Eteve, in further view of Azamoff (Rejection II). The Examiner rejected claim 16 over Bua, Mauvais-Jarvis, and Masini-Eteve, in further view of Walters (Rejection III). Appellant does not separately argue Rejections II and III, and instead agrees those rejections stand or fall with Rejection I. (App. Br. 11; Reply Br. 2.) So, having affirmed Rejection I, we also affirm Rejections II and III. 20 Appeal2014-000820 Application 11/249, 122 Issue REJECTION IV The Examiner rejected claims 1---6, 8, 9, 12-15, and 17 over Mauvais- Jarvis in view of Masini-Eteve. The issues with respect to this rejection are similar to those discussed above, except the Examiner is not relying on Bua and, instead, relies on Mauvais-Jarvis alone with respect to the concentration of 4-0HT, which in Mauvais-Jarvis is 0.15%. Here again, we decide on appeal whether the Examiner established a prima facie case of obviousness and, if so, whether secondary considerations (the same as discussed above) overcome the prima facie case. Findings of Fact FF 5. The Examiner's findings of fact and statement of the rejection of claims 1---6, 8, 9, 12-15, and 17 under 35 U.S.C. Â§ 103(a) overMauvais- Jarvis and Masini-Eteve may be found at pages 6-8 and 13 of the Examiner's Answer dated August 23, 2013. (See also, Final Act. dated Oct. 22, 2012 at 4--9.) We adopt those findings unless otherwise stated, and further incorporate by reference Findings of Fact 3 and 4 above. Analysis The Examiner finds that Mauvais-Jarvis discloses a composition having a 4-0HT concentration of 0.15% along with the other elements of claim 1 except "the inclusion of isopropyl myristate" as a penetration enhancer. (Ans. 7.) The Examiner concludes that it would have been obvious to include isopropyl myristate "because Masini-Eteve et al. discloses that the inclusion of an ingredient such as isopropyl myristate promotes diffusion of the active ingredient through the skin." (Id.) 21 Appeal2014-000820 Application 11/249, 122 As to claim 1, Appellant does not contest that Mauvais-Jarvis and Masini-Eteve disclose a composition within the scope of the claim and, instead, Appellant "primarily relies on the secondary considerations of non- obviousness." (App. Br. 13.) The Examiner has the better position. We are not persuaded that Appellant's evidence of secondary considerations overcomes the Examiner's prima facie case for the reasons discussed above. Moreover, we note that Appellant does not provide evidence of unexpected results compared to the 4-0HT formulation disclosed in Mauvais-Jarvis. In re Baxter Travenol Labs., 952 F.2d at 392 ("[W]hen unexpected results are used as evidence of nonobviousness, the results must be shown to be unexpected compared with the closest prior art."). We thus affirm the rejection as to claim 1. As to claims 2---6, 8, 9, 12-15, and 17, however, we reach a different result. In the absence of Bua' s teachings, we are not persuaded these narrower claims would have been prima facie obvious over Mauvais-Jarvis, which "discloses a single composition comprising 4-0HT and progesterone, which includes 0.15% by weight 4-0HT" that is outside the claimed ranges. (App. Br. 14.) Masini-Eteve does not mention 4-0HT, much less any particular concentration. We thus reverse the rejection of claims 2---6, 8, 9, 12-15, and 17 over Mauvais-Jarvis and Masini-Eteve. Conclusion of Law We conclude the Examiner established by a preponderance of the evidence that claim 1 would have been obvious over Mauvais-Jarvis and Masini-Eteve. We conclude that a preponderance of the evidence does not, 22 Appeal2014-000820 Application 11/249, 122 however, show that claims 2---6, 8, 9, 12-15, and 17 would have been obvious over Mauvais-Jarvis and Masini-Eteve. REJECTIONS V & VI The Examiner rejected claims 10 and 11 over Mauvais-Jarvis and Masini-Eteve, in further view of Azamoff (Rejection V). The Examiner rejected claim 16 over Mauvais-Jarvis and Masini-Eteve, in further view of Walters (Rejection VI). Appellant does not separately argue Rejections V and VI, and instead agrees those rejections stand or fall with Rejection IV. (App. Br. 11; Reply Br. 2.) Because claims 10, 11, and 16 depend directly or indirectly from claim 2, and because we reverse Rejection IV as to claim 2, we also reverse Rejections V and VI. SUMMARY We affirm the rejection of claims 1-6 and 8-17. 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. Â§ 1.136(a). AFFIRMED 23