Ex Parte Klein et alDownload PDFPatent Trial and Appeal BoardJun 7, 201712469801 (P.T.A.B. Jun. 7, 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. 12/469,801 05/21/2009 Bjarke Mimer Klein 10192.0025-00 2599 22852 7590 06/09/2017 FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER LLP 901 NEW YORK AVENUE, NW WASHINGTON, DC 20001-4413 EXAMINER CHERNYSHEV, OLGA N ART UNIT PAPER NUMBER 1649 NOTIFICATION DATE DELIVERY MODE 06/09/2017 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): regional-desk @ finnegan. com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte BJARKE MIMER KLEIN, JENS PETER NORGAARD, and BRAD SHUMEL1 Appeal 2015-005196 Application 12/469,801 Technology Center 1600 Before JOHN G. NEW, CHRISTOPHER G. PAULRAJ, and KRISTI L. R. SAWERT, Administrative Patent Judges. NEW, Administrative Patent Judge. 1 Appellants state the real party-in-interest is Ferring B.V. App. Br. 1. Appeal 2015-005196 Application 12/469,801 DECISION ON APPEAL Appellants file this appeal under 35 U.S.C. § 134(a) from the Examiner’s Final Rejection of claims 40-46, 73—79, 83, 103—109, 113—123, 127, 128, and 141—149 as unpatentable under 35 U.S.C. § 103(a) over the combination of Larsson et al. (US 5,985,835, November 16, 1999) (“Larsson”) and Nilsson et al. (US 7,560,429 B2, July 14, 2009) (“Nilsson”). We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM-IN-PART. NATURE OF THE CLAIMED INVENTION Appellants’ invention is directed to gender, age, and dose effects of desmopressin on reducing nocturnal voids, increasing an initial period of undisturbed sleep, and/or reducing nocturnal urine volume. Abstract. REPRESENTATIVE CLAIM Claim 40 is representative of the claims on appeal and recites: 40. A method for reducing nocturnal urine volume in a female patient in need thereof comprising: administering to the female patient prior to bedtime an orodispersible dose of desmopressin of 10 pg or 25 jig, wherein the dose is measured as the free base of desmopressin, the dose taken over a treatment period reduces the female patient’s nocturnal urine volume as compared to without administration of desmopressin, and the dose taken over the treatment period reduces the female patient’s nocturnal urine volume as compared to a male patient administered the orodispersible dose of desmopressin of 10 pg or 25 pg over the treatment period. App. Br. 31. 2 Appeal 2015-005196 Application 12/469,801 ISSUES AND ANALYSES For those claims for which we affirm the Examiner’s rejection (claims 40-46, 73—79, 83, 103—109, and 113) we adopt the Examiner’s findings and conclusion that the claims are obvious over the combined cited prior art. We address the arguments raised by Appellants below. A. Rejection of claims 40-46, 73—79, 83, 103—109, 113, and 141—149 Issue 1 Appellants argue the Examiner erred because, at the time of Appellants’ invention, differentiating doses of orodispersible desmopressin based on gender would have been neither predictable nor would have been expected to lead to successful results by a person of ordinary skill in the art. App. Br. 9. Analysis The Examiner finds Larsson teaches treatment of nocturia by administration of desmopressin for 3 months. See Non-Final Act. 4, February 8, 2013 (“Non-Final Act.”) (citing Larsson Abstr., Exs. 7, 8, Table 2, claim 1). The Examiner finds Larsson also teaches oral administration of desmopressin in the dose of 100 pg (0.1 mg) in Example 8. Id. at 4—5. The Example further finds that, in Example 7, Larsson specifically discloses higher sensitivity of women patients given the same dose of desmopressin compared to men. Id. at 5 (citing Larsson col. 5). The Examiner finds Larsson does not teach treatment by administration of orodispersible dose of desmopressin of 10, 25 or 100 pg. Id. 3 Appeal 2015-005196 Application 12/469,801 The Examiner finds Nilsson teaches treatment of nocturia by administration of orodispersible dosages of desmopressin in the range of 0.5 pg to 1 mg, preferably 0.5 pg to 50 pg (column 2) and specifically 25 pg, 50 pg, 75 pg and 200 pg. Non-Final Act. 5 (citing Nilsson col. 17). The Examiner concludes that, at the time of invention, it would have been obvious to a person of ordinary skill in the art to treat a patient in need of reducing nocturnal urine volume by administration of orodispersible dosages of desmopressin of 10, 25 or 100 pg as taught by the combined cited prior art references. Non-Final Act. 5. The Examiner finds that an ordinary artisan would have been motivated to do so because the combined references expressly teach these doses and the effect it produces. The Examiner further finds that a person of ordinary skill in the art would reasonably expect male and female patients to respond differently to the same dosage administrated, as taught by Larsson. Id. (citing Larsson Ex. 7). Appellants respond that, at the time of Appellants’ filing, it would not have been predictable that female patients would respond to 10 pg and 25 pg doses of desmopressin with greater sensitivity than male patients “such that the disparity rises to the level of administering of a different dose of desmopressin” to female patients compared to male patients. App. Br. 9. Appellants argue that, prior to Appellants’ filing date: “The Food and Drug Administration (“FDA”) reviewed 300 new drug applications between 1995 and 2000. Of the 163 that included a sex analysis, 11 drugs showed a > 40% difference in pharmacokinetics between males and females, which was listed on the product label, yet no dosing recommendations were made based on sex.” Id. at 10 (quoting G.D. Anderson, Sex and Racial Differences in Pharmacological Response: Where is the Evidence? Pharmacogenetics, 4 Appeal 2015-005196 Application 12/469,801 Pharmacokinetics, and Pharmacodynamics, 14(1) J. Women’s Health 19— 29 (2005) (“Anderson”)). Appellants contend that slight differences between male and female patients in response to administered drugs, similar to those observed in Larsson’s Example 7, have not been enough to suggest a difference in treatment regime based on gender as captured by the instant claims. Id. Similarly, Appellants argue, “Although gender differences in pharmacokinetics have been identified for several drugs, these differences usually do not result in changes in dosing because most drugs have a wide difference between efficacy and toxicity. For drugs with a wide therapeutic index, dose adjustment is not thought to be necessary.” Id. (quoting M. A. Miller, Gender-Based Differences in the Toxicity of Pharmaceuticals—The Food and Drug Administration’s Perspective, 20(3) Int’l J. of Toxicol. 149-152 (2001) (“Miller”)). Appellants next point to a post-filing article K.V. Juul et al., Gender Difference in Antidiuretic Response to Desmopressin, 300(5) Am. J. Physiol. FI 116—22 (2011) (“Juul”), which that states “there are no significant gender specific differences in PK [pharmacokinetic] properties of desmopressin, and that the estimates of regression coefficients suggest dose proportionality and inverse proportionality to weight.” App. Br. 10 (quoting Juul FI 118). According to Appellants, Juul teaches that, when the results of the clinical trial described in Appellants’ Specification are placed in context with other clinical trials and teachings in the art, the magnitude of the difference is apparent. Id. at 10-11. Specifically, Appellants point to Juul’s teaching that: “In this post hoc analysis, we found that the relative male/female sensitivity to antidiuretic effect of desmopressin in nocturia is 2.7, corresponding to significantly higher desmopressin sensitivity in 5 Appeal 2015-005196 Application 12/469,801 females and thus, in comparison with males, a narrower therapeutic window for avoiding hyponatremia without compromising efficacy.” Id. at 11 (quoting Juul FI 120). Appellants contend Juul teaches the gender difference captured by the claims on appeal is present independent of bodyweight. Id. Appellants argue further that Juul also teaches that the gender difference in dose response was not seen or predictable from the pharmacokinetics of male and female patients. Id. Consequently, Appellants argue, an artisan of ordinary skill could not have predicted the gender difference at the recited doses and, therefore, given this alleged unpredictability, there would not be a reasonable expectation of success such that the claimed invention would have been obvious. Id. at 11—12. Appellants therefore assert that there was an expectation in the art of similar desmopressin efficacy in men and women, which, Appellants contend, is consistent with the teachings of Larsson and Nilsson. App. Br. 12. Appellants argue that Nilsson teaches that, when male test subjects were given 200, 400, and 800 pg orodispersible dosage forms of desmopressin, “[t]he pharmacokinetics of desmopressin is linear....” Id. (citing Nilsson Ex. 7, col. 17,11. 22—24). Appellants also point to Larsson’s teaching that when 24 patients, ages 60-74 years old, were given desmopressin tablets comprising 100, 200, and 400 pg, “desmopressin gave a lower nocturnal diuresis ... compared to placebo” and “appeared to be well tolerated in the treatment of nocturnal polyuria in elderly healthy men and women.” Id. (quoting Larsson col. 9,11. 60—61, col. 10,11. 6—8). Appellants suggest that the implication in Larsson is a similar dose-response effect from 100 to 400 pg for male and female patients. Id. 6 Appeal 2015-005196 Application 12/469,801 Appellants next point to their Specification which, they argue, demonstrates that, rather than similar dose-response between male and female patients, the dose response for nocturnal urine volume reduction of female patients to an orodispersible dose of desmopressin is unexpectedly shifted to the left as compared to male patients (i.e., a lower dose corresponds to a similar response level in women when compared to men). App. Br. 12—13 (citing Specification || 172, 179, 180, 182, Fig. 4). Appellants contend that these results are different and in contrast to what would be predictable based on the prior art and is, therefore, an unpredictable gender difference. Id. at 13. We are not persuaded by Appellants’ arguments. Appellants argue that a person of ordinary skill in the art would not have predicted, based on the combined cited prior art, that nocturitic women are more sensitive to desmopressin then are nocturitic men. We disagree. Larsson teaches that, in a test involving 7 elderly men and 14 elderly women given a dosage of 40 pg desmopressin: Among the men, nocturnal diuresis had decreased by 21% from the initial value after one month and by 20% after two months (Table 2). The corresponding figures for the women were 36% and 34%. For the men an insignificant decrease was still present one month after the last day of treatment, while the women had 17% less nocturnal diuresis at the corresponding time. All the men reduced their nocturnal diuresis by less than 400 ml after both one and two months. For the women, the corresponding figures were 9 and 7 women, respectively. The reduction in the nocturnal diuresis was greatest in those who, before treatment, had a large part of their diuresis during the night. The redistribution of diuresis from night to day was more marked in women than in men. 7 Appeal 2015-005196 Application 12/469,801 The decrease in average diuresis during the night was twice as large in women as in men during the treatment (Table 2). The men’s nocturnal diuresis returned to its earlier level within one month after treatment while, among the women, half of the reduction remained one month after treatment. The effect of desmopressin was greatest among those persons who had most nocturnal diuresis. As regards the number of nocturnal micturitions, we also found that the women were affected most positively by the treatment. Larsson col. 7—8,11. 35—52. We find this data strongly indicative that a person of ordinary skill would have understood that women exhibit a greater sensitivity to desmopressin, i.e., an identical dose of 40 jig exhibits a greater reduction of nocturia in women than in men. We are also not persuaded by Appellants’ arguments with respect to Anderson. Anderson teaches: “11 drugs [of 163 tested] showed a > 40% difference in pharmacokinetics between males and females, which was listed on the product label, yet no dosing recommendations were made based on sex. Female sex has been shown to be a risk factor for clinically relevant adverse drug reactions.” Anderson Abstr. Anderson thus acknowledges, in some cases, gender-based differences in pharmacokinetics which pose a potential risk of adverse effects in women. Anderson is thus directed to drawing attention to potential risks to women based on gender-related pharmacokinetics. As such, it directly suggests that women might be more sensitive to drugs, as Larsson demonstrates in the case of desmopressin. Nor do we find Appellants’ argument with respect to Miller any more persuasive. Miller is directed to the issue of gender-based toxicity in drugs rather than gender-based effective dosage sensitivity. 8 Appeal 2015-005196 Application 12/469,801 A major concern of the FDA OWH research program has been to determine why women experience more adverse events than men do. Reporting bias does not seem to be a major factor in explaining why women experience more adverse events than men do. Pharmacokinetic differences exist between men and women and can influence dosing for drugs with a narrow therapeutic index. Miller 152. Nevertheless, Miller teaches that women might suffer adverse effects of drugs at a greater rate for the same dosage as men. This also directly suggests a greater dose sensitivity in women to some drugs, such as is taught for desmopressin by Larsson. Nor do we find the teachings of Juul persuasive. As an initial matter, Appellants admit Juul was published subsequent to Appellants’ filing date: it cannot therefore serve as prior art. Moreover, the teachings of Juul reciting “we found that the relative male/female sensitivity to antidiuretic effect of desmopressin in nocturia is 2.7, corresponding to significantly higher desmopressin sensitivity in females,” directly confirms the findings of Larsson demonstrating that women are more sensitive than men to the same dosage of desmopressin. Juul FI 120. Furthermore, JuuFs teaching that the gender difference in dose response was not seen or predictable from the pharmacokinetics of male and female patients is not persuasive, because Larsson is directed to sensitivity and not to pharmacokinetics. In summary, we are not persuaded by Appellants’ argument that, due to the alleged unpredictability of the art, a person of ordinary skill would not have reasonably understood from the teachings of Larsson that women are likely to be more sensitive than men to an equal dosage of desmopressin. 9 Appeal 2015-005196 Application 12/469,801 Issue 2 Appellants next argue the Examiner erred because Example 7 of Larsson does not teach or suggest a gender difference in efficacy. App. Br. 14. Analysis Appellants argue that, contrary to the Examiner’s findings, Example 7 of Larsson does not disclose, either explicitly or inherently, a gender difference in efficacy of desmopressin or greater effectiveness in females as compared to males. App. Br. 14. According to Appellants, the Examiner’s allegedly erroneous interpretation of Larsson’s Example 7 is the linchpin of its obviousness rejection. Id. However, Appellants argue, rather than demonstrating efficacy, Example 7 simply discloses changes in nocturnal diuresis without a correlation to efficacy or a meaningful way to compare the changes experienced by the male patients to the changes experienced by the female patients. Id. Rather, Appellants argue, Example 8 of Larsson “provides efficacy and safety data for oral desmopressin.” Id. at 15 (quoting Larsson col. 9,11. 60-61). Furthermore, Appellants argue, the single dose tested in Example 7 (i.e., a 40 pg intranasal dose of desmopressin) does not teach or suggest an orodispersible dose of 10 pg or 25 pg desmopressin in women of a certain age, as recited in the claims. Id. Appellants contend that, without a control group, the importance of the changes in nocturnal diuresis of Example 7, either over the test group as a whole or as between the genders of the participants, could have several different meanings. App. Br. 15. Therefore, Appellants argue the notion of efficacy of the treatment tested in Example 7 amounts to no more than a 10 Appeal 2015-005196 Application 12/469,801 speculative, possible result, but not necessarily the only result. Id. at 16. Consequently, Appellants argue, a person of ordinary skill would not have known what scientific value Example 7’s simple comparison between the outcomes of the men and women of the study actually provides. Id. In summary, Appellants assert, there is nothing in Example 7 that supports drawing a connection from a response difference to a dose difference among men and women. Id. Appellants contend that Example 7 does not, in fact, state any reason at all for the difference in response between men and women. Id. Furthermore, Appellants argue, the Examiner has acknowledged at least one other possible reason than gender for the differences demonstrated in Example 7, viz., the difference in weight between the male and the female subjects of the study. App. Br. 16 (citing Final Act. 5) (noting that Appellants’ assertion that any difference in response between male and female participants may reasonably be attributable to the difference in weight between the male and female participants ‘“is not entirely without merit.’”). Id. Furthermore, argue Appellants, Example 7 explicitly teaches, without reference to gender, that the “reduction in nocturnal diuresis was greatest in those who, before treatment, had a large part of their diuresis during the night.” Id. at 16—17 (citing Larsson col. 8,11. 49-52, see also Fig. 1 (showing that the two month reduction in diuresis was directly proportional to pre-treatment daytime diuresis as a percent of total diuresis)). The Examiner responds that claims 40-46 recite a method for reducing nocturnal urine volume in a female patient by administering an orodispersible dose of 25 pg of desmopressin, regardless of age. Ans. 11. The Examiner finds Nilsson teaches the same procedure, i.e., administering 11 Appeal 2015-005196 Application 12/469,801 25 jig of desmopressin to ‘“a subject’” (either male or female) to treat nocturia. Id. The Examiner finds Larsson teaches data that explicitly demonstrates different responses by female and male patients to treatment by desmopressin. Id. at 12. The Examiner finds that even assuming, arguendo, that Example 7 of Larsson does not explicitly provide for gender difference in efficacy, such differences would have been inherent to that process, and the motivation for a person of ordinary skill to have considered gender difference effects of desmopressin administration is still present. Ans. 12. The Examiner finds that it is well known in the art that no drug is administered without first considering at least the gender, age, and weight of a subject under treatment. Id. The Examiner finds that Larsson demonstrates a differential response to desmopressin by female and male patients, thus making it obvious to take into account dose optimization based on gender. Id. The Examiner points out that Nilsson expressly teaches the doses that are recited within the claims, i.e., 25 pg of orodispersible desmopressin - as well as the doses within the close range to those in the claims — 50 pg, 75 pg and 200 pg. Ans. 12 (citing Nilsson col. 17). The Examiner points to claim 10 of Nilsson, which recites the treatment of nocturia in a subject by the oral administration of 25 pg of an orodispersible form of desmopressin as one of a small and finite number of alternate embodiments of the invention claimed therein. Id. at 12—13. We are not persuaded by Appellants’ arguments. Although we agree with Appellants that Example 7 of Larsson does not directly teach the efficacy of desmopressin in men and women, we find Appellants’ argument is not commensurate with, or relevant to, the scope of the claims. 12 Appeal 2015-005196 Application 12/469,801 Specifically, claim 40 recites: “the dose taken over the treatment period reduces the female patient’s nocturnal urine volume as compared to a male patient administered the orodispersible dose of desmopressin of 10 pg or 25 pg over the treatment period.” The claim, therefore, does not speak at all to the efficacy of desmopressin, which is defined as “The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions.” MediLexicon, available at: http://www.medilexicon.com/dictionary/28064 (last visited May 8, 2017). In other words, the term efficacy refers to the maximal effect of the beneficial result (i.e., the extent) independent of dosage. The language of claim 40, however, speaks only to the relative responses of males and females to given doses, viz., lOpg or 25 pg of desmopressin (“the dose ... reduces the female patient’s nocturnal urine volume as compared to a male patient”). Example 7 of Larsson teaches the following data: One month Two months Three months Diuresis-night: Men -21 -20 -6 % deviation from Women -36 -34 -17 initial value See Larsson Table 2. Larsson thus teaches that, with a nasally administered dose of 40 pg, the women in the study show a consistently and persistently greater decrease in night-time diuresis than men. We find this is consistent with the scope of the claim which requires that “the dose ... reduces the female patient’s nocturnal urine volume as compared to a male patient.” Appellants argue further that a patient’s weight may be a confounding factor in the analysis of Larsson, i.e., that sensitivity to the effects of desmopressin may not be gender-related at all, but rather may be a function 13 Appeal 2015-005196 Application 12/469,801 of patient weight. See, e.g., App. Br. 16. We agree that Appellants’ argument may be correct on this particular point, but we do not find the argument persuasive of nonobviousness. Larsson does not provide patient weights in its analysis, so Appellants’ argument is without material support. However, we find that a person of ordinary skill in the art would realize, as is well known generally, that the population of male patients in a study would generally have greater mass than a corresponding population of female patients. We find that a person of ordinary skill in the art knowing this fact, and understanding the teachings of Larsson that women demonstrate a greater reduction in nocturia then do men given the same dosage of desmopressin, would realize that, no matter the cause of the difference, women given a dose of desmopressin would generally tend to have a reduced “nocturnal urine volume as compared to a male patient,” as required by the claims. Nothing in the claims requires that the difference be exclusively gender-related, only that the effect on nocturia be greater in a female patient than in a male patient. We consequently agree with the Examiner’s findings and conclusions in this respect. Issue 3 Appellants argue the Examiner erred in concluding that it would have been obvious to: [OJptimize pharmaceutical doses within the disclosed range to achieve the best treatment outcome.... Moreover, ... the doses disclosed in the cited patents are identical (25pg) or very close to those recited in the claims (10 and 100 pg), thus making these 14 Appeal 2015-005196 Application 12/469,801 doses the first choice solution because it presents the best chances for success. App. Br. 21 (citing Non-Final Act. 6). Analysis Appellants argue that “[a] particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation.” App. Br. 21 (quoting MPEP § 2144.05(H)(8)). According to Appellants, prior to the filing date of their application, a patient’s gender was not recognized as a result-effective variable that would have to be adjusted to change the nocturnal urine volume. Id. at 22. In other words, Appellants contend, female patients were not recognized as having increased sensitivity that rises to the level of administering of a different dose of desmopressin as compared to male patients. Id. Appellants repeat their arguments supra that the cited prior art references do not recognize such a difference between either gender, let alone gender as a result- effective variable. Id. Appellants also point out that the Examiner found that Nilsson teaches dosages of 10 pg and 25 pg of desmopressin recited by the claims, and Larsson teaches a dosage of 100 pg of desmopressin, as recited by the claims. App. Br. 22 (citing Non-Final Act. 5; see also 6, 9-10, and 12). Appellants assert that Larsson discloses a 40 pg intranasal composition and a 100 pg tablet of desmopressin whereas the claims recite “an orodispersible dose of desmopressin” of 100 pg. Id. (citing Larsson col. 9,1. 4). 15 Appeal 2015-005196 Application 12/469,801 Appellants therefore argue that the Examiner’s conclusion that “the methods of the ’835 [Larsson] and ’429 [Nilsson] patents used the same compositions” is incorrect. Id. (quoting Non-final Act. 12). Finally, Appellants argue, some of the rejected claims recite methods for specific patient populations based on gender. App. Br. 22. Appellants observe that differential doses based on gender are noticeably absent from any of the cited references. Id. We are not persuaded by Appellants’ arguments. Appellants contend that gender was not, at the time of filing, recognized as a result-effective variable. Appellants offer no proof in support of this assertion, other than to re-argue their assertion that the cited prior art references do not recognize a difference between either gender, let alone gender as a result-effective variable. See App. Br. 22. This is directly contradicted by Appellants’ prior citations to Anderson and Miller supra, which explicitly recognized gender- related differences in responses to various drugs, with special reference to the greater vulnerability of women to adverse effects at a given dosage. More importantly, we find Appellants’ argument misses the point. We have explained why we agree with the Examiner that Larsson teaches differential effects of the same dosage of desmopressin (40 pg intranasal) on male and female subjects. Consequently, we agree with the Examiner that desmopressin dosage is a result-effective variable, because the same dosage demonstrably produces differential effects on individuals of different gender. Appellants appear to argue further that Larsson’s teaching of a 100 pg tablet of desmopressin does not constitute an “orodispersible dose” as recited in the claims. See App. Br. 22. However, Nilsson expressly teaches “It has now been discovered that desmopressin can be administered as a 16 Appeal 2015-005196 Application 12/469,801 solid orodispersible dosage form which provides improved bioavailability compared to conventional oral tablets of desmopressin.” Nilsson col. 1,11. 51—55. Nilsson teaches further that, for its orodispersible dosages of desmopressin: The daily dosage of desmopressin, measured as the free base, will generally be from 0.5 or 1 pg to 1 mg per dosage form. In one preferred dosage range, the dosage will typically range from 2 jig to 800 jig per dosage form and preferably from 10 pg to 600 pg. Relative low doses are also specifically contemplated, for example from 0.5 pg to 75 pg, preferably 0.5 or 1 pg to 50 pg. When one dosage form per day is administered, as is usual for PNE and nocturia, this will typically be the dose per dosage form. Id. at col. 2,11. 4—12. Nilsson thus expressly teaches a dosage range of orodispersible desmopressin encompassing the ranges including the “10 pg, and 25 pg,” “50 pg, or 100 pg” recited by the claims. See, e.g., claim 141, App. Br. 45. Larsson also teaches a nasal dosage of 40 pg in Example 7 which, like the orodispersible embodiments of Nilsson, has higher bioavailability but is more acceptable to patients. See Nilsson col. 1,11. 27— 28 (“Intranasal administration leads to higher bioavailability, but is less preferred by patients”). Finally, we have explained supra why we agree with the Examiner that a person of ordinary skill in the art would reasonably understand from the teachings of Larsson that females are more sensitive to the same dosage of desmopressin than are females. Consequently, we agree with, and adopt the Examiner’s conclusion that claims 40-46, 73—79, 83, 103—109, 113, and 17 Appeal 2015-005196 Application 12/469,801 141—149 are obvious over the combined cited prior art references and we affirm the Examiner’s rejection of the claims on this ground.2 B. Rejection of claims 114—123, 127, 128, 141, and 149 Issue Appellants argue that the Examiner erred because the combined cited prior art references fail to teach or suggest the limitation reciting “continuing the administration of the dose of desmopressin over a treatment period if the male patient has a serum sodium level of at least 130 mmol/L,” as recited by claims 114 and 141. App. Br. 23. Analysis Appellants argue the combined cited prior art neither teaches nor suggests “continuing” the method over the treatment period “if the male patient meets the criteria” of “a serum sodium level at least 130 mmol/L.” App. Br. 23. Appellants argue neither Larsson nor Nilsson teach or suggest the steps of measuring a male patient’s serum sodium before administration and “measuring the male patient's serum sodium level at a time interval after administration.” Id. at 24 (quoting claim 114). Appellants assert that the 2 Appellants also argue in their Reply Brief that Nilsson is not prior art to their application under 35 U.S.C. § 103(c). See Reply Br. 3^4. However, because Appellants failed to present this argument in their Appeal Brief, we do not reach the merits of their argument. See 37 C.F.R. § 41.37(c)(l)(vii) (2009); see also Ex parte Borden, 93 USPQ2d 1473, 1474 (BPAI 2010) (Informative): Arguments not raised in the Appellate Brief are considered waived. (“[T]he reply brief [is not] an opportunity to make arguments that could have been made in the principal brief on appeal to rebut the Examiner’s rejections, but were not”). 18 Appeal 2015-005196 Application 12/469,801 Examiner’s finding that the limitation can be met by “routine optimization” is insufficient. Id. Rather, Appellants contend, routine optimization cannot apply until the parameter, in this instance measuring and re-measuring the serum sodium level and continuing administration only if it is at least 130 mmol/L, is recognized by the cited references as a result-effective variable. Id. Appellants argue the Examiner has not adduce any evidence of record to suggest that serum sodium level is a result-effective variable, let alone evidence pointing to maintaining a level of at least 130 mmol/L. Id. The Examiner responds that if the data within the Examples of Larsson showed no changes in serum sodium concentration, the sodium level in serum must have been monitored. Ans. 14 (citing Larsson col. 8,11. 36—37; see also Nilsson Table 1 specifying blood test for “natrium” (i.e., sodium)). The Examiner finds that the treatment of nocturia was administered without monitoring levels of serum sodium would be analogous to an assertion that the treatment of an infectious disease is done without monitoring body temperature. Id. The Examiner also finds that the normal range for serum sodium level is approximately 135—145 mmol/L. Ans. 14. Therefore, the Examiner reasons, a person of ordinary skill in the art would have assumed that patients under treatment must have had sodium serum levels of at least 130 mmol/L sodium levels and, as in the Examples of Larsson, the level did not change during 3 months treatment period. Id. We are not persuaded by the Examiner’s findings and conclusions. Larsson teaches: “Body weight did not change during treatment, nor did osmolality, sodium or potassium in serum.” Larsson col. 8,11. 36—37. Nilsson similarly teaches that patients’ “Osmolality, creatinine, natrium [i.e., 19 Appeal 2015-005196 Application 12/469,801 sodium] and kalium [i.e., potassium] in serum” were tested monthly over a 3-month period. See Nilsson Table 1. We consequently agree with the Examiner that both references teach the limitation of the claims reciting “measuring the patient’s serum sodium level at a time interval after administration.” However, we can find no evidence that either reference expressly or implicitly teaches or suggests the limitation of the claims reciting: “continuing the administration of the dose of desmopressin over a treatment period if the male patient has a serum sodium level of at least 130 mmol/L.” This limitation expressly conditions continuing the administration of desmopressin as long as the serum sodium level of the male patient is equal to or greater than 130 mmol/L; and implicitly requires cessation of administration should the serum sodium level drop below that express criterion. The Examiner may be correct that the serum sodium levels of the exemplary male subjects of Larsson and Nilsson remained normal throughout their respective studies (Nilsson is inconclusive in this respect), and that this directly indicates a continuing measurement of serum sodium levels, but we find the references are silent with respect to discontinuing the treatment should the serum sodium level decrease below the “normal” range. Because we agree with Appellants that the cited references neither teach nor suggest the limitation of the claims reciting “continuing the administration of the dose of desmopressin over a treatment period if the male patient has a serum sodium level of at least 130 mmol/L,” we reverse the Examiner’s rejection of claims 114—123, 127, 128, 141, and 149. Moreover, because claims 142—148 depend from claim 141, we similarly reverse the Examiner’s rejection of those claims. 20 Appeal 2015-005196 Application 12/469,801 DECISION The Examiner’s rejection of claims 40-46, 73—79, 83, 103—109, and 113 as unpatentable under 35 U.S.C. § 103(a) is affirmed. The Examiner’s rejection of claims 114—123, 127, 128, and 141—149 as unpatentable under 35 U.S.C. § 103(a) is reversed. No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a)(1). See 37 C.F.R. § 1.136(a)(l)(iv). AFFIRMED-IN-PART 21 Copy with citationCopy as parenthetical citation