Ex Parte Klein et al

Patent Trial and Appeal Board

Jun 7, 2017

12469801 (P.T.A.B. Jun. 7, 2017)

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.
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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.
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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,
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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
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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.
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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.
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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.
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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.
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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
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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
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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.
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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
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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
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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).
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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
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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
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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”).
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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.,
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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.
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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
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