Douglas Sears et al.

Patent Trials and Appeals Board

Jul 31, 2019

14046528 - (D) (P.T.A.B. Jul. 31, 2019)

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.
14/046,528 10/04/2013 Douglas Sears 3IPAT1.0001US 5091
110121 7590 07/31/2019
Entralta P.C.
2127 Olympic Parkway, Suite 1006
#367
Chula Vista, CA 91915
EXAMINER
RAMACHANDRAN, UMAMAHESWARI
ART UNIT PAPER NUMBER
1627
NOTIFICATION DATE DELIVERY MODE
07/31/2019 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):
docketing@entralta.com
justin.sanders@entralta.com
tamara.rodriguez@entralta.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte DOUGLAS SEARS and MICHAEL REILLY
__________

Appeal 2018-000956
Application 14/046,528
Technology Center 1600
__________

Before JEFFREY N. FREDMAN, TAWEN CHANG, and DAVID COTTA,
Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal1,2 under 35 U.S.C. § 134 involving claims to a
method of treating an individual with a disorder associated with an attention
deficit disorder. The Examiner rejected the claims as obvious. We have
jurisdiction under 35 U.S.C. § 6(b). We affirm.

1 Appellants identify the Real Party in Interest as Attentive Therapeutics,
Inc. (see App. Br. 3).
2 We have considered refer to the Specification of Oct. 4, 2013 (“Spec.”);
Final Office Action of Feb. 8, 2017 (“Final Action”); Appeal Brief of June
26, 2017 (“App. Br.”); Examiner’s Answer of Sept. 7, 2017 (“Ans.”); and
Reply Brief of Nov. 3, 2017 (“Reply Br.”). An oral hearing was held on
July 8, 2019.
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Statement of the Case
Background
“ADHD [attention deficit hyperactivity disorder] is one of the most
common childhood psychiatric conditions. It has been diagnosed in
approximately 8.4% of all children aged 3-17 years old” (Spec. ¶ 2). “It is
widely recognized in ADHD patients, and especially in children, that there is
a documented link between patients missing meals and learning impairment”
(id. ¶ 9). “For instance, overnight and morning fasting among
schoolchildren was found to have a deleterious effect on the children’s
memory, attention, performance in academic pursuits and ability to interact
with other children socially” (id.).
“Various drugs and methods have been used to treat ADHD, including
amphetamine and methylphenidate based drugs. While these drugs are
generally effective in treating ADHD, the side effects suffered by the
children taking them can include loss of appetite resulting in . . . loss of
attentiveness” (id. ¶ 6). “Therefore it would be preferable to treat the side
effects such as appetite reduction that prevent the proper use and optimal
levels of amphetamine and/or methylphenidate therapy that are necessary to
meet the treatment guidelines to treat ADHD . . . . One way to do this is
through the use of appetite stimulants” (id. ¶ 13).
The Claims
Claims 21, 24, 37, and 42–50 are on appeal. Claim 42 is
representative and reads as follows:
32. A method of treating an individual with a disorder
associated with an attention deficit disorder, the method
comprises the step of administering in the morning to an
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individual in need thereof a long acting pharmaceutical
composition which comprises administration of
methylphenidate to treat the attention deficit disorder and
cyproheptadine to treat a reduction in appetite, wherein
administration reduces a symptom associated with a loss of
attentiveness by at least 10% and increases the attentiveness of
the individual by at least 10%, and further wherein, the long
acting pharmaceutical composition can provide peak mean
plasma level activity of the methylphenidate and
cyproheptadine for at least 6 hours following administration so
that peak mean plasma level activity exists in the afternoon,
thereby treating the individual.
The Rejections
A. The Examiner rejected claims 21, 24, 37, and 42–50 under 35 U.S.C.
§ 103(a) as obvious over Horst,3 CONCERTA®,4 Cyproheptadine,5 and
Chandrakala6 (Ans. 3–7).
B. The Examiner rejected claims 21, 24, 37, and 42–50 under 35 U.S.C.
§ 103(a) as obvious over Circleofmoms,7 Ritalin,8 Cyproheptadine, and
Chandrakala (Ans. 7–10).

3 Robert Horst & Erik Youngdale, ADHD Medications: The Nuts and Bolts
of Management, 11 Consultant for Pediatricians S10–15 (2012).
4 CONCERTA®, CONCERTA Extended Release Tablets CII (2007) (We
number the pages in consecutive order as pages 1–23).
5 Cyproheptadine, CYPROHEPTADINE HYDROCHLORIDE tablet
(2010).
6 Chandrakala et al., Formulation and Evaluation of Bioadhesive
Cyproheptadine Tablets, 10 Tropical J. Pharmaceutical Res. 365–73 (2011).
7 Circle of Moms, http://www.circleofmoms.com/moms-kids-adhd/how-to-
help-a-12-year-old-boy-on-concerta-gainweight-607328 (2010) (We number
the pages in consecutive order as pages 1–15).
8 Ritalin, Ritalin-SR/Ritalin-LA (Methylphenidate) (2008) (We will refer to
this reference as “Ritalin”).
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C. The Examiner rejected claims 21, 24, 37, and 42–50 under 35 U.S.C.
§ 103(a) as obvious over Managing ADHD,9 Daviss,10 CONCERTA®, and
Chandrakala (Ans. 10–14).
D. The Examiner rejected claims 21, 24, 37, and 42–50 under 35 U.S.C.
§ 103(a) as obvious over Mandelkorn11 and Chandrakala (Ans. 14–16).

Because Appellants argue the rejections in combination, we will
consider these rejections together.
The issues with respect to this rejection are:
(i) Does a preponderance of the evidence of record support the
Examiner’s conclusion that the prior art suggests combination therapy of
methylphenidate and cyproheptadine for ADHD and reduced appetite to
provide peak mean plasma levels activity for 6 hours lasting into the
afternoon as required by claim 42?
(ii) If so, have Appellants presented evidence of secondary
considerations that, when weighed with the evidence of obviousness, is
sufficient to support a conclusion of non-obviousness?

9 Crespi-Lofton, Addressing challenging situations in the management of
ADHD, Pharmacy Today 57–67 (2011) (We will refer to this document as
“Managing ADHD” for consistency with the Examiner and Appellants).
10 W. Burleson Daviss & John Scott, A Chart Review of Cyproheptadine for
Stimulant-Induced Weight Loss, 14 J. Child and Adolescent
Psychopharmacology 65–73 (2004).
11 Theodore Mandelkorn, All about Medications for ADHD, Part II,
http://adhdrollercoaster.org/the-basics/all-about-medications-for-adhd-
part-ii/ (2010)(We number the pages in consecutive order as pages 1–13).
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Findings of Fact
1. Horst teaches that for “uncomplicated ADHD in children,
psychostimulants are first-line therapy” (Horst S10, col. 3).
2. Horst teaches “[r]apid-acting, long duration stimulants are
generally preferred over intermediate-acting stimulants and stimulants with a
short duration. Rapid-acting, long duration stimulants include Concerta”
(Horst S11, col. 1). Horst also teaches the “combination of an alpha-
adrenergic agonist and a stimulant is often used to ameliorate stimulant-
associated insomnia” (Horst S11, col. 3).
3. Horst teaches “[l]ong-duration formulations are preferable to
multiple doses of short duration or intermediate-duration preparations
because the former decrease stigmatization, eliminate the need for in-school
dosing (thereby decreasing medication diversion in schools), probably have
less abuse potential, are more easily titrated, and improve adherence” (Horst
S10, col. 3 to S11, col. 1).
4. Horst teaches that one potential adverse effect of stimulant
therapy is “Appetite depression” which may be managed using strategies
including treatment with cyproheptadine (Horst S12, Table).
5. CONCERTA® teaches “[e]ach extended-release tablet for once-
a-day oral administration contains . . . methylphenidate HCl USP and is
designed to have a 12-hour duration of effect” (CONCERTA® 1).
CONCERTA® teaches “CONCERTA® should be administered orally once
daily in the morning with or without food” (CONCERTA® 19).
6. CONCERTA® teaches common side effects include decreased
appetite and stomach ache, among others (CONCERTA® 23).
CONCERTA® teaches “studies demonstrated significant improvements in
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attention and behavior in patients treated with CONCERTA® versus placebo
that were maintained through 12 hours after dosing” (CONCERTA® 6).
7. Circleofmoms teaches
Periactin or Cyproheptadine. (same drug/two names) Its an
antihistamine (like benadryl) no drug interactions with Ritalin
LA. My son takes Ritalin LA and Periactin, his appetite is
fantastic. First day or two it will make them sleepy, and then it
just makes them hungry. I know it[’]s given to children with
Failure to Thrive, and also to children who have cancer and
have lost their appetite. It comes in a liquid and a pill form.
(Circleofmoms 7).
8. Ritalin teaches “Ritalin-LA (Methylphenidate extended release
. . . is used primarily in treating attention-deficit/hyperactivity disorder
(ADHD) . . . . Ritalin increases the child’s ability to concentrate, extends
attention span, and decreases hyperactivity” (Ritalin 1).
9. Ritalin teaches “antidepressants can provide symptomatic relief
and improvement beyond that experienced with antidepressants alone”
(Ritalin 1).
10. Ritalin teaches
Ritalin-SR, a sustained release tablet, has a duration of
approximately 8 hours and can be taken once a day in the
morning in place of regular Ritalin. A single tablet provides a
duration of effect corresponding to the total daily dosage of
regular Ritalin. The disadvantage of the –SR tablet is that it
takes about 2–3 hours before peak clinical effects are seen,
which may be problematic, especially for school-age children.
Ritalin-LA, a dual action preparation, overcomes this drawback.
Ritalin-LA provides both immediate- and extended-release of
the stimulant. The -LA capsules contain methylphenidate
incorporated in two types of beads: one set of beads releases the
stimulant immediately after ingestion, whereas the second set of
beads provides gradual release of methylphenidate lasting up to
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8 hours. The stimulant in the body decreases by evening, so that
by bedtime the medication should not interfere with sleep.
(Ritalin 1–2).
11. Ritalin teaches that “Ritalin-SR tablets and -LA capsules should
be swallowed whole and not chewed or crushed” and that “Ritalin-SR and -
LA should be taken early in the morning” (Ritalin 2, 4).
12. Ritalin teaches “common side effects associated with taking
Ritalin are rapid heart rate, palpitations, nervousness, restlessness,
insomnia, dry mouth, constipation, nausea, diarrhea, loss of appetite, weight
loss” (Ritalin 2).
13. Managing ADHD teaches “[s]timulants (e.g.,
methylphenidate/dexmethylphenidate and dextroamphetamine or mixed
amphetamine salts) are first-line therapy for ADHD and are generally
comparable in efficacy” (Managing ADHD 59, col. 1).
14. Managing ADHD teaches “[a]dverse events associated with
stimulants include upset stomach, insomnia . . . . Upset stomach and appetite
suppression are the most common adverse effects associated with
stimulants” and that “[e]nsuring that stimulants are taken in the morning so
that their effects have worn off during bedtime is important . . . evidence
suggests that melatonin or cyproheptadine may be used to manage insomnia.
Cyproheptadine also promotes weight gain” (Managing ADHD 59, col. 1).
15. Daviss teaches “[s]timulant medications are used most
effectively in pediatric attention deficit hyperactivity disorders (ADHDs)
when doses are pushed higher to optimize clinical response . . . . However,
side effects associated with stimulants such as anorexia or weight loss”
(Daviss 65, col. 1).
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16. Daviss “reports weight changes from a consecutive series of
child psychiatry outpatients with ADHD, all treated with cyproheptadine for
stimulant-induced weight loss” (Daviss 66, col. 1). Daviss teaches “daily
doses of dextroamphetamine, Adderall, or Adderall XR at 22.5 mg (or of
Concerta at 54 mg) would be equivalent to methylphenidate at 45 mg/day”
(Daviss 66, col. 2).
17. Daviss teaches “cyproheptadine was started at 2 mg qhs for 2
nights, then increased to 4 mg qhs. Those who continued to experience
either weight loss or insomnia at subsequent visits had doses of
cyproheptadine increased to as high as 8 mg qhs” (Daviss 68, col. 2).
18. Daviss teaches “[a]ll patients experienced immediate weight
gain while on cyproheptadine. The group’s 2.2-kg mean absolute weight
gain and 7.5% mean percentage weight gain were both statistically and
clinically significant” (Daviss 71, col. 1).
19. Daviss teaches “our preliminary findings suggest that
cyproheptadine may be useful in youths with ADHD who experience weight
loss . . . on stimulant medication” (Daviss 72, col. 1).
20. Mandelkorn teaches a long acting methylphenidate composition
such as Ritalin LA or CONCERTA® for ADHD (Mandelkorn 1).
21. Mandelkorn teaches “side effects are often noted with the use of
stimulants” and teaches:
Most will note decreased appetite during the effective hours of
the medication. This often means minimal lunch intake. I
suggest a small protein lunch such as milk, peanut butter
crackers, beef or turkey jerky to get through the day. A milk
shake after school helps. Many find their appetite returns late in
the evening (around 8-9pm) when their medication wears off,
and they need to be allowed to eat at that time. If weight gain is
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a continued concern, I often add cyproheptadine (Periactin)
4mg, ½ tablet at breakfast and dinner. Periactin is an
antihistamine similar to Benedryl, which enhances appetite and
often results in 1-2lbs-weight gain per month.
(Mandelkorn 5; emphasis added).
22. Chandrakala teaches:
Cyproheptadine hydrochloride is well absorbed after oral
administration. It has a short half life of 3 h and hence require
frequent administration to maintain optimum plasma
concentration which cause patients’ non-compliance. These
characteristics make it a good candidate for the formulation of
an extended-release dosage form to minimize patients non-
compliance and maximum utilization of drug within the
therapeutic range.
(Chandrakala 366, col. 2).
23. Chandrakala teaches a “numerical optimization technique by
the desirability approach was used to generate the optimum setting for the
formulation using maximum adhesive force as well as favorable drug release
time, K, n and R2. When this was done, F0 showed drug release for up to
16 h” (Chandrakala 372, col. 1).
24. Chandrakala teaches the “final optimized cyproheptadine
hydrochloride formulation, incorporating Carbopol 934p and HPMC,
resulted in tablets with superior bioadhesion and prolonged release”
(Chandrakala 372, col. 1).
25. Chandrakala teaches “[t]hough the oral route is the most
commonly employed route of drug administration, it is not suitable for drugs
which are susceptible to gut and/or hepatic metabolism as well as drugs
which cause gastrointestinal side effects” but also teaches “[p]rolongation of
GRT [gastric retention time] may sustain drug release behavior and provide
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a better alternative for maintenance of systemic drug concentration within
the therapeutic window” (Chandrakala 366, col. 1, 2).
Principles of Law
“The combination of familiar elements according to known methods
is likely to be obvious when it does no more than yield predictable results.”
KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
Prima facie obviousness can be rebutted by presenting evidence of
secondary considerations and when such evidence is submitted, all of the
evidence must be considered anew. In re Piasecki, 745 F.2d 1468, 1472–73
(Fed. Cir. 1984).
Analysis
We adopt the Examiner’s findings regarding the scope and content of
the prior art (Ans. 3–14) and agree with the conclusion that the method of
claim 42 would have been obvious in view of the cited prior art (FF 1–25).
We address Appellants’ arguments below.
Prima facie obviousness
Teaching away
Appellants contend “the Chandrakala reference teaches away from
each of the four prior art combinations in the Rejections, since Chandrakala
states that its bioadhesive tablet is incompatible with drugs that cause
gastrointestinal side effects, such as methylphenidate” (App. Br. 5).
Appellants note that several of the references identify upset stomach,
abdominal pain, and vomiting as side effects of methylphenidate (see App.
Br. 6–7). Appellants contend “Chandrakala issues a clear warning that the
disclosed bioadhesive cyproheptadine HCl tablet formulation ‘is not suitable
for drugs which are susceptible to gut and/or hepatic metabolism as well as
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drugs which cause gastrointestinal side effects’” (App. Br. 6; citing
Chandrakala 366, col. 1, para. 2).
We are not persuaded that Chandrakala teaches away nor that the
prior art, when considered as a whole, teaches away from the combination of
sustained release methylphenidate with sustained release cyproheptadine. In
Medichem, the court explained that
[w]here the prior art contains “apparently conflicting” teachings
(i.e., where some references teach the combination and others
teach away from it) each reference must be considered “for its
power to suggest solutions to an artisan of ordinary skill . . .
consider[ing] the degree to which one reference might
accurately discredit another.”
Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157, 1165 (Fed. Cir. 2006)
(quoting In re Young, 927 F.2d 588, 591 (Fed. Cir. 1991)).
In this case, a number of the references discuss side effects of
methylphenidate including both gastrointestinal distress and decreased
appetite (FF 6, 12, 14). While Chandrakala generally teaches oral delivery is
not suitable for drugs that “cause gastrointestinal side effects” (FF 25),
CONCERTA® teaches oral delivery of a sustained release form of
methylphenidate (FF 5) despite also teaching that methylphenidate may
cause gastrointestinal side effects (FF 6). Ritalin also teaches oral
administration of the sustained release methylphenidate (FF 10) despite also
teaching gastrointestinal side effects (FF 12). Thus, the prior art recognizes
the need to balance the benefits of sustained release against side effects such
as weight loss or gastrointestinal concerns.
Indeed, if gastrointestinal side effects alone were sufficient reason to
teach away from the use of a sustained release compound for ADHD, then
methylphenidate itself would not be administered because the prior art is
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replete with teachings that methylphenidate administration results in
gastrointestinal side effects (FF 6, 12, 14). However, there is limited
discussion in the cited prior art of treatments for the side effect of
gastrointestinal issues. In contrast, the prior art is also replete with teachings
that methylphenidate results in the side effect of loss of appetite and weight
loss (FF 4, 6, 12, 14, 15, 19, 21), and that cyproheptadine treats this side
effect (FF 4, 7, 14, 17–19). Thus, the evidence of record suggests that the
side effect of weight loss is more significant than that of gastrointestinal
distress because the ordinary artisan was more concerned with treatment of
weight loss than any other side effect.
Also, Chandrakala teaches that cyproheptadine is a good candidate for
extended release because the short half-life may cause patient non-
compliance (FF 22). Similar reasons supporting extended release are also
identified by Horst regarding methylphenidate administration because
extended release formulations result in “decrease stigmatization, eliminate
the need for in-school dosing (thereby decreasing medication diversion in
schools), probably have less abuse potential, are more easily titrated, and
improve adherence” (FF 3).
Lastly, while Chandrakala teaches a particular way to effect sustained
release for cyproheptadine using bioadhesive tablets (FF 24), the prior art
recognizes other ways to effect sustained release drug compounds. For
example, CONCERTA® teaches the use of osmotic pressure to deliver
methylphenidate HCl at a controlled rate using a “precision-laser drilled
orifice” and membrane that “controls the rate at which water enters the tablet
core, which in turn controls drug delivery” (CONCERTA® 1). Neither the
claims nor the prior art are limited to particular sustained release
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compositions, and the ordinary artisan would have been able to select and
optimize sustained release compositions to minimize side effects (FF 23–
24). See In re Keller, 642 F.2d 413, 425 (CCPA 1981) (citations omitted)
(“The test for obviousness is not whether the features of a secondary
reference may be bodily incorporated into the structure of the primary
reference; nor is it that the claimed invention must be expressly suggested in
any one or all of the references. Rather, the test is what the combined
teachings of the references would have suggested to those of ordinary skill
in the art.”)
Thus, as we balance the detailed teachings to optimize drugs for
sustained release, the multiple modes by which sustained release may occur,
and the desire for a combination of methylphenidate and cyproheptadine in
the prior art, against a teaching by Chandrakala that a particular sustained
release formulation is less desirable for drugs causing gastrointestinal side
effects, we find that the evidence considered as a whole does not
demonstrate a teaching away from the use of combined sustained release
formulations of methylphenidate and cyproheptadine.
Teaching all claim limitations
Horst, CONCERTA®, Cyproheptadine, and Chandrakala
Appellants contend that “Horst alone, or in combination with the cited
secondary references, does not teach or suggest combining methylphenidate
and cyproheptadine into a single formulation – this element is simply
missing from the teachings” (App. Br. 10). Appellants contend that,
“[i]mportantly, Horst does not teach that taking cyproheptadine at the same
time as methylphenidate (separately or in the same formulation) increases
patient attentiveness beyond what is expected with methylphenidate alone”
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(App. Br. 11; citing Sears12 Decl. ¶ 7). Appellants contend “the Examiner
erred by not providing a sufficient reason with rational underpinning as to
why a person of ordinary skill in the art would have modified Horst to create
the claimed composition” (App. Br. 11). Appellants also contend that the
Examiner’s argument “does not sufficiently explain, if weight gain is a
concern, why would that concern lead one to combine the two medications.
Cyproheptadine can be taken any time of day, as shown by the variety of
dosing schedules taught in the prior art” (App. Br. 12).
We find this argument unpersuasive because the Examiner provides
specific reasons to combine cyproheptadine with methylphenidate and
reasons to formulate these compositions into a single pill. The Examiner
finds “Horst recognizes the combination therapy of methylphenidate with
cyproheptadine in ADHD patients” and finds it obvious “to administer both
the agents in a single formulation in a combination therapy . . . for the
purpose of treating ADHD, to reduce the side effects of the stimulant and to
improve the compliance of patients” (Ans. 24–25). See KSR, 550 U.S. at
420 (“Under the correct analysis, any need or problem known in the field of
endeavor at the time of invention and addressed by the patent can provide a
reason for combining the elements in the manner claimed.”) Because the
Examiner identified a reason to combine the references — even if the reason
does not address the same problem identified by Appellants — we are not
persuaded that the Examiner erred.
The evidence supports the Examiner’s position, as Horst teaches
treatment of ADHD with methylphenidate (FF 2) and treatment of

12 Declaration of Dr. Douglas Sears, M.D., dated Jan. 6, 2017.
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methylphenidate side effects with cyproheptadine (FF 4), reasonably
suggesting treatment with both medications. “The only difference between
the prescribed combination and the patented invention is that the
prescription was not contained in a single tablet. Such a combination was
clearly suggested by the prior art.” Richardson-Vicks Inc. v. Upjohn Co.,
122 F.3d 1476, 1483–84 (Fed. Cir. 1997).
Here, Horst provides specific reasons to administer both compounds
as sustained release because sustained release will “decrease stigmatization,
eliminate the need for in-school dosing (thereby decreasing medication
diversion in schools), probably have less abuse potential, are more easily
titrated, and improve adherence” (FF 3). Moreover, Horst teaches
combinations of methylphenidate with other compounds (FF 4). The
ordinary artisan would have reasonably recognized that combining both
compounds into a single pill would have improved adherence and
convenience because only a single pill would need to be administered rather
than multiple pills (see FF 3; Ans. 25). “It is prima facie obvious to combine
two compositions each of which is taught by the prior art to be useful for the
same purpose, in order to form a third composition which is to be used for
the very same purpose.” In re Kerkhoven, 626 F.2d 846, 850 (CCPA 1980).
As to the timing of administration, CONCERTA® teaches that
“CONCERTA® should be administered orally once daily in the morning
with or without food” (FF 5). Thus, the ordinary artisan interested in
simplifying administration for children in school would have had reason to
combine a sustained release form of cyproheptadine into a single pill with
methylphenidate compositions like CONCERTA® in order to obtain the
benefits including avoiding a need for in-school medication as well as
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improved adherence (FF 3). In addition, as the Examiner points out, “it is
within the skill of the physician to have adjusted the timing of the drug
based on the outcome of the therapy” (Ans. 25).
Appellants contend that “[w]hat taking cyproheptadine at night will
not do is lead to an appetite at lunch time such that attentiveness is increased
by 10% in the afternoon as the cyproheptadine has a mean peak blood level
of 3 hours, which means it would not have an effect at lunch time” (App. Br.
12).
We find this argument unpersuasive because CONCERTA®
specifically teaches that “CONCERTA® should be administered orally once
daily in the morning with or without food” (FF 5). Thus, the ordinary
artisan, interested in administering methylphenidate and cyproheptadine in a
single sustained release pill would have reasonably administered the
composition in the morning. As the Examiner points out,
administration of a long-duration formulation prepared from the
prior art that comprises methylphenidate and cyproheptadine to
an ADHD patient in the morning would reduce the symptoms
and increase the attentiveness as claimed, can provide extended
release for 6 h and until afternoon because if the extended
release tablets is prepared as Concerta formulation (which
works for 12 h or more, administered once daily).
(Ans. 25).
We also agree with the Examiner (see Ans. 26–27) that the ordinary
artisan would have expected administration of a sustained release
composition composed of methylphenidate and cyproheptadine in the
morning to be effective in increasing attention span due to the efficacy of
sustained release compositions such as CONCERTA®. There would also
have been an expectation of peak mean plasma levels over six hours as
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taught by the 12-hour duration of CONCERTA® (FF 5) and the 16 hour
duration of sustained-release cyproheptadine taught by Chandrakala (FF 23).
Appellants contend that:
The Examiner’s explanation of the motivation is conclusory,
generic in nature and fails to provide sufficient motivation to
combine. The proffered motivation to combine could be
inserted into the rejection of any pharmaceutically focused
claim, and is tantamount to stating that one of skill in the art
would be motivated to combine by some broad, general desire
to improve patient outcome.
(App. Br. 13).
We find this argument unpersuasive because such reasons for
combining methylphenidate and cyproheptadine into a single pill comport
with Dystar’s teaching that
when the “improvement” is technology-independent and the
combination of references results in a product or process that is
more desirable, for example because it is stronger, cheaper,
cleaner, faster, lighter, smaller, more durable, or more efficient.
Because the desire to enhance commercial opportunities by
improving a product or process is universal—and even
common-sensical—we have held that there exists in these
situations a motivation to combine prior art references even
absent any hint of suggestion in the references themselves.
DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464
F.3d 1356, 1368 (Fed. Cir. 2006). Appellants do not argue, and indeed
cannot reasonably argue, that the combination of two drugs used to treat the
same patient into a single pill was novel or unusual at the time of invention.
Thus, Horst’s motivations of improved adherence, less abuse potential,
decreased stigmatization, and eliminating the need for in-school dosing (FF
4) provide persuasive reason to form a single pill of methylphenidate and
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cyproheptidine where both were prescribed to single individuals (FF 2, 4)
consistent with Dystar.
Appellants contend that “[j]ust because Concerta teaches that long
duration methylphenidate can be taken in the morning, does not mean that
one of skill in the art would have been motivated to administer
cyproheptadine at the same time in the morning” (App. Br. 14).
We do not find this argument persuasive because, as already
discussed, the ordinary artisan would have had reason to combine
methylphenidate and cyproheptadine into a single pill in order to obtain the
benefits including avoiding a need for in-school medication as well as
improved adherence (FF 3). The ordinary artisan would have prescribed the
resulting combined pill for morning administration because CONCERTA®
specifically teaches “CONCERTA® should be administered orally once daily
in the morning with or without food” (FF 5).
Circle of Moms, Ritalin, Cyproheptadine, and Chandrakala
Appellants contend “[m]uch like Horst, Circleofmoms, alone or in
combination with the cited secondary references, does not teach or suggest
combining methylphenidate and cyproheptadine into a single long acting
formulation” (App. Br. 16). Appellants contend:
one skilled in the art would not have been motivated by the
teachings of Circleofmoms in view of the secondary references
to combine standard cyproheptadine with methylphenidate for
administration in the morning, due to concerns with
drowsiness; and the solution provided by Chandrakala is not
compatible with methylphenidate due to gastrointestinal
concerns. Further, Circleofmoms is cumulative to Horst,
merely teaching that cyproheptadine may help to increase
appetite in children taking methylphenidate, and not much
more. The issue with drowsiness when taking short-acting
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cyproheptadine in the morning applies similarly to the
remaining three obviousness rejections.
(App. Br. 16; cf. App. Br. 17 “there is no guidance on when or how to take
the cyproheptadine.”). Appellants also contend “Circleofmoms is claimed to
teach a composition of methylphenidate and cyproheptadine; yet there is no
plausible motivation in the Circleofmoms reference, alone or in combination
with the secondary references to create such a composition” (App. Br. 16).
We find these arguments unpersuasive for the same reasons as given
above regarding the rejection including Horst. In particular, Circleofmoms
specifically suggests treating a particular individual with both
methylphenidate and cyproheptadine to increase appetite (FF 7). Ritalin
teaches morning administration, specifically that “Ritalin-SR, a sustained
release tablet, has a duration of approximately 8 hours and can be taken once
a day in the morning in place of regular Ritalin” (FF 10). As the Examiner
notes
One of ordinary skill in the art would have been motivated to
administer the both drugs in combination in the morning
because Ritalin is administered in the morning and the subjects
can be given a onetime administration. One would have been
motivated to combine both the drugs and administer as a single
formulation to (i) for ease of administration (ii) for patient
compliance and (iii) to negate the adverse effects associated
with methylphenidate.
(Ans. 32). Therefore, the Examiner’s rejection expressly lists “a motivation
to select the references and to combine them in the particular claimed
manner to reach the claimed invention.” Unigene Laboratories, Inc. v.
Apotex, Inc., 655 F.3d 1352, 1361 (Fed. Cir. 2011) (citation omitted).
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Appellants contend
Circleofmoms and Horst in view of the secondary references do
not appreciate the problem solved by the present invention as
claimed — how to increase attentiveness in the afternoon (or
the period serval hours and more following the administration
of methylphenidate), which is solved by administering a long
acting composition comprising methylphenidate and
cyproheptadine in the morning that maintains mean peak blood
levels for at least 6 hours.
(App. Br. 17).
We find this argument unpersuasive. As to increased attentiveness in
the afternoon, Ritalin teaches administration in the morning (FF 11) that
“extends attention span” (FF 8) and teaches “gradual release of
methylphenidate lasting up to 8 hours” (FF 10) that will result in increased
attentiveness in the afternoon, and maintain peak blood levels for at least 6
hours. We have already explained why we agree with the Examiner that the
combination of methylphenidate and cyproheptadine would have been
obvious and we also agree with the Examiner that the use of a sustained
release form of cypropheptadine would have been obvious “to relieve the
side effects associated with the stimulant . . . to provide the agents together
as a single medication for ease of administration . . . [and] for patient drug
compliance” (Ans. 35). See In re Kemps, 97 F.3d 1427, 1430 (Fed. Cir.
1996) (citation omitted) (“[T]he motivation in the prior art to combine the
references does not have to be identical to that of the applicant to establish
obviousness.”).
Appellants contend that:
even if cyproheptadine was given in the morning, it could not
maintain the mean peak blood level beyond 3 hours, which
would not result in a patient eating lunch and having the
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claimed attentiveness in the afternoon. See Dr. Sears Aff., para.
15. It is the recognition that the combination of
methylphenidate and cyproheptadine, wherein both are given in
a long duration formulation, provides the claimed result, was
first discovered by Appellants and is not taught or disclosed by
the prior art cited by the Examiner.
(App. Br. 17).
We find this argument unpersuasive. We appreciate that claim 42
recites “peak mean plasma level activity of the methylphenidate and
cyproheptadine for at least 6 hours following administration so that peak
mean plasma level activity exists in the afternoon.” However, Chandrakala
directly teaches a preference for sustained release cyproheptadine in order
“to minimize patients non-compliance and maximum utilization of drug
within the therapeutic range” (FF 22). Thus, the ordinary artisan would have
had reason to combine sustained release cyproheptadine with sustained
release methylphendiate in order to further minimize non-compliance and
simplify administration as already discussed. Both CONCERTA®,and
Ritalin suggest morning administration (FF 5, 10).
The evidence of record shows that the prior art sustained release
methylphenidate improves attention because methylphenidate in the form of
Ritalin “increases the child’s ability to concentrate, extends attention span,
and decreases hyperactivity” (FF 8). Similarly CONCERTA® teaches
“studies demonstrated significant improvements in attention and behavior in
patients treated with CONCERTA® versus placebo that were maintained
through 12 hours after dosing” (FF 6). Lastly, Chandrakala teaches “drug
release for up to 16 h” (FF 23).
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Therefore, the obvious combined sustained release combination would
have been expected to result in peak mean plasma levels for at least 6 hours
following administration as required by claim 42.
We recognize that the Sears Declaration states, regarding Daviss, that
“[b]ecause the peak plasma level of cyproheptadine is 1-3 hours, evening
dosing cannot impact daytime appetite issues” (Sears Decl. ¶ 15). However,
Daviss cannot support this reasoning because despite dosing at night, Daviss
teaches “[a]ll patients experienced immediate weight gain while on
cyproheptadine. The group’s 2.2-kg mean absolute weight gain and 7.5%
mean percentage weight gain were both statistically and clinically
significant” (FF 18). Thus, patients ate more food when receiving
cyproheptadine, consistent with the Examiner’s reasoning that a “person of
ordinary skill in the art at the time of the invention would have been
motivated to combine methylphenidate with cyproheptadine and administer
to ADHD subjects to counteract the side effects of methylphenidate, namely
appetite suppression/weight loss in ADHD patients and thus improve
appetite/weight gain in ADHD subjects” (Ans. 37). Thus, Daviss supports
the Examiner’s obviousness position because the ordinary artisan would
have had reason to administer cyproheptadine for weight gain as suggested
by Circleofmoms in a single pill with methylphenidate for the reasons
discussed above.
Managing ADHD, Daviss, CONCERTA®, and Chandrakala
Appellants contend “there is absolutely no logic to the Rejection’s
suggestion that the disclosure of Managing ADHD should be modified with
the teachings of Daviss” (App. Br. 19). Appellants contend “one of skill in
the art would not be motivated to modify Managing ADHD, when Managing
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ADHD is cumulative to Daviss with respect to ADHD stimulant related
appetite loss, and cyproheptadine’s ability to promote weight gain” (App.
Br. 19).
We find this argument unpersuasive because both Managing ADHD
and Daviss suggest that when weight loss is occurring due to
methylphenidate administration, “cyproheptadine may be useful in youths
with ADHD who experience weight loss” (FF 14, 17–19). That multiple
references, including Managing ADHD, Daviss, Horst, Circleofmoms, and
Mandelkorn all teach the same thing, that cyproheptadine is useful in
combination with methylphenidate to increase appetite, makes the
obviousness case more persuasive, not less (FF 14, 19, 4, 7, 21).
Appellants contend:
Much like the argument against Horst above, Managing ADHD
in view of Daviss fails to recognize or even teach that
methylphenidate and cyproheptadine taken at the same time
(such as in the morning), in a single composition (or even as
two separate pills), increases attentiveness by at least 10%
beyond taking methylphenidate alone, due to the ability to eat
food at the appropriate time so that blood glucose level is
increased when academic or social focus is required, such as in
the afternoon.
(App. Br. 19).
We remain unpersuaded by this argument for the reasons already
given. Briefly, the ordinary artisan would have had reason to combine
methylphenidate and cyproheptadine into a single pill in order to obtain
benefits including avoiding a need for in-school medication as well as
improved adherence. The ordinary artisan would have prescribed the
resulting combined pill for morning administration because CONCERTA®
specifically teaches “CONCERTA® should be administered orally once daily
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in the morning with or without food” (FF 5; cf. FF 14). And “studies
demonstrated significant improvements in attention and behavior in patients
treated with CONCERTA® versus placebo that were maintained through 12
hours after dosing” (FF 6). Thus, the ordinary artisan would have expected
improved attention due to the sustained-release methylphenidate
composition when combined with the sustained-release cyproheptadine
suggested by Chandrakala (FF 23) in order to achieve weight gain as taught
by Managing ADHD and Daviss (FF 14, 19).
Mandelkorn and Chandrakala
Appellants contend
it may appear that Mandelkorn somehow understands and
appreciates the full benefit of methylphenidate and
cyproheptadine. However, a close study of Mandelkorn’s exact
statement and a review the Cyproheptadine reference (cited in
the Examiner’s first and second rejections discussed supra)
shows that Mandelkorn, more likely than not, simply deferred
to the dosage regimen recommended in the Cyproheptadine
reference.
(App. Br. 21). Appellants contend “[a]t best, it appears that Mandelkorn
teaches taking cyproheptadine to possibly encourage weight gain, because
cyproheptadine has been described in the art to possibly aid in weight gain
with a variety of diseases, including ADHD related side effects” (App. Br.
22).
We find this argument unpersuasive because it fails to confront the
obviousness issue, which is whether the ordinary artisan would have had
reason to treat ADHD patients with both methylphenidate and
cyproheptadine in sustained release form to treat both attention issues and
the side effects of appetite reduction. Mandelkorn expressly teaches
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treatment with sustained-release methylphenidate (FF 20) that is given in the
morning (FF 5, 10) as well as 2 mg of cyproheptadine in the morning (FF
21). That the reason Mandelkorn gives for administering the combination of
methylphenidate and cyproheptadine differs from that of Appellants is of no
moment because “any need or problem known in the field of endeavor at the
time of invention,” and addressed by the pertinent prior art references, “can
provide a reason for combining the elements in the manner claimed.” KSR,
550 U.S. at 420. It is sufficient that references suggest doing what
Appellants did, although the Appellants’ particular purpose was different
from that of the references. In re Heck, 699 F.2d 1331, 1333 (Fed. Cir.
1983).
Appellants contend
If Mandelkorn’s teachings, arguendo, were modified as the
Examiner has suggested, this would create a more complex
regimen than claimed by adding a new medication
(cyproheptadine and cyproheptadine/ methylphenidate) and a
new dosing time. . . . As a result the dosage given at night
would have no effect on a patient’s eating lunch to maintain
attentiveness and the dosage in the morning would likely wear
off in the morning, thus, failing to stimulate the patient to eat
lunch. . . . Without eating lunch, the attentiveness of the patient
will decrease, not increase as required by claim 42.
(App. Br. 23) (citations omitted).
We find this argument unpersuasive for several reasons. First,
Mandelkorn expressly teaches administration of cyproheptadine in the
morning (FF 21). Second, the advantages of a single sustained release
compisiton with both methylphenidate and cyproheptadine have already
been discussed above, because the combination would “decrease
stigmatization, eliminate the need for in-school dosing (thereby decreasing
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medication diversion in schools), probably have less abuse potential, are
more easily titrated, and improve adherence” (FF 3). Thus, the ordinary
artisan would have had reason to provide such a combined therapy as
rendered obvious by Mandelkorn and the other prior art, and would have
expected improved attention based on the teachings in CONCERTA® that
“studies demonstrated significant improvements in attention and behavior in
patients treated with CONCERTA® versus placebo that were maintained
through 12 hours after dosing” (FF 6).
Appellants contend that “Mandelkorns regimen would not encourage
eating midday to increase attentiveness in the afternoon” (App. Br. 23).
We find this argument unpersuasive because there is no requirement
in claim 42 that the individual eat at midday. See In re Self, 671 F.2d 1344,
1348 (CCPA 1982) (“[A]ppellant’s arguments fail from the outset because
. . . they are not based on limitations appearing in the claims.”)
Hindsight
Appellants contend that “[b]ecause there is no reason for the prior art
to combine the two medications, it is clear that the Examiner has relied on
hindsight bias to develop an obviousness argument by cobbling together an
obviousness rejection that fails the legal test for 35 U.S.C. § 103(a)” (App.
Br. 27). Appellants contend “[t]here is no purpose to combine the prior art
into the claimed composition and practice the claimed method” (App. Br.
27). Appellants contend that the “first suggestion of administering a
composition comprising methylphenidate and cyproheptadine came from the
Appellants’ specification” (App. Br. 28).
While we are fully aware that hindsight bias may plague
determinations of obviousness, Graham v. John Deere Co., 383 U.S. 1, 36
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(1966), we are also mindful that the Supreme Court has clearly stated that
the “combination of familiar elements according to known methods is likely
to be obvious when it does no more than yield predictable results.” KSR,
550 U.S. at 416. In this case, as discussed above, there is substantial
evidence in the record suggesting that cyproheptadine treats side effects of
methylphenidate adminstration, that combination therapy was expected to be
advantageous, and that combining medications into a single pill for morning
administration has benefits such as “decrease[d] stigmatization,
eliminate[ion of] the need for in-school dosing (thereby decreasing
medication diversion in schools) . . . less abuse potential . . . and improve[d]
adherence” (FF 1–25). Consequently, we agree with the Examiner that “the
combined teachings of the prior art are not a case of improper hindsight,
rather, prima faci[e] obviousness” (Ans. 51).
Secondary Considerations
Appellants contend
The claimed benefit of administering a composition that
reduces “a symptom associated with a loss of attentiveness by
at least 10% and increases the attentiveness of the individual by
at least 10%” and maintains “peak mean plasma level activity
of the methylphenidate and cyproheptadine for at least 6 hours
following administration so that peak mean plasma level
activity exists in the afternoon” is an unexpected result that was
completely unknown and newly discovered by the present
inventors.
(App. Br. 25). Appellants contend “Dr. Sears was able to provide additional
evidence of this relationship in his double-blind, placebo-controlled study
which involved 99 patients, ages 6-12, diagnosed with ADHD” (App. Br.
26). Appellants contend Dr. Sears demonstrated that the “combination of
methylphenidate and cyproheptadine administered once per day showed not
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only the expected weight gain, but also an unexpected increase in
attentiveness of ADHD patients beyond that expected from the
psychostimulant alone” (App. Br. 26).
We are not persuaded because Appellants provide no comparison to
the closest prior art of either Circleofmoms or Mandelkorn demonstrating
that the result is, in fact, unexpected. Mandelkorn teaches treatment of
individual patients with cyproheptadine in the morning (FF 21) and
methylphenidate in the form of CONCERTA® or Ritalin LA, that are also
taken in the morning (FF 5, 10). By contrast, the study referred to in Exhibit
B of the Sears Declaration reports treatments with methylphenidate alone
compared to combination therapy with low and high dose cyproheptadine, in
2.5 mg or 5 mg dose amounts very close to the 4 mg dose disclosed by
Mandelkorn (FF 21). The study therefore simply demonstrates that the
dosing suggested by Mandelkorn would have been expected to obtain the
results recited by claim 42. See In re Skoner, 517 F.2d 947, 950 (CCPA
1975) (“Expected beneficial results are evidence of obviousness of a claimed
invention.”)
There is no evidence in the study cited by Dr. Sears showing any
improvement by using a sustained-release cyproheptadine combination with
sustained-release methylphenidate and no comparison of such a dual
sustained-release composition with Mandelkorn’s treatment using
cyproheptadine and the sustained-release methylphenidate of Ritalin-LA (FF
21; Sears Decl. Exhibit B ¶¶ 1, 8). Indeed, there is not even comparison
evidence that the claimed treatment is superior to the treatment of Daviss,
where methylphenidate is given along with a nighttime administration of 2
or 4 mg of cyproheptadine (FF 16–17). See In re Baxter Travenol Labs.,
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952 F.2d 388, 392 (Fed. Cir. 1991) (“[W]hen unexpected results are used as
evidence of nonobviousness, the results must be shown to be unexpected
compared with the closest prior art.”). In the absence of a proper
comparison with the closest prior art, there is no persuasive showing that the
claimed invention is nonobvious due to unexpected results.
Conclusion of Law
(i) A preponderance of the evidence of record supports the Examiner’s
conclusion that the prior art suggests combination therapy of
methylphenidate and cyproheptadine for ADHD and reduced appetite to
provide peak mean plasma levels activity for 6 hours lasting into the
afternoon as required by claim 42.
(ii) Appellants have not presented evidence of secondary
considerations, that when weighed with the evidence of obviousness, is
sufficient to support a conclusion of non-obviousness.
SUMMARY
We affirm the rejection of claim 42 under 35 U.S.C. § 103(a) as
obvious over Horst, CONCERTA®, Cyproheptadine, and Chandrakala.
Claims 21, 24, 37, and 43–50 fall with claim 42.
We affirm the rejection of claim 42 under 35 U.S.C. § 103(a) as
obvious over Circleofmoms, Ritalin, Cyproheptadine, and Chandrakala
Claims 21, 24, 37, and 43–50 fall with claim 42.
We affirm the rejection of claim 42 under 35 U.S.C. § 103(a) as
obvious over Managing ADHD, Daviss, CONCERTA®, and Chandrakala.
Claims 21, 24, 37, and 43–50 fall with claim 42.
We affirm the rejection of claim 42 under 35 U.S.C. § 103(a) as
obvious over Mandelkorn and Chandrakala. Claims 21, 24, 37, and 43–50
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fall with claim 42.

No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a).

AFFIRMED