Ex Parte Thyaga Rajan

Patent Trial and Appeal Board

Aug 28, 2017

13866313 (P.T.A.B. Aug. 28, 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.
13/866,313 04/19/2013 Kothanda Raman Thyaga Rajan 19081 (AP) 1153
51957 7590
ALLERGAN, INC.
2525 DUPONT DRIVE, T2-7H
IRVINE, CA 92612-1599
EXAMINER
NEAGU, IRINA
ART UNIT PAPER NUMBER
1627
NOTIFICATION DATE DELIVERY MODE
08/30/2017 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):
patents_ip @ allergan. com
pair_allergan @ firsttofile.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte KOTHANDA RAMAN THYAGA RAJAN1
Appeal 2017-003905
Application 13/866,313
Technology Center 1600
Before JEFFREY N. FREDMAN, JOHN G. NEW, and
JOHN E. SCHNEIDER, Administrative Patent Judges.
NEW, Administrative Patent Judge.
DECISION ON APPEAL
appellant states the real party-in-interest is Allergan, Inc. App. Br. 3.
Appeal 2017-003905
Application 13/866,313
SUMMARY
Appellant files this appeal under 35 U.S.C. § 134(a) from the
Examiner’s Final Rejection of claims 1, 7—10, and 12—15 as unpatentable
under 35 U.S.C. § 103(a) as being obvious over the combination of V.
Yaylali et al., Comparative Study of 0.1% Olopatadine Hydrochloride and
0.5% Ketorolac Tromethamine in the Treatment of Seasonal Allergic
Conjunctivitis, 81 Acta Ophthalmol. Scand. 378-82 (2003) (“Yaylali”),
Alcon, Inc., Prescribing Information for Patanol® Ophthalmic solution (3
April 2006) (“Patanol”) and Allergan, Inc., Material Safety Data Sheet for
ACULAR LS® (July 23, 2008) (“Acular”).
Claims 1, 7—10, and 12—15 also stand rejected as unpatentable under
35 U.S.C. § 103(a) as being obvious over the combination of Yaylali,
Patanol, Acular, and Lane (US 2006/0263350 Al, November 23, 2006)
(“Lane”).2
We have jurisdiction under 35 U.S.C. § 6(b)
We AFFIRM.
NATURE OF THE CLAIMED INVENTION
Appellant’s invention is directed to a stable formulation of a
combination of ketorolac (non-steroidal anti-inflammatory drug) with
olopatadine (anti-histaminic drug) intended for ophthalmic use. This
2 The Examiner also rejected claim 1 as unpatentable under 35 U.S.C. § 112,
second paragraph, as indefinite, and claims 7—9 as unpatentable under
35 U.S.C. § 112, fourth paragraph as being dependent on the allegedly
indefinite claim 1. See Final Act. 5—6. The Examiner has withdrawn these
rejections. Ans. 9.
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pharmaceutical composition is used for treatment of ophthalmic diseases and
conditions, particularly seasonal ocular surface allergy. Abstract.
REPRESENTATIVE CLAIM
Claim 1 representative of the claims on appeal and recites:
1. A topical ophthalmic composition for treating or
preventing seasonal allergic conjunctivitis in a human patient,
wherein the ophthalmic composition comprises a combination of
olopatadine hydrochloride at about 0.1% w/v and ketorolac
tromethamine at about 0.4% w/v.
App. Br. 20.
ISSUES AND ANALYSIS
We agree with, and adopt, the Examiner’s reasoning and conclusion
that the claims on appeal are prima facie obvious over the combined cited
prior art. We address the arguments presented by Appellant below.
A. Rejection of claims E 7—10, and 12—15 over Yavlali, Patanof and
Acular-
Issue 1
Appellant argues the Examiner erred because a person of ordinary
skill in the art would have found no teaching, suggestion, or motivation to
3 Appellant argues claims 1—10 and 12—15, however claims 2—6 are
canceled. App. Br. 9. Consequently, we consider only claims 1, 7—10, and
12-15.
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Application 13/866,313
combine the teachings of the art arrive at the claimed combination. App. Br.
10.
Analysis
The Examiner finds Yaylali teaches topical ophthalmic composition
comprising 0.1% olopatadine hydrochloride can be used to topically treat
seasonal allergic conjunctivitis. Final Act. 7 (citing Yaylali 379). The
Examiner finds Yaylali also teaches a topical ophthalmic composition of
0.5% ketorolac tromethamine used to treat seasonal allergic conjunctivitis.
Id. at 8. However, the Examiner finds Yaylali does not teach a topical
ophthalmic formulation comprising a combination of 0.1% w/v olopatadine
hydrochloride and ketorolac tromethamine 0.4% w/v. Id. The Examiner
finds Patanol teaches a topical ophthalmic solution comprising 0.1%
olopatadine hydrochloride as active ingredient and 0.01% benzalkonium
chloride as a preservative. Id. The Examiner finds Acular teaches a topical
ophthalmic solution comprising 0.4% ketorolac tromethamine and 0.006%
benzalkonium chloride as a preservative. Id.
The Examiner concludes that it would have been obvious to a person
of ordinary skill in the art to combine olopatadine and ketorolac in an
ophthalmic solution, and optimize the content of each ingredient in the
formulation to achieve the best therapeutic effect in treating seasonal allergic
conjunctivitis. Final Act 9. The Examiner further concludes that such a
person of ordinary skill would have been motivated to combine olopatadine
and ketorolac in an ophthalmic solution and use the resulting combination to
treat seasonal allergic conjunctivitis. Id. The Examiner reasons that a
person of ordinary skill would have reasonably expected that combining the
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ophthalmic solutions, known to be useful for the same purpose, would result
in an ophthalmic solution useful for treating seasonal allergic conjunctivitis.
Id.
Appellant argues that there is no teaching, suggestion or motivation in
Yaylali, Patanol, or Acular that would have led a person of ordinary skill in
the art to arrive at the claimed combination of olopatadine and ketorolac.
App. Br. 10. According to Appellant, Yaylali concludes that 0.1% w/v
olopatadine hydrochloride (i.e., Patanol) is superior in efficacy and side
effects to 0.5% w/v ketorolac tromethamine (i.e., Acular), but there is no
teaching or suggestion in Yaylali of combining 0.1% w/v olopatadine
hydrochloride and 0.4% w/v ketorolac tromethamine into a single
composition. Id.
Appellant argues further that, given that twice a day olopatadine is a
dual action drug which is more efficacious at treating seasonal allergic
conjunctivitis (“SAC”) with fewer side effects than four times a day 0.5%
w/v ketorolac tromethamine, “it is difficult to understand why one of
ordinary skill in the art would have been motivated to combine olopatadine
with ketorolac.” App. Br. 11. Appellant asserts that drug combinations are
difficult and are rarely successful or approved by the FDA. Id. Appellant
contends the drugs must be soluble at the same pH and have comparable
dosing frequency and timing. Id. Appellant argues that Patanol has a pH of
7 and is administered twice a day, whereas Acular has a pH of 7.4 and is
administered four times a day. Id. Appellant contends that the compositions
contain different concentrations of the preservative benzalkonium chloride
with Patanol having 0.01% w/v and Acular having 0.006% w/v. Id.
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Appellant asserts that Yaylali teaches that 0.1% w/v olopatadine
hydrochloride is effective in treating SAC on its own, and the fact that
Yaylali also teaches that 0.5% w/v ketorolac tromethamine is also effective
at treating SAC, does not give rise to the motivation for their combination.
App. Br. 12. Appellant alleges that the Examiner reasons “that if one drug is
good, two drugs must be better.” Id. However, Appellant argues, this
reasoning ignores the difficulty of formulating drug combinations and
obtaining their approval: if topical dmg combinations for the eye were
always superior, contends Appellant, there would be no drug monotherapies.
Id. Nevertheless, Appellant argues, topical eye monotherapies outnumber
the few commercially available drug combinations used for the eye. Id.
The Examiner responds that both ketorolac and olopatadine are
known to be effective in treating SAC, as taught by Yaylali, regardless of the
mechanism by which each of the two drugs works, or of the side effects
produced by either drug. Ans. 10. The Examiner finds that the fact that
Yaylali compares the efficacy of olopatadine and ketorolac in the treatment
of SAC does not diminish in any way Yaylali’s teaching that olopatadine
and ketorolac were known to be effective in treating SAC. Id. at 10-11.
The Examiner finds Appellant’s argument that drug combinations are
difficult and rarely successful, or approved by FDA, is neither relevant to,
nor a requirement for, patentability of Appellant’s composition. Ans. 11.
The Examiner finds that ophthalmic formulations of ketorolac and
olopatadine were both well known in the art and commercially available
before the effective filing date of Appellant’s application. Id.
With respect to Appellant’s argument related to combining the two
ophthalmic solutions, the Examiner finds that the optimal pH of ophthalmic
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solutions is 7.4, because the pH of tears is approximately 7.4. Ans. 11. The
Examiner finds that it is known in the art that the eye can tolerate a fairly
wide range of pH, and that the useful range of pH to prevent corneal damage
extends between 6.5 and 8.5. Id. The Examiner finds that each of the
ophthalmic solutions of olopatadine and ketorolac has a pH within the
acceptable range, and close to the optimal pH for ophthalmic administration;
therefore, finds the Examiner a difference of pH 7 versus pH 7.4 would not
have deterred a skilled artisan from combining the two drugs in a
composition, useful for the same purpose, as an ophthalmic formulation. Id.
The Examiner also finds that both adjusting the concentration of the
preservative benzalkonium chloride in an ophthalmic composition to
optimize the stability of the composition, and adjusting the dose/frequency
of administration for the active ingredients, olopatadine and ketorolac, in the
composition, with the aim of achieving optimum therapeutic effect, would
have been well within the competency of an artisan of ordinary skill. Id. at
12.
Finally, the Examiner finds that because Yaylali, Patanol, and Acular
expressly teach that ketorolac and olopatadine are known to be effective in
treating SAC and were known to be formulated as topical ophthalmic
compositions, a person of ordinary skill in the art would have been
motivated to combine olopatadine and ketorolac in an ophthalmic solution
and to use the resulting combination to treat SAC. Ans. 12. The Examiner
also finds that a person of ordinary skill in the art would have reasonably
expected that combining olopatadine and ketorolac, which were known to be
useful for the same purpose, would result in an ophthalmic solution useful
for treating SAC. Id. at 12—13.
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We are not persuaded by Appellant’s arguments. Yaylali teach that
both olopatadine and ketorolac are effective as topical compositions for the
treatment of SAC. Yaylali Abstr. Furthermore, Yaylali teaches the use of
concentrations of both compositions that are basically the same as those
recited in the claims: claim 1 recites: “olopatadine hydrochloride at about
0.1% w/v and ketorolac tromethamine at about 0.4% w/v,” whereas Yaylali
teaches use of compositions comprising “0.1 % olopatadine hydrochloride
and 0.5% ketorolac tromethamine.” Yaylali Abstr.
Yaylali also teaches that:
Both olopatadine and ketorolac ophthalmic solutions were
found to be effective in the treatment of SAC compared to
placebo. These two drugs act via different pharmacological
mechanisms. Olopatadine ... inhibits the release of preformed
and newly synthesized inflammatory mediators from mast cells
upon allergen challenge, and also has antihistaminic properties
towards Hi receptors. Its dual activity is an advantage and the
drug may be used both as a therapeutic and prophylactic agent.
The dual action also renders the drug superior in terms of clinical
effectiveness, rapid onset and length of duration of action. On
the other hand, ketorolac is an NSAID; it works through the
inhibition of cyclooxygenase, which produces prostaglandins.
Prostaglandin D2 is among the newly synthesized mediators
released by mast cells following antigen stimulation, and
inhibition of the production of this mediator can decrease the
signs and symptoms of SAC. Antipruritogenic and
antihyperaemic actions of ketorolac in the treatment of SAC can
be explained by inhibition of prostaglandin synthesis,
particularly prostaglandins D2 and E2.
Yaylali 379—80 (internal citations omitted). Yaylali thus teaches that
olopatadine and ketorolac are both effective treatment ophthalmic
compositions for the treatment of SAC, although they have different
mechanisms of action. We agree with the Examiner’s conclusion that a
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person of ordinary skill in the art would have been motivated to combine
olopatadine and ketorolac in a topical ophthalmic solution to produce a more
efficient treatment of SAC by exploiting the different mechanisms of action
of the two compositions. We similarly agree with the Examiner’s
conclusion that a person of ordinary skill in the art would have a reasonable
expectation of success in combining the olopatadine and ketorolac
compositions as a treatment for SAC. See KSR Int 7 Co. v. Teleflex Inc., 550
U.S. 398, 416 (2007) (“The combination of familiar elements according to
known methods is likely to be obvious when it does no more than yield
predictable results.”)
Nor are we persuaded by Appellant’s arguments with respect to the
different pH of the olopatadine and ketorolac compositions or the differing
dosage regimes and concentrations of benzalkonium chloride preservative
taught by Patanol and Acular respectively. Neither the pHs, dosage regimes,
nor the concentrations of benzalkonium chloride are recited in the claims on
appeal. Furthermore, we agree with the Examiner that it would be well
within the skill of an ordinary artisan to compose a buffered solution within
the range of acceptable pH for a topical ophthalmic solution, with an
appropriate concentration of preservative and dosage regime.
Similarly, we are not persuaded by Appellant’s argument that “asserts
that drug combinations are difficult and are rarely successful or approved by
the FDA.” See App. Br. 11. Appellant adduces no evidence of record in
support of these contentions. See In re Schulze, 346 F.2d 600, 602
(C.C.P.A. 1965) (Argument in the brief does not take the place of evidence
in the record). Furthermore, approval by the FDA is not relevant to the
criteria for patentability that is evaluated by the Office.
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In summary, we are not persuaded by Appellant’s arguments that no
teaching, suggestion, or motivation in the combined cited prior art to
combine the teachings of the art arrive at the claimed combination.
Issue 2
Appellant argues the claimed composition is not obvious because it
exhibits properties that would be unexpected by a person of ordinary skill in
the art. App. Br. 13.
Analysis
Appellant argues that treatment of test subjects with the claimed
composition comprising 0.1% w/v olopatadine hydrochloride and 0.4% w/v
ketorolac tromethamine results in a lower incidence of ciliary hyperemia as
compared 0.1% w/v olopatadine hydrochloride monotherapy, and that this
trend increased over time, becoming statistically significant after weekly
visit 4 and thereafter. App. Br. 13 (citing Spec. 13, Fig. 1). Appellant
contends that these results would have been unexpected by one of ordinary
skill in the art because olopatadine and ketorolac are each known to cause
hyperemia as a side effect and the combination would therefore be
reasonable expected to cause more ciliary hyperemia than monotherapy with
either active agent. Id. (citing Patanol and Acular).
The Examiner responds that, as an initial matter, to establish whether
the effect seen with the combination of olopatadine and ketorolac is
synergistic, one must compare side-by-side the effect of olopatadine alone
versus the effect of ketorolac alone versus the effect of the combined
olopatadine plus ketorolac. Ans. 14. The Examiner finds Appellant has
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provided data only for a comparison between olopatadine alone (at a
concentration of 0.1% w/v) versus olopatadine (0.1% w/v) plus ketorolac
(0.4% w/v). Id. The Examiner finds that, since there is no data for the effect
seen with ketorolac alone (at concentration 0.4% w/v), one cannot draw a
conclusion regarding synergistic effects with the instantly claimed
composition. Id.
The Examiner finds Appellant’s argument regarding unexpected
reduction in ciliary hyperemia with the claimed composition is not
persuasive because, although Yaylali teaches that 0.1% w/v olopatadine
caused slightly less hyperemia than 0.5% w/v ketorolac, the data presented
by Yaylali was obtained from a different patient population, with a different
solution of ketorolac and using a different treatment regimen than that
disclosed by the Specification. Ans. 14. Specifically, the Examiner finds
Yaylali discloses patients being evaluated after day 2, day 7, and day 15,
whereas the Specification discloses patients evaluated after the first week,
and weekly thereafter. Id. As such, finds the Examiner, the scores of
hyperemia taught by Yaylali cannot be meaningfully compared to those in
Appellant’s Specification. Id.
We agree with the Examiner’s findings and conclusions. Appellant’s
Specification does not provide sufficient data such that a meaningful
comparison can be made between the effects generated by either olopatadine
or ketorolac individually, compared to a combination of the two, that
supports a reasonable finding of unexpected results. Appellant is required to
show that the results would be unexpected to a person of ordinary skill in the
art when compared to the teachings of Yaylali. See In re Baxter Travenol
Labs., 952 F.2d 388, 392 (Fed. Cir. 1991) (“[W]hen unexpected results are
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used as evidence of nonobviousness, the results must be shown to be
unexpected compared with the closest prior art”).
Both Acular and Patanol teach that between 1% and 7% of patients
may experience hyperemia (unspecified or conjunctival) as an adverse side
effect of treatment. See Patanol 1; Acular 4. At the same time, hyperemia is
also a known primary symptom of SAC (see Yaylali 378 (“Other signs and
symptoms [of SAC] include conjunctival hyperaemia, tearing, mucus
discharge, chemosis and lid oedema”)) and both olopatadine and ketorolac
are expressly taught by Yayalali as being effective in treating the signs and
symptoms of SAC. See Yaylali Abstr. Furthermore, Yaylali also teaches
that olopatadine and ketorolac operate via different mechanisms. See
Yaylali 379-80. Generally speaking, then, a person of ordinary skill in the
art would reasonably expect to see an additive effect of treatment with
olopatadine or ketorolac in reducing hyperemia in the 93—99% of individuals
with SAC-related symptoms, including hyperemia, and who do not suffer an
adverse response to either drug.
Yaylali is silent with respect to measuring ciliary hyperemia,
presenting data only for itching and conjunctival hyperemia. Consequently,
it is impossible, without direct comparative evidence to the closest prior art,
to determine whether the results disclosed in the Specification would be
unexpected to a person of ordinary skill in the art. Furthermore, the lack of
data in the Specification concerning treatment with ketorolac alone, and the
disparity in the duration of the testing regimes between the Specification
(weekly, extending from 0—3 weeks) and Yaylali (30 minutes, 2, 7, and 15
days), make it impossible to tell whether the results presented in Appellant’s
Specification would be unexpected compared to Yaylali. See Spec. 13, Fig.
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2; Yaylali Abstr. Moreover, our reasoning that a person of ordinary skill in
the art would have reasonably expected to see an additive decrease in SAC-
related symptoms generally, including hyperemia, in response to the
combination of the active agents, in patients not suffering adverse side
effects, is applicable.
With respect to conjunctival hyperemia, Appellant argues: “one of
ordinary skill in the art would expect that a combination of active agents
known to cause hyperemia would cause more conjunctival hyperemia than
the monotherapy of either active agent.” App. Br. 14. However, Yaylali
expressly teaches that treatment with either olopatadine or ketorolac causes
measurable and significant decreases in conjunctival hyperemia. See
Yaylali Table 2, Fig. 2. Consequently, and contrary to Appellant’s
argument, a person of ordinary skill in the art could reasonably have
expected to see a decrease in conjunctival hyperemia in response to
combination treatment as a result of the additive effects of olopatadine or
ketorolac in individuals not suffering adverse effects from the active agents.
Similarly, Yaylali presents no data with respect to measuring either
episcleral hyperemia or chemosis, but expressly teaches a decrease in the
symptoms of SAC (which expressly include hyperemia and chemosis) to
both active agents. See Yaylali 378, Abstr. (“Both olopatadine and ketorolac
ophthalmic solutions were found to be effective in alleviating the clinical
signs and symptoms of SAC compared to placebo”). Therefore, and for the
same reasons explained supra, we are not persuaded by Appellant’s
arguments that the results disclosed in Appellant’s Specification would be
unexpected by a person of ordinary skill in the art in view of the teachings of
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Yaylali. We consequently affirm the Examiner’s rejection of the claims on
this ground.
B. Rejection of claims E 7—10, and 12—15 over Yaylali, Patanof and
Acular, and Lane
Appellant relies upon the same arguments presented with respect to
the prior rejection, arguing that Lane fails to cure the alleged deficiencies of
Yaylali, Patanol, and Acular. App. Br. 15—16. Because, for the reasons
presented supra, we affirm the rejection of claims 1, 7—10, and 12—15 over
the combination of Yaylali, Patanol, and Acular, we similarly affirm the
rejection of the claims on this ground.
DECISION
The Examiner’s rejection of claims 1, 7—10, and 12—15 as
unpatentable under 35 U.S.C. § 103(a) is affirmed.
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
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