Ex Parte KOO et al

Patent Trials and Appeals Board

Jun 5, 2019

14425443 - (D) (P.T.A.B. Jun. 5, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
14/425,443 03/03/2015
23914 7590 06/07/2019
HENRY HADAD
BRISTOL-MYERS SQUIBB COMPANY
PA TENT DEPARTMENT
POBOX4000
PRINCETON, NJ 08543-4000
FIRST NAMED INVENTOR
OTILIA MAY YUE KOO
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www .uspto.gov
ATTORNEY DOCKET NO. CONFIRMATION NO.
12190USPCT 6652
EXAMINER
ROSENTHAL, ANDREWS
ART UNIT PAPER NUMBER
1613
NOTIFICATION DATE DELIVERY MODE
06/07/2019 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):
patents@bms.com
wendy.torres@bms.com
bms _pair@firsttofile.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte OTILIA MAY YUE KOO, FARANAK NIKFAR, JING TAO,
NIRANJAN KUMAR KOTTALA, and SAILESH A. VARIA
Appeal2019-000542
Application 14/425,443
Technology Center 1600
Before DEBORAH KATZ, ULRIKE W. JENKS, and JOHN G. NEW,
Administrative Patent Judges.
JENKS, Administrative Patent Judge.
DECISION ON APPEAL
Appellants 1 submit this appeal2 under 35 U.S.C. § 134(a) involving
claims to formulations of atazanavir and cobicistat. Examiner rejected the
claims as obvious. 3 We have jurisdiction under 35 U.S.C. § 6(b ).
We AFFIRM.
1 Appellants identify the Real Party in Interest as Bristol-Myers Squibb
Company. App. Br. 1.
2 We have considered and herein refer to the Specification of March 3, 2015
("Spec."); Final Office Action of July 14, 2016 ("Final Act."); Appeal Brief
of March 7, 2017 ("App. Br."); and Examiner's Answer of April 13, 2017
("Ans.").
3 Examiner withdrew the rejection of claims 5-13, 24--34, 36--38, and 43--47
under 35 U.S.C. § 112(b) for being indefinite. Ans. 12.
Appeal 2019-000542
Application 14/425,443
STATEMENT OF THE CASE
"[S]ignificant reductions in death rates among AIDS patients have
been recently documented as a consequence of the widespread application of
combination therapy." Spec. 2:9-11. "Because all HIV drugs must be taken
as part of a combination regimen, there must be new and better ways to
ensure that the patient actually takes each medication as prescribed." Id. at
5 :2--4. "[W]hat is now needed in the art are new, easily administered
combination formulations containing potent antiretroviral drugs which are
useful in the treatment against HIV ... [, are] physically stable and have low
degradant levels, and [] provide efficacious dosing of important HIV
medications." Id. at 5: 10-14.
"In particular, stable, easily administered fixed dose combinations
(FDCs) containing atazanavir and cobicistat are desired." Spec. 5: 16-1 7.
"[ A ]tazanavir, has now established itself as a firstline antiretroviral in the
treatment of HIV." Id. at 2:21-22. "Like other protease inhibitors,
[atazanavir] is used only in combination with other HIV medications." Id. at
3: 6-7. Cobicistat "has significant ability to inhibit liver enzymes that
metabolize other medications used to treat HIV .... It also inhibits intestinal
transport proteins, increasing the overall absorption of several HIV
medications, including atazanavir." Id. at 4:9-12. Cobicistat 150 mg tablets
(TYBOSTâ„¢) are indicated as a boosting agent for atazanavir 300 mg once
daily. Id. at 4:20-24.
Claims 2-13, 24--34, 36-38 and 43--47 are on appeal, and can be
found in the Claims Appendix of the Appeal Brief. 4 Independent claims 25
4 Claims 1, 21-23, and 39--42 are cancelled. Claims 14--20 and 35 are
withdrawn.
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Application 14/425,443
and 26 are representative of the different claim groups and are reproduced
below:
25. A tableted composition comprising atazanavir, cobicistat
and a pharmaceutically acceptable carrier, said composition
providing a blood concentration profile of atazanavir in healthy
subjects as measured by AUC(O-T) that is from about 80% to
125% of 34848 ng·h/mL.
26. A tableted composition comprising atazanavir, cobicistat
and a pharmaceutically acceptable carrier, said composition
being in the form of a bilayer tablet and comprising less than or
equal to about 4.0% of total cobicistat impurities.
App. Br. 13-14 (Claims Appendix).
Appellants request review of Examiner's rejection of claims 2-13,
24--34, 36-38 and 43--47 under 35 U.S.C. § 103(a) over Nikfar, 5 Tybost6 and
Kottala. 7
Obviousness over Nilifar, Tybost, and Kottala
Examiner found Nifkar teaches a bilayer tablet containing atazanavir
and cobicistat. Ans. 4. Examiner found Tybost teaches an effective
combination of 300 mg of atazanavir and 150 mg of cobicistat. Id. at 6. As
to the blood profile limitations of claims 24 and 25, and the stability
limitations of claims 26 and 30, Examiner found these properties are
necessarily present in the combined teaching of the prior art. See id. at 7-8.
5 Nikfar et al., WO 2011/127244 A8, published October 13, 2011 ("Nikfar").
6 European Medicines Agency, Assessment Report Tybost,
EMA/CHMP/609914/2013 (July 25, 2013) ("Tybost").
7 N. Kottala et al., Influence of compaction properties and interfacial
topography on the performance of bilayer tablets, 436 INTL. J.
PHARMACEUTICS 171-178 (2012) ("Kottala").
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Application 14/425,443
Appellants contend that the cited references to do not establish a
reasonable likelihood of success. App. Br. 7-8. In particular, Appellants
argue that Nikfar "equate[s] monolithic tablets and multi-layer tablets
without indicating any impact on the bioavailability of the atazanavir caused
by the presence of cobicistat or the control of impurities and degradation
products." Id. Appellants argue that the secondary references "fail to
compensate for the shortcomings of the primary reference, Nikfar." Id. at 9.
The issue is whether the preponderance of the evidence of record
supports Examiner's conclusion that the combination of references renders a
bilayer composition containing atazanavir and cobicistat obvious.
Findings of Fact
We agree with and adopt the findings concerning the scope and
content of the prior art as well as the conclusion as set forth in the
Examiner's Answer and the Final Office Action. The findings of fact
reproduced below are referenced to highlight certain pertinent evidence.
FF 1. Nikfar teaches compressed tablets containing atazanavir sulfate and an
acidifying agent, optionally with another anti-HrV active agent.
Nikfar, Abstr. The other active agent may include cobicistat. Id. at
13:28-29; see also p. 21, claims 1, 7.
FF2. Nifkar teaches"[ w ]hen another agent having anti-HIV activity is
included in the compressed tablet, it may be included within the same
phase as the atazanavir sulfate or its formulation, i.e., as a monolithic
tablet, or it may be included within another phase, i.e., a multi-layer
tablet." Nikfar 19:4--20:2. "When included in a multi-layer tablet, the
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Application 14/425,443
atazanavir sulfate is in one layer and the other agent ( or agents) are in
another layer, e.g., bilayer." Id. at 20:4--5.
FF3. Tybost teaches cobicistat ( 150 mg) is a pharmaco-enhancer co-
administered with atazanavir (300 mg), taken orally, once daily with
food. Tybost 9--10.
FF4. Tybost teaches "cobicistat under ambient conditions undergoes
moisture and temperature induced phase transition from a foam into a
rubber-like material. To increase physical stability of cobicistat it is
adsorbed on silicon dioxide." Tybost 11.
FF5. Tybost teaches "[ t ]he choice of dosage form for the cobicistat drug
product was also determined by the physical and chemical stability of
the active ingredient, degradation pathways of the active ingredient,
size of the unit dose, manufacturability, and biopharmaceutical
performance of the active substance." Tybost 12-13. Tybost teaches
"[t]he formulation was further adjusted for a dry granulation process,"
wherein "[b ]oth tablet formulations ( dry granulation formulation and
Phase 1/2 formulation) were confirmed to be bioequivalent." Tybost
13.
Principles of Law
"[P]roper analysis under § 103 requires, inter alia, consideration of
two factors: (1) whether the prior art would have suggested to those of
ordinary skill in the art that they should make the claimed composition or
device, or carry out the claimed process; and (2) whether the prior art would
also have revealed that in so making or carrying out, those of ordinary skill
would have a reasonable expectation of success." PAR Pharm., Inc. v. TWI
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Application 14/425,443
Pharm., Inc., 773 F.3d 1186, 1196 (Fed. Cir. 2014). "The reasonable
expectation of success requirement for obviousness does not necessitate an
absolute certainty for success." Id. at 1198.
Analysis
Examiner found that the prior art teaches "a tablet, in the form of a
bilayer, is a suitable arrangement of [atazanavir and cobicistat] along with a
carrier for the treatment of HIV. Moreover, the art suggests the same dosage
as claimed." Ans. 8; see also FFsl-3. Examiner acknowledged "that the
prior art does not teach the claimed blood profile" of claims 24 and 25.
Ans. 9. However, Examiner concluded "[m]ere recognition of latent
properties in the prior art does not render nonobvious an otherwise known
invention. The fact that Appellant has recognized another advantage which
would flow naturally from following the suggestion of the prior art cannot
be the basis for patentability ... " Id. As to claims 26 and 30, reciting an
upper limit of cobicistat impurities and degradants, Examiner found "Nikfar
already teaches the claimed composition comprising atazanivir and
cobicistat and Tybost is applied for its teachings of a more stable form of the
latter drug." Id. at 11; see FF 4, 5. Examiner concluded "it would have been
obvious to use the more stable form of cobicistat in the bilayer tablet of
Nikfar and since Tybost teaches that no degradation is present, the skilled
artisan would have had a reasonable expectation of success that the bilayer
tablet would also be stable and show no degradation." Ans. 11.
Appellants contend "the references, when viewed as a whole without
the benefit of knowing what Appellant's invention is, fail to provide the
motivation to combine them in the manner suggested by the Patent Office
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with a reasonable likelihood of success." App. Br. 9. Moreover, Appellants
contend the "specification and drawings demonstrate the effectiveness the
multilayer tablet had on the bioavailability and control of impurities and
degradants." Id. at 9--10.
In particular, Appellants contend that the Specification demonstrates a
bilayer tablet maintains cobicistat impurities of less than 2% at 12 months.
App. Br. 8, citing Fig. 6. In contrast, a monolithic tablet, in which cobicistat
and atazanavir are mixed, is characterized by cobicistat impurities of 3 .5% at
8 weeks. Id. Appellants contend "[t]his result could not have been predicted
by the disclosure ofNikfar." Id.
As to the secondary references, Appellants contend that Kottala and
Tybost do not "disclose tableted compositions comprising atazanavir and
cobicistat ... could be prepared with sufficient bioavailablity to approximate
the bioavailability of atazanavir and cobicistat when administered
separately; and ... [at the same time] control the impurities and degradation
of cobicistat in the tableted composition by utilizing a multi-layer tablet
rather than a monolithic tablet." App. Br. 9.
We are not persuaded. The prior art suggests to a person of ordinary
skill in the art to make a bilayer tablet containing atazanavir in one layer and
cobicistat in another layer for combination therapy of HIV. That the prior
art also suggests a monolithic tablet as an alternative, and that the monolithic
tablet is insufficient to provide a suitable drug product, does not negate the
reasonable expectation of success, as "obviousness cannot be avoided
simply by a showing of some degree of unpredictability in the art."
Allergan, Inc. v. Sandoz Inc., 726 F.3d 1286, 1292 (Fed. Cir. 2013).
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Here, Examiner established a reasonable expectation of success based
on Nikfar's teachings of a bilayer tablet and Tybost's teachings regarding
co-administration of atazanavir and stabilized cobicistat. Appellants have
not provided any evidence that a person of ordinary skill in the art would
have expected a bilayer tablet of atazanavir and cobicistat to suffer from
reduced bioavailability and stability. See PAR Pharm., 773 F .3d at 1196
("The presence or absence of a reasonable expectation of success is [] a
question of fact"). Rather, as cited by the Examiner, Tybost teaches toward
effective co-administration of the compounds and stable formulations of
cobicistat. See id. Therefore, we agree with Examiner's conclusion that a
person of ordinary skill in the art would have had a reasonable expectation
of success in preparing a bilayer tablet for co-administering atazanavir and
cobicistat.
The independent claims include further limitations regarding a blood
concentration profile of atazanavir ( claims 24 and 25), total cobicistat
impurities ( claim 26), and presence of cobicistat degradants ( claim 30).
App. Br. 2-3. Appellants contend "[t]he claims on appeal do not stand or
fall together." App. Br. 2. However, Appellants do not present separate
arguments for the independent claims as compared to the prior art.
Separately arguing a claim requires "more substantive arguments in an
appeal brief than a mere recitation of the claim elements and a naked
assertion that the corresponding elements were not found in the prior art."
In re Lovin, 652 F.3d 1349, 1357 (Fed. Cir. 2011). Accordingly we consider
the claims together.
Appellants contend "the Patent Office has not provided any reason,
apart from its own statement to the contrary, to question the inventiveness of
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Application 14/425,443
the claims which recite blood concentration levels and limitations on the
presence of impurities and degradants." App. Br. 9. In response, Examiner
argues that these are latent properties in the formulation and do not support
patentability. See Ans. 9.
We agree with the Examiner. As discussed above, the bilayer
formulation would have been obvious to a person of ordinary skill in the art.
"[ A ]n obvious formulation cannot become nonobvious simply by
administering it to a patient and claiming the resulting serum
concentrations." Santarus, Inc. v. Par Pharm., Inc., 694 F.3d 1344, 1354
(Fed. Cir. 2012 ). Likewise, as applied to the claim limitations of impurities
and degradants, we conclude that these limitations add nothing of patentable
consequence, as "[t]o hold otherwise would allow any formulation-no
matter how obvious-to become patentable merely by testing and claiming
an inherent property." Id.
Having considered all of Appellant's arguments and having found
them to be unpersuasive, we affirm Examiner's rejections of claims 24, 25,
26, and 30 for the reasons of record. Claims 2-13, 27-29, 31-34, 36-38,
and 43--47 fall with claims 24, 25, 26, and 30.
SUMMARY
We affirm the rejection under 35 U.S.C. § 103(a) over Nikfar, Tybost,
and Kottala.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(l)(iv).
AFFIRMED
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