Trials@uspto.gov
`Tel: 571-272-7822
`
`
`
` Paper 10
` Entered: October 14, 2014
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`NOVEN PHARMACEUTICALS, INC.,
`Petitioner,
`
`v.
`
`NOVARTIS AG AND LTS LOHMANN THERAPIE-SYSTEME AG,
`Patent Owners.
`____________
`
`Case IPR2014-00550
`Patent 6,335,031 B1
`_____________
`
`
`Before FRANCISCO C. PRATS, ERICA A. FRANKLIN, and
`SCOTT E. KAMHOLZ, Administrative Patent Judges.
`
`FRANKLIN, Administrative Patent Judge.
`
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`Tel: 571-272-7822
`
`
`
` Paper 10
` Entered: October 14, 2014
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`NOVEN PHARMACEUTICALS, INC.,
`Petitioner,
`
`v.
`
`NOVARTIS AG AND LTS LOHMANN THERAPIE-SYSTEME AG,
`Patent Owners.
`____________
`
`Case IPR2014-00550
`Patent 6,335,031 B1
`_____________
`
`
`Before FRANCISCO C. PRATS, ERICA A. FRANKLIN, and
`SCOTT E. KAMHOLZ, Administrative Patent Judges.
`
`FRANKLIN, Administrative Patent Judge.
`
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`IPR2014-00550
`Patent 6,335,031 B1
`
`
`I.
`
`INTRODUCTION
`
`Noven Pharmaceuticals, Inc. (“Petitioner”) filed a Petition to institute
`
`an inter partes review of claims 1–3, 7, 15, 16, and 18 of U.S. Patent No.
`
`6,335,031 (Ex. 1001, “the ’031 patent”). Paper 1 (“Pet.”). Novartis AG and
`
`LTS Lohmann Therapie-Systeme AG (collectively, “Patent Owner”), filed a
`
`Preliminary Response to the Petition. Paper 7 (“Prelim. Resp.”).
`
`We have jurisdiction under 35 U.S.C. § 314, which provides that an
`
`inter partes review may not be instituted “unless . . . there is a reasonable
`
`likelihood that the petitioner would prevail with respect to at least 1 of the
`
`claims challenged in the petition.” Upon considering the Petition and
`
`Preliminary Response, we determine that Petitioner has shown a reasonable
`
`likelihood that it would prevail in showing the unpatentability of claims 1–3,
`
`7, 15, 16, and 18 of the ’031 patent. Accordingly, we institute an inter
`
`partes review of those claims.
`
`A. Related Proceedings
`
`According to Petitioner and Patent Owner, the ’031 patent is involved
`
`in various district court actions, including two actions involving the parties
`
`to this proceeding, titled: Novartis Pharm. Corp. v. Noven Pharm. Inc., 1:13-
`
`cv-00527 (D. Del.); and, Novartis Pharm. Corp. v. Noven Pharm. Inc., 1:14-
`
`cv-00111 (D. Del.). Pet. 1–2; Paper 6 at 2.
`
`Additionally, Petitioner has filed a petition for inter partes review of
`
`related U.S. Patent No. 6,316,023. IPR2014-00549, Paper 1.
`
`
`
`
`
`
`
`
`
`2
`
`
`
`
`
`IPR2014-00550
`Patent 6,335,031 B1
`
`
`B. The ’031 Patent (Ex. 1001)
`
`The ’031 patent is directed to a pharmaceutical composition
`
`comprising (S)-N-ethyl-3-[(1-dimethylamino)ethyl]- N-methyl-phenyl-
`
`carbamate (“compound A”; “rivastigmine”; “S-enatiomer of RA7”) in the
`
`form of a free base or acid addition salt, an antioxidant, and a diluent or
`
`carrier. Ex. 1001, 1:7–47. “Compound A is useful in inhibiting
`
`acetylcholinesterase in the central nervous system, e.g. for the treatment of
`
`Alzheimer’s disease.” Id. at 1:14–16. A transdermal composition
`
`comprising compound A in the form of a free base or acid addition salt, two
`
`polymers, and a plasticizer is disclosed in the prior art. Id. at 1:17–21. The
`
`inventors of the ‘031 patent explained that the composition of the prior art
`
`“is susceptible to degradation, particularly in the presence of oxygen.” Id. at
`
`1:22–24.
`
`The ’031 patent states:
`
`The present applicant has found that stable pharmaceu-
`tical compositions comprising compound A can now be
`obtained, which show insignificant degradation of
`compound A over a prolonged time period, e.g. 2 years,
`as indicated by standard tests, e.g. stress tests.
`
`
`In one aspect, the invention provides a pharmaceutical
`composition comprising Compound A in free base or
`acid addition salt form and an anti-oxidant.
`
`
`The pharmaceutical compositions of the present
`invention show a reduction in degradation by-products in
`stress stability tests.
`
`Id. at 1:29–39.
`
`
`
`
`
`3
`
`
`
`IPR2014-00550
`Patent 6,335,031 B1
`
`
`The ’031 patent discloses that an effective stabilization effect is
`
`achieved “when the antioxidant is selected from tocopherol, esters thereof,
`
`e.g. tocopherol acetate, ascorbyl palmitate, ascorbic acid,
`
`butylhydroxytoluene, butylhydroxyanisone or propyl gallate, preferably α-
`
`tocopherol or ascorbyl palmitate.” Id. at 4:11–16. “The antioxidant may be
`
`conveniently present in an amount of from about 0.01 to about 0.5% . . . by
`
`weight based on the total weight of the pharmaceutical composition.” Id. at
`
`4:16–19.
`
`Additionally, the ’031 patent teaches that “[t]he pharmaceutical
`
`compositions of the invention may contain high amounts of compound A,
`
`e.g. from 1 to 40% by weight.” Id. at 1:40–42.
`
`C. Illustrative Claims
`
`Independent claims 1, 7 and 15 of the ’031 patent are illustrative of
`
`the claims at issue:
`
`1.
`(a)
`
`A pharmaceutical composition comprising:
`a therapeutically effective amount of (S)-N-ethyl-3-{(1-
`dimethylamino)ethyl}-N-methyl-phenyl carbamate in
`free base or acid addition salt form (Compound A);
`about 0.01 to about 0.5 percent by weight of an
`antioxidant, based on the weight of the composition, and
`a diluent or carrier.
`
`Ex. 1001, 8:14–21.
`
`
`(b)
`
`(c)
`
`A transdermal device comprising a pharmaceutical
`7.
`composition as defined by claim 1, wherein the pharmaceutical
`composition is supported by a substrate.
`
`Id. at 8:49–51.
`
`
`
`
`4
`
`
`
`IPR2014-00550
`Patent 6,335,031 B1
`
`
`(S)-N-ethyl-3-{(1-
`stabilizing
`of
`15. A method
`dimethylamino)ethyl}-N-methyl-phenyl-carbamate in free
`base or acid addition salt form (Compound A), wherein the
`method comprises forming a composition by combining
`Compound A with an amount of anti-oxidant effective to
`stabilize Compound A from degradation.
`
`Id. at 9:10–15.
`
`
`D. The Prior Art
`
`Petitioner relies on the following prior art:
`
`Enz
`
`UK Patent Application GB 2,203,040 A,
`published Oct. 12, 1988 (“Enz”)
`
`Handbook Handbook of Pharmaceutical Excipients, (A.
`Wade & P.J. Weller eds., 2d ed. 1944)
`(“the Handbook”)
`
`Sasaki
`
`Ebert
`
`Rosin
`
`Elmalem
`
`JP Patent Application 58-57689, published
`Oct. 19, 1984 (“Sasaki”)
`
`WO 95/24172, published Sept. 14, 1995
`(“Ebert”)
`
`US 4,948,807, issued Aug. 14, 1990
`(“Rosin”)
`
`Antagonism of Morphine-Induced
`Respiratory Depression by Novel
`Anticholinesterase Agents, 3o
`NEUROPHARMACOLOGY. 1059-1064 (1991)
`(“Elmalem”)
`
`Ex. 1002
`
`Ex. 1003
`
`Ex. 1005
`
`
`Ex. 1006
`
`Ex. 1008
`
`Ex. 1009
`
`Petitioner also relies on declarations of Dr. Agis Kydonieus
`
`(Ex. 1010) and Dr. Christian Schöneich (Ex. 1011).
`
`
`
`
`
`
`
`
`
`5
`
`
`
`
`
`IPR2014-00550
`Patent 6,335,031 B1
`
`
`E. The Asserted Grounds
`
`Petitioner challenges claims 1–3, 7, 15, 16, and 18 of the ’031 patent
`
`on the following grounds:
`
`
`Reference(s)
`
`Elmalem
`
`Basis
`
`Claims
`
`§ 102
`
`15
`
`Elmalem and the Handbook
`
`§ 103(a) 16 and 18
`
`Enz and the Handbook, optionally
`in view of Rosin and/or Elmalem
`and/or Ebert
`Enz and the Handbook and/or Rosin
`and/or Ebert
`Enz and Sasaki
`
`
`
`§ 103(a) 1, 2, 7, 15, and 18
`
`§ 103(a) 3 and 16
`
`§ 103(a) 1–3, 7, 15, 16, and 18
`
`35 U.S.C. § 315(a)
`
`Patent Owner asserts that 35 U.S.C. § 315(a) bars the petition.
`
`II.
`
`Prelim. Resp. 1. 35 U.S.C. § 315(a) states, in part:
`
`INTER PARTES REVIEW BARRED BY CIVIL
`(1)
`ACTION.—An inter partes review may not be instituted if,
`before the date on which the petition for such a review is filed,
`the petitioner or real party in interest filed a civil action
`challenging the validity of a claim of the patent.
`
`
`
`Patent Owner asserts that Petitioner “effectively” filed a civil action
`
`challenging the validity of a claim of the ’031 patent before the date of its
`
`petition by filing with the U.S. Food and Drug Administration (“FDA”) a
`
`certification pursuant to 21 U.S.C. § 355(j)(2)(A)(vii)(IV) (“Paragraph IV
`
`certification”) challenging the validity of the ‘031 patent. Id. at 1–2.
`
`According to Patent Owner, upon receiving notice of the Paragraph IV
`
`certification, Patent Owner was forced to bring a civil action to defend the
`
`
`
`6
`
`
`
`IPR2014-00550
`Patent 6,335,031 B1
`
`’031 patent. Id. at 2. Patent Owner asserts that the Federal Circuit “has
`
`characterized the Paragraph IV filer, rather than the patent owner, as the
`
`party who initiates the challenge to patent validity.” Id. (citing In re
`
`Rosuvastatin Calcium Patent Litig., 703 F.3d 511, 515 (Fed. Cir. 2012) and
`
`In re Ciprofloxacin Hydrochloride Antitrust Litig., 544 F.3d 1323, 1334
`
`(Fed. Cir. 2008)). Thus, Patent Owner asserts that although Patent Owner
`
`filed the civil action, Petitioner’s Paragraph IV certification “effectively
`
`constituted the filing of a civil action.” Id. at 4.
`
`
`
`We disagree with Patent Owner. When the statute refers to filing a
`
`civil action, it refers to filing a complaint with a court to commence a civil
`
`action. See, e.g., Baldwin Cnty. Welcome Ctr. v. Brown, 466 U.S. 147, 149
`
`(1984) (a civil action is brought upon filing a complaint with a court);
`
`Ariosa Diagnostics v. Isis Innovation Ltd, Case IPR2012-00022, , slip op. at
`
`4 (PTAB Feb. 12, 2013)(Paper 20) (citing Baldwin, 466 U.S. at 149).
`
`Petitioner’s initiating a challenge to patent validity by filing of a Paragraph
`
`IV certification with the FDA did not involve filing of a complaint with a
`
`court. Thus, Petitioner’s action does not bar institution on the present
`
`Petition under 35 U.S.C. 315(a).
`
`
`
`III. ANALYSIS
`
`A. Claim Construction
`
`In an inter partes review, the Board interprets claim terms in an
`
`unexpired patent according to the broadest reasonable construction in light
`
`of the specification of the patent in which they appear. 37 C.F.R.
`
`§ 42.100(b). Under that standard, and absent any special definitions, we
`
`give claim terms their ordinary and customary meaning, as would be
`
`
`
`7
`
`
`
`IPR2014-00550
`Patent 6,335,031 B1
`
`understood by one of ordinary skill in the art at the time of the invention.
`
`In re Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007). Any
`
`special definitions for claim terms must be set forth with reasonable clarity,
`
`deliberateness, and precision. In re Paulsen, 30 F.3d 1475, 1480 (Fed.
`
`Cir. 1994).
`
`Petitioner proposes constructions for the claim terms “pharmaceutical
`
`composition,” “antioxidant,” “diluent or carrier,” “transdermal device,”
`
`“substrate,” and “adhesive layer.” Pet. 7–8. Patent Owner has not proposed
`
`constructions for these terms. We have determined that express construction
`
`of these terms is not necessary at this time. We, therefore, decline to enter
`
`an express construction of those terms at this time.
`
`Additionally, Petitioner asserts that the claim term “stabilizing” means
`
`“reducing degradation.” Pet. 8 (citing Ex. 1001, 4:5–30). Patent Owner
`
`proposes that this term means “significantly reducing degradation of
`
`Compound A over a prolonged period of time.” Prelim. Resp. 12.
`
`The term “stabilizing” is recited in claim 15, i.e., “A method of
`
`stabilizing … Compound A.” The Specification does not define this term
`
`expressly. The Specification states, “stable pharmaceutical compositions
`
`comprising compound A can now be obtained, which show insignificant
`
`degradation of compound A over a prolonged time period, e.g. 2 years, as
`
`indicated by standard tests, e.g. stress tests.” Ex. 1001, 1:29–33. The
`
`Specification discloses that the addition of tocopherol to a composition
`
`containing compound A resulted in a smaller percentage of degradation
`
`products as compared to compositions not containing tocopherol. Ex. 1001,
`
`at 4:20–30. The percentages of degradation products were determined using
`
`two or three month stress tests. Id. at 4:25, 30.
`
`
`
`8
`
`
`
`IPR2014-00550
`Patent 6,335,031 B1
`
`
`On the current record, we determine that Petitioner’s interpretation is
`
`the broadest reasonable construction in light of the Specification. Although
`
`the Specification describes obtaining stable compositions which show
`
`insignificant degradation of compound A over a prolonged time period and
`
`using a two- or three-month stress test to determine a reduction in
`
`degradation, neither these disclosures, nor the language of claim 15, limit
`
`“stabilizing” to refer only to a reduction in degradation that is significant, or
`
`over a “prolonged” period of time, as urged by Patent Owner. Rather, as
`
`claimed, “stabilizing” broadly covers any reduction in degradation over any
`
`period of time.
`
`Similarly, Petitioner asserts that the claim phrase “an amount of
`
`antioxidant effective to stabilize Compound A from degradation” means “an
`
`amount of antioxidant that reduces oxidative degradation of Compound A.”
`
`Pet. 8 (citing Ex. 1001, 1:29-33). Patent Owner proposes that this term
`
`means “an amount of antioxidant that will significantly reduce degradation
`
`of Compound A over a prolonged period of time.” Prelim. Resp. 8–9. On
`
`the current record, we agree that Petitioner’s interpretation is the broadest
`
`reasonable construction in light of the Specification for the same reason
`
`discussed regarding the term “stabilizing.”
`
`Petitioner proposes also that we construe the term “(S)-N-ethyl-3-{(1-
`
`dimethylamino)ethyl}-N-methylphenyl carbamate” as referring to
`
`rivastigmine, i.e., the S-enantiomer of a racemic mixture known as RA7. Id.
`
`at 8–9. Patent Owner agrees with this characterization, and further clarifies
`
`that the racemate, RA7, is N-ethyl-3-{(1-dimethylamino)ethyl}-N-methyl-
`
`phenyl-carbamate HCl. Prelim. Resp. 13. Upon consideration of the record,
`
`we determine that the agreed-upon construction is consistent with the plain
`
`
`
`9
`
`
`
`IPR2014-00550
`Patent 6,335,031 B1
`
`and ordinary meaning in the context of the Specification. We adopt the
`
`agreed-upon construction.
`
`Additionally, Petitioner proposes that we construe the term
`
`“comprising” as “embrac[ing] compositions containing both rivastigmine
`
`and its enantiomer, including compositions containing racemic RA7.” Pet. 9.
`
`Patent Owner asserts that although the term “comprising” indicates that “the
`
`challenged claims can encompass some amount of (R)-enantiomer, that
`
`amount cannot be equal to or greater than the amount of (S)-enantiomer.”
`
`Prelim. Resp. 14. We note, however, that Enz, which Petitioner relies upon
`
`for each ground that we address in the Petition, discloses a pharmaceutical
`
`composition containing rivastigmine, i.e., the S-enantiomer. Ex. 1002,
`
`Abstract. In other words, the grounds addressed in this decision do not rely
`
`on a disclosure of a composition comprising the racemate RA7 to meet the
`
`limitation in the claims specifically reciting the S-enantiomer. Accordingly,
`
`for purposes of this decision, we determine that no express claim
`
`construction is necessary for the claim term “comprising.”
`
`B. Obviousness of Claims 1, 2, 7, 15, and 18 over Enz (Ex. 1002) and
`the Handbook (Ex. 1003), Optionally in View of Rosin (Ex. 1008 )
`and/or Elmalem (Ex. 1009) and/or Ebert (Ex. 1006)
`
`Petitioner contends that claims 1, 2, 7, 15, and 18 are unpatentable
`
`
`
`over the combination of Enz and the Handbook, optionally in view of Rosin
`
`and/or Elmalem and/or Ebert. Pet. 30-41.
`
`1.
`
`Enz
`
`Enz discloses compositions for systemic transdermal administration
`
`containing (S)-N-ethyl-3-[(1-dimethylamino)ethyl]-N-methyl-phenyl
`
`carbamate of formula I
`
`
`
`10
`
`
`
`IPR2014-00550
`Patent 6,335,031 B1
`
`
`
`
`
`
`in free base or acid addition salt form. Ex. 1002, 1–2.
`
`Enz explains that the racemic mixture (±)-N-ethyl-3-[1-
`
`dimethylamino)ethyl]-N-methyl-phenyl-carbamate in the form of its
`
`hydrochloride is known as RA7. Id. Enz teaches that (S)-N-ethyl-3-[(1-
`
`dimethylamino)ethyl]-N-methylphenyl carbamate in free base may be
`
`prepared from the racemate by separation of the enantiomers in accordance
`
`with known methods. Id. The acid addition salts may be prepared from the
`
`free base according to a known manner. Id. Enz teaches that Compound A,
`
`the compound of formula I in form of its hydrogen tartrate, is “slightly
`
`superior than” the racemic mixture. Id. at 3–5.
`
`Additionally, Enz discloses providing “a pharmaceutical composition
`
`comprising a compound according to the invention in association with at
`
`least one pharmaceutical carrier or diluent.” Id. at 10. In Example 2, Enz
`
`discloses a preparation of a transdermal composition comprising 20% of a
`
`compound of formula I, e.g., compound A, 30% of a hydrophilic polymer,
`
`e.g., Eudragit E 100, 44% of a non-swellable acrylate polymer, e.g.,
`
`Durotack 280-2416, and 6% of a plasticizer, e.g., Brij 97. Id. at 19. The
`
`composition is spread on top of an aluminized foil to produce a film that is
`
`allowed to dry. Id. Thereafter, the aluminum foil is cut into patches. Id.
`
`Enz discloses that an indicated daily dosage is in the range from about
`
`0.1 to about 25 mg, e.g., 0.1 to about 5 mg of a compound according to the
`
`invention. Id. at 10.
`
`
`
`11
`
`
`
`IPR2014-00550
`Patent 6,335,031 B1
`
`
`2.
`
`The Handbook
`
`The Handbook lists pharmaceutical excipients and provides a
`
`description of each excipient, including nonproprietary and chemical names,
`
`structural formula, functional category, applications in pharmaceutical
`
`formulation or technology, and in some cases, the normal usage
`
`concentration range. Ex. 1003, 5. The Handbook identifies several
`
`excipients as antioxidants, including alpha tocopherol, normally used in the
`
`concentration range of 0.001–0.05%. Id. at 5–7.
`
`3.
`
`Rosin
`
`Rosin discloses phenyl carbamates that inhibit acetylcholinesterase in
`
`the mammalian brain after systemic administration, e.g., orally or
`
`parenterally. Ex. 1008, 4:16–20. Preferred compounds of the invention
`
`include N-ethyl, N-methyl-3[(1-dimethylamino)ethyl]phenyl carbamate, i.e.,
`
`RA7. Id. at 5:40–45; 12:56–60; 14:17–19. The compounds may be
`
`combined “with a physiologically acceptable vehicle, carrier, excipient,
`
`binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called
`
`for by accepted pharmaceutical practice.” Id. at 7:19–24. The compositions
`
`may be formulated as tablets, capsules or elixirs for oral administration or in
`
`sterile solutions or suspensions for parenteral administration. Id. at 7:15–19.
`
`Rosin states:
`
` Sterile compositions for injection can be formulated
`according to conventional pharmaceutical practice by
`dissolving or suspending the active substance in a vehicle
`such as water for injection. Buffers, preservatives,
`antioxidants and the like can be incorporated as required.
` Preferred antioxidants for use with the compounds of
`the present invention include sodium metabisulphite
`and ascorbic acid.
`
`
`
`
`
`12
`
`
`
`IPR2014-00550
`Patent 6,335,031 B1
`
`Id. at 7:45–53.
`
`4.
`
`Elmalem
`
`Elmalem is a journal article discussing a study comparing the effects
`
`of three anticholinesterase agents, including RA7, with those of
`
`physostigmine on the respiratory depression induced by morphine in rabbits.
`
`Ex. 1009 at 1059. Elmalem explains that each of these four drugs was
`
`“made up freshly in sterile saline, which included an equal weight of sodium
`
`metabisulphite, to prevent oxidation.” Id. at 1060.
`
`5.
`
`Ebert
`
`Ebert discloses a drug-containing adhesive composite transdermal
`
`delivery device comprising a substantially drug impermeable proximal
`
`release liner and a method for making the device. Ex. 1006, Abstract. Ebert
`
`explains that although its disclosure specifically refers to nicotine as the
`
`active drug, “any other liquid drug contained in an active gel which can be
`
`transdermally or transmucosally delivered may be substituted in place of
`
`nicotine.” Id. at 15:30–35. With respect to nicotine, Ebert explains that a
`
`“trait of nicotine that can be problematic is its tendency to oxidize readily in
`
`the presence of light and air.” Id. at 21:18–20. Ebert teaches that “[d]uring
`
`fabrication of nicotine patches, oxidation is controlled by addition of an
`
`antioxidant to the active gel,” wherein BHT is a preferred antioxidant. Id. at
`
`21:23–26. Ebert teaches mixing BHT with nicotine preferably in the range
`
`of about 0.01–1.0% w/w. Id. at 21:26–28.
`
`6.
`
`Analysis
`
`Based on the information presented in the Petition, we are persuaded
`
`that Petitioner has made a sufficient showing the inventions of claims 1, 2, 7,
`
`15, and 18 of the ’031 patent would have been obvious over the combination
`
`Enz, the Handbook, Rosin, Elmalem, and Ebert to a person of ordinary skill
`
`
`
`13
`
`
`
`IPR2014-00550
`Patent 6,335,031 B1
`
`in the art at the time of the invention.
`
`a.
`
`Claim 1
`
`Petitioner asserts that Enz teaches a composition that meets every
`
`limitation of claim 1, except the addition of an antioxidant. Pet. 30.
`
`Specifically, Petitioner asserts that Enz discloses in Example 2 a
`
`pharmaceutical composition, e.g., a transdermal device, comprising the
`
`hydrogen tartrate salt of rivastigmine, i.e., (S)-N-ethyl-3-[(1-
`
`dimethylamino)ethyl]-N-methylphenyl carbamate, Eudragit E 100 (a
`
`hydrophilic polymer) and Durotack 280-2416 (an acrylic adhesive), i.e., a
`
`diluent or carrier, and Brij 97 (a plasticizer). Id. at 30–31. Petitioner asserts
`
`that Enz discloses a daily dosage of from about 0.1 to about 25 mg of
`
`rivastigmine, i.e., a therapeutically effective amount of Compound A. Id. at
`
`31 (citing Ex. 1002 at 10). At this time, Patent Owner has not disputed that
`
`Enz discloses these limitations of claim 1. See Prelim. Resp. 1–28. Based
`
`on the information presented at this stage of the proceeding, Petitioner has
`
`shown sufficiently that Enz teaches these limitations of claim 1.
`
`According to Petitioner, at the time of the invention, a person of
`
`ordinary skill in the art who endeavored to formulate rivastigmine into a
`
`transdermal patch, as taught by Enz, would have investigated the stability of
`
`the drug. Id. at 32; Ex. 1010 ¶ 59. Petitioner asserts that each of Elmalem
`
`and Rosin teach or suggest the addition of an antioxidant to compositions
`
`comprising RA7. Id. (citing Ex. 1009 at 2, Ex. 1010 ¶ 59; Ex. 1008 at 7:45–
`
`53). Petitioner asserts that a person of ordinary skill in the art would have
`
`understood from these references that RA7 was susceptible to oxidation and
`
`“would have known that there would be little or no difference between
`
`rivastigmine and RA7 with respect to oxidation.” Id. at 32–33 (citing Ex.
`
`
`
`14
`
`
`
`IPR2014-00550
`Patent 6,335,031 B1
`
`1010 ¶ 60).
`
`Further, Petitioner asserts that in investigating the stability of
`
`rivastigmine, a person of ordinary skill in the art “would have reasonably
`
`expected, based on the molecular structure of the drug, that rivastigmine
`
`would be susceptible to oxidative degradation.” Id. at 34–35 (citing Ex.
`
`1010 ¶ 63; Ex. 1011¶¶ 52–59). In particular, Petitioner submits the
`
`declaration of Dr. Christian Schӧneich, as supporting the position that a
`
`person of ordinary skill in the art would have recognized the similarities
`
`between the structure of rivastigmine and nicotine and “would have
`
`expected that rivastigmine would be susceptible to oxidative degradation at
`
`the benzylic C-H bond and the adjacent tertiary amine via similar
`
`mechanisms as nicotine and to roughly the same extent as nicotine.” Id. 35–
`
`36 (citing Ex. 1011 ¶ 59).
`
`In this vein, Petitioner asserts that Ebert taught that “nicotine was
`
`known to readily oxidize in the presence of light and air, and that adding an
`
`antioxidant . . . could reduce that oxidation.” Id. at 36 (citing Ex. 1006 at
`
`[21]). Therefore, according to Petitioner, a person of ordinary skill in the art
`
`would have had reason to combine rivastigmine with an antioxidant to
`
`protect against degradation based on the teachings of Rosin, Elmalem, and
`
`Ebert. Id. at 37 (citing Ex. 1010 ¶ 64). Moreover, Petitioner asserts that
`
`these teachings would have provided a person of ordinary skill a reasonable
`
`expectation of successfully protecting rivastigmine against oxidative
`
`degradation by adding an antioxidant to the composition. Id. (citing Ex.
`
`1006 at 21; Ex. 1010 ¶ 63; Ex. 1011 ¶61).
`
`Based on the information presented in the Petition, we are persuaded
`
`that Petitioner has established a reasonable likelihood of showing that it
`
`
`
`15
`
`
`
`IPR2014-00550
`Patent 6,335,031 B1
`
`would have been obvious to a person of ordinary skill in the art at the time
`
`of the invention to combine an antioxidant with the pharmaceutical
`
`composition disclosed by Enz. Specifically, on this record, Petitioner has
`
`shown sufficiently that each of Rosin and Elmalem suggests combining an
`
`antioxidant with the racemate, RA7, may be useful. Ex. 1008 at 7:45–50;
`
`Ex. 1009 at 1059. Elmalem discloses adding an antioxidant to prevent
`
`oxidation of various compounds, including RA7. Ex. 1009 at 1059.
`
`Petitioner provided testimony that a person of ordinary skill in the art at the
`
`time of the invention would have considered the prior art teaching or
`
`suggestion to add an antioxidant to RA7 to be applicable also to its S-
`
`enantiomer, rivastigmine. Pet. 32–33 (citing Ex. 1010 ¶ 60).
`
`Further, Petitioner provided testimony discussing the chemical
`
`structure of rivastigmine and an explanation why a person of ordinary skill
`
`in the art would have understood from its structure that rivastigmine was
`
`susceptible to oxidation. Pet. 34–35 (citing Ex. 1010 ¶ 63; Ex. 1011¶¶ 52–
`
`59). Moreover, this discussion involved a comparison of similar features
`
`present in the chemical structures of rivastigmine and nicotine, a drug
`
`known to be susceptible to oxidation, wherein such oxidation is controlled
`
`by the addition of an antioxidant. Id. at 35 (citing Ex. 1011 ¶¶ 56–60; Ex.
`
`1006 at 21). Thus, on the current record, Petitioner has articulated sound
`
`reasoning with rational underpinning to support a motivation for combining
`
`the teachings of the prior art. See In re Kahn, 441 F.3d 977, 988 (Fed. Cir.
`
`2006), cited with approval in KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398,
`
`417–18 (2007).
`
`Petitioner also asserts that a person of ordinary skill in the art easily
`
`would have determined the optimal antioxidant and its concentration by
`
`
`
`16
`
`
`
`IPR2014-00550
`Patent 6,335,031 B1
`
`referencing the Handbook and by routine experimentation. Pet. 37.
`
`Moreover, Petitioner asserts that the antioxidant range of 0.01 to 0.5 weight
`
`percent of the composition recited in claim 1 overlaps the antioxidant ranges
`
`taught in the prior art. Id. Therefore, Petitioner asserts that it would have
`
`been obvious for a person of ordinary skill in the art at the time the invention
`
`was made to have modified the transdermal device in Enz to include an
`
`antioxidant within the range recited in claim 1. Id.
`
`Based on the information presented in the Petition, we are persuaded
`
`that Petitioner has made a sufficient showing of obviousness with respect to
`
`the weight percent range of antioxidant recited in claim 1, considering the
`
`recited range overlaps the ranges disclosed in the Handbook and the prior
`
`art. See In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003) (“A prima
`
`facie case of obviousness typically exists when the ranges of a claimed
`
`composition overlap the ranges disclosed in the prior art.”); Ex. 1003 at 5–
`
`23.
`
`b.
`
`Claim 2
`
`Claim 2 depends from claim 1, further requiring the pharmaceutical
`
`composition of claim 1 to contain “1 to 40% by weight of Compound A.”
`
`Petitioner asserts that in Example 2, Enz discloses a preparation of a
`
`transdermal composition comprising 20% by weight of compound A, which
`
`falls within the range required by claim 2. Pet. 38 (citing Ex. 1002 at 20).
`
`Therefore, based on the information presented in the Petition, we are
`
`persuaded that Petitioner has made a sufficient showing that claim 2 would
`
`have been obvious over the combined references to a person of ordinary skill
`
`in the art at the time the invention was made.
`
`
`
`
`
`17
`
`
`
`IPR2014-00550
`Patent 6,335,031 B1
`
`
`c.
`
`Claim 7
`
`Claim 7 depends from claim 1, further requiring that the
`
`pharmaceutical composition of claim 1 is part of a transdermal device that is
`
`supported by a substrate. Petitioner asserts that in Example 2, Enz discloses
`
`a transdermal device comprising an aluminum foil backing layer which is a
`
`substrate that supports the composition. Pet. 38 (citing Ex. 1002 at 20; Ex.
`
`1010 ¶ 67). Based on the information presented at this stage of the
`
`proceeding, Petitioner has shown sufficiently that Enz teaches these
`
`additional limitations of claim 7.
`
`d.
`
`Claims 15 and 18
`
`Independent claim 15 is directed to a method of “stabilizing”
`
`Compound A, wherein the method comprises combining Compound A with
`
`“an amount of anti-oxidant effective to stabilize Compound A from
`
`degradation.” Claim 18 depends from claim 15 and further recites that “the
`
`anti-oxidant is present in an amount of from about 0.01 to 0.5% by weight
`
`based on the weight of the composition.” Petitioner asserts that a person of
`
`ordinary skill in the art would have been motivated to combine rivastigmine
`
`with an antioxidant for the reasons discussed regarding claim 1. Pet. 38–40.
`
`Specifically, Petitioner asserts that Ebert teaches that adding an antioxidant
`
`reduces the oxidation during manufacture. Id. at 39 (citing Ex. 1006 at 21.)
`
`Further, Petitioner asserts that Ebert and the Handbook teach adding an
`
`amount of antioxidant that overlaps the amount recited in claim 18.
`
`According to Petitioner, adding an antioxidant in this amount to the
`
`composition of Enz for the purpose of reducing degradation would have
`
`resulted in a person of ordinary skill in the art practicing the method of claim
`
`15. Id.
`
`
`
`18
`
`
`
`IPR2014-00550
`Patent 6,335,031 B1
`
`
`We have interpreted the claim term “stabilizing” to mean “reducing
`
`degradation,” and the claim phrase “an amount of anti-oxidant effective to
`
`stabilize Compound A from degradation” to mean “an amount of anti-
`
`oxidant that reduces oxidative degradation of Compound A.” Based on
`
`these constructions and the information presented at this stage of the
`
`proceeding, Petitioner has shown sufficiently that practicing the method of
`
`claim 15 would have been obvious to a person of ordinary skill in the art
`
`who made the modified composition discussed regarding claim 1.
`
`In sum, we are persuaded that Petitioner has made a sufficient
`
`showing, on the current record, that the cited references teach or suggest the
`
`inventions of claims 1, 2, 7, 15, and 18 of the ’031 patent. Accordingly, we
`
`determine that Petitioner has established a reasonable likelihood of
`
`prevailing on its assertion that claims 1, 2, 7, 15, and 18 would have been
`
`obvious over the combination of Enz, the Handbook, Rosin, Elmalem, and
`
`Ebert under 35 U.S.C. § 103(a).
`
`C. Obviousness of Claims 3 and 16 over Enz (Ex. 1002) and
`the Handbook (Ex. 1003) and/or Rosin (Ex. 1008 )
`and/or Ebert (Ex. 1006)
`
`Petitioner contends that claims 3 and 16 would have been obvious to a
`
`
`
`person of ordinary skill in the art at the time of the invention over the
`
`combination of Enz and the Handbook and/or Rosin and/or Ebert. Pet. 41–
`
`43. Claim 3 depends from claim 1 and further recites “wherein the anti-
`
`oxidant is tocopherol, esters thereof, ascorbic acid, butylhydroxytoluene,
`
`butylhydroxyanisole or propyl gallate.” Claim 16 depends from claim 15
`
`and also further recites “wherein the anti-oxidant is tocopherol, esters
`
`thereof, ascorbic acid, butylhydroxytoluene, butylhydroxyanisole or propyl
`
`gallate.”
`
`
`
`19
`
`
`
`IPR2014-00550
`Patent 6,335,031 B1
`
`
`Petitioner asserts that a person of ordinary skill in the art would have
`
`been motivated to modify Enz’s transdermal patch by adding an antioxidant
`
`for the reasons discussed regarding the challenge of claims 1 and 15. Pet.
`
`41–42. Additionally, Petitioner asserts that many of the antioxidants recited
`
`in claims 3 and 16 are listed in the Handbook. Id. at 42 (citing Ex. 1003 at
`
`3–23). According to Petitioner, a person of ordinary skill in the art at the
`
`time of the invention would have been motivated to select one of these
`
`known antioxidants listed in the Handbook because inclusion in the
`
`Handbook indicates approved use in pharmaceuticals. Id. (citing Ex. 1010 ¶
`
`74).
`
`
`
`Further, Petitioner asserts that Rosin provides motivation with a
`
`reasonable expectation of success to select ascorbic acid as an antioxidant.
`
`Id. Petitioner asserts that Rosin teaches that preferred antioxidants for use
`
`with compounds of its invention, e.g., RA7, include ascorbic acid. Id. (citing
`
`Ex. 1008 at 5:44–45; 7:51–53). Additionally, Petitioner asserts that Ebert
`
`provides motivation with a reasonable expectat
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
