Trials@uspto.gov
`571-272-7822
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` Paper 12
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`Entered: August 17, 2016
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`DR. REDDY’S LABORATORIES, LTD. and
`DR. REDDY’S LABORATORY, INC.,
`Petitioner,
`
`v.
`
`HELSINN HEALTHCARE S.A.,
`Patent Owner.
`_______________
`
`Case PGR2016-00007
`Patent 9,173,942 B2
`_______________
`
`
`Before TONI R. SCHEINER, LORA M. GREEN, and
`JACQUELINE WRIGHT BONILLA, Administrative Patent Judges.
`
`SCHEINER, Administrative Patent Judge.
`
`
`DECISION
`Denying Institution of Post-Grant Review
`35 U.S.C. § 324; 37 C.F.R. § 42.208
`
`
`
`
`
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`571-272-7822
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` Paper 12
`
`
`Entered: August 17, 2016
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`
`
`
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`DR. REDDY’S LABORATORIES, LTD. and
`DR. REDDY’S LABORATORY, INC.,
`Petitioner,
`
`v.
`
`HELSINN HEALTHCARE S.A.,
`Patent Owner.
`_______________
`
`Case PGR2016-00007
`Patent 9,173,942 B2
`_______________
`
`
`Before TONI R. SCHEINER, LORA M. GREEN, and
`JACQUELINE WRIGHT BONILLA, Administrative Patent Judges.
`
`SCHEINER, Administrative Patent Judge.
`
`
`DECISION
`Denying Institution of Post-Grant Review
`35 U.S.C. § 324; 37 C.F.R. § 42.208
`
`
`
`
`
`
`
`PGR2016-00007
`Patent 9,173,942 B2
`
`
`I. INTRODUCTION
`Dr. Reddy’s Laboratories, Ltd. and Dr. Reddy’s Laboratories, Inc.
`(collectively, “Petitioner” or “DRL”) filed a Petition on February 5, 2016
`(Paper 1; “Pet.”) requesting post-grant review of claims 1–6, 10, and 11 of
`U.S. Patent No. 9,173,942 B2 (Ex. 1001; “the ’942 patent”). Helsinn
`Healthcare S.A. (“Patent Owner” or “Helsinn”) filed a Patent Owner
`Preliminary Response. Paper 10 (“Prelim. Resp.”).1
`We have authority to determine whether to institute a post-grant review.
`35 U.S.C. § 324(c); 37 C.F.R. § 42.4(a). The standard is set forth in
`§ 324(a), which provides that a post-grant review shall not be instituted
`unless “the Director determines that the information presented in the petition
`filed under section 321, if such information is not rebutted, would
`demonstrate that it is more likely than not that at least 1 of the claims
`challenged in the petition is unpatentable.”
`After considering the Petition and the Preliminary Response, we
`determine that Petitioner has failed to demonstrate that it is more likely than
`
`
`1 Helsinn represents that
`Roche Palo Alto LLC, which was previously a co-assignee of
`U.S. Patent No. 9,173,942 . . . and a real party-in-interest in this
`proceeding, has assigned to Helsinn all right, title, and interest in
`and to the ’942 patent. Accordingly, for purposes of this
`proceeding, Helsinn is the only remaining real party-in-interest.
`Paper 9 (Updated Mandatory Notices, filed May 18, 2016), 2.
`
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`2
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`Patent 9,173,942 B2
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`not that at least one claim of the ’942 patent is unpatentable. Accordingly,
`we do not institute a post-grant review.
`
`A. Related Proceedings
`The ’942 patent has been asserted against Petitioner in Helsinn
`
`Healthcare S.A. v. Dr. Reddy’s Labs., Ltd., Civil Action No. 15-8662
`(D.N.J.), filed December 15, 2015. Pet. 2; Paper 8, 2.
`
`In addition, several parent applications of the ’942 patent and other
`related patents have been asserted by Patent Owner in a number of civil
`actions. For example, U.S. Patent No. 7,947,724 has been asserted in
`Helsinn Healthcare S.A. v. Dr. Reddy’s Labs., Ltd., Civil Action No. 12-
`2867 (D.N.J.); and U.S. Patent Nos. 7,947,724, 7,947,725, 8,518,981,
`8,598,218, and 8,598,219 have been asserted in Helsinn Healthcare S.A. v.
`Dr. Reddy’s Labs., Ltd., Civil Action Nos. 11-3962, 11-5579, 13-5815
`(consolidated) (D.N.J.). See Pet. 2–3; Paper 8, 2–3.
`
`Finally, Petitioner filed concurrently a Petition for post-grant review
`of claims 1–19 of the ’942 patent. PGR2016-00008.
`
`B. The ’942 Patent (Ex. 1001)
`The ’942 patent is directed to formulations “for the treatment and
`prevention of emesis using palonosetron,” a previously known 5-HT3
`(5-hydroxytryptamine) receptor antagonist. Ex. 1001, 1: 29, 57–58. The
`specification teaches that palonosetron “is an order of magnitude more
`potent than most existing 5-HT3 receptor antagonists, has a surprising half-
`life of about 40 hours, and is effective to reduce delayed-onset nausea
`3
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`induced by chemotherapeutic agents.” Id. at 1:59–62. The specification
`discloses formulations that “are shelf stable for periods greater than 24
`months at room temperature.” Id. at 2:65–3:1. In addition, the specification
`discloses that “palonosetron can be formulated in some instances at
`concentrations of only about 1/10th the amount of other previously known
`compounds for treating emesis, [which] surprisingly allows the use of
`concentrations of palonosetron far below those that would ordinarily be
`expected.” Id. at 4:54–58.
`[I]n one embodiment . . . a pharmaceutically stable solution for
`preventing or reducing emesis compris[es] a) from about 0.01
`mg/mL to about 5 mg/mL palonosetron or a pharmaceutically
`acceptable salt thereof; and b) a pharmaceutically acceptable
`carrier. . . . In alternative embodiments, the formulation includes
`palonosetron or a pharmaceutically acceptable salt thereof in a
`concentration from about 0.02 mg/mL to about 1.0 mg/mL, from
`about 0.03 mg/mL to about 0.2 mg/mL, and most optimally about
`0.05 mg/ml.2
`Id. at 4:58–5:6.
`In one particular embodiment the palonosetron is supplied in
`vials that comprise 5 ml. of solution, which equates to about 0.25
`mg of palonosetron at a concentration of about 0.05 mg/ml.
`Id. at 5:12–15.
`[F]urther . . . by adjusting the formulation’s pH and/or excipient
`concentrations it is possible to increase the stability of
`
`2 According to the specification of the ’942 patent, “[w]hen concentrations
`of palonosetron are given herein, the concentration is measured in terms of
`the weight of the free base. Concentrations of all other ingredients are given
`based on the weight of ingredient added to the solution.” Ex. 1001, 4:14–18.
`4
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`palonosetron formulations. Therefore, in another embodiment,
`. . . a pharmaceutically stable solution for preventing or reducing
`emesis compris[es] a) palonosetron or a pharmaceutically active
`salt thereof; and b) a pharmaceutically acceptable carrier, at a
`pH from about 4.0 to about 6.0. . . . In alternative embodiments,
`the pH is from about 4.5 to about 5.5, and most optimally about
`5.0.
`Id. at 5:16–30.
`[I]n another embodiment . . . a pharmaceutically stable solution
`of palonosetron compris[es] . . . from about 0.01 to about 5.0
`mg/ml palonosetron or a pharmaceutically acceptable salt thereof
`and (i) from about 10 to about 100 millimoles citrate buffer,
`and/or (ii) from about 0.005 to about 1.0 mg/ml EDTA.
`Id. at 5:40–46.
`[I]n another embodiment . . . a pharmaceutically stable solution
`of palonosetron compris[es]
`.
`.
`. a) palonosetron or a
`pharmaceutically
`acceptable
`salt
`thereof
`and
`b)
`a
`pharmaceutically acceptable carrier . . . compris[ing] a chelating
`agent and mannitol. . . . In various embodiments the mannitol is
`present in a concentration of from about 10.0 mg/ml to about 80
`mg/ml, from about 20 mg/mL to about 60.0 mg/ml, or from about
`40.0 to about 45.0 mg/ml.
`Id. at 6:4–18.
`Finally, the specification teaches that “palonosetron concentration was
`also a critical factor in chemical stability, with greatest stability seen at the
`lowest palonosetron concentrations.” Id. at 7:40–43.
`
`5
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`Patent 9,173,942 B2
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`C. Illustrative Claim
`Claim 1 is the only independent claim of the challenged claims.
`
`Claims 1 and 2 are illustrative.
`1. A formulation comprising a pharmaceutical sterile
`aqueous intravenous solution, wherein said pharmaceutical
`sterile aqueous intravenous solution comprises:
`
`palonosetron hydrochloride or another pharmaceutically
`acceptable salt of palonosetron at a concentration of 0.05
`mg/mL based on the weight of the palonosetron free base; and
`from 10 mg/mL to 80 mg/mL mannitol;
`wherein the pharmaceutical sterile aqueous intravenous
`
`solution has a pH of 4.0 to 6.0.
`
`2. The formulation of claim 1, wherein said
`pharmaceutical sterile intravenous solution comprises
`palonosetron hydrochloride or another pharmaceutically
`acceptable salt of palonosetron in amount of 0.25 mg.
`
`D. The Asserted Grounds of Unpatentability
`Petitioner asserts the challenged claims are unpatentable on the
`following grounds. Pet. 24–61.3
`
`
`3 Petitioner also relies on the Declarations of Dr. Christopher Fausel (Ex.
`1026) and Dr. Joanne Broadhead (Ex. 1012).
`6
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`Patent 9,173,942 B2
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`References
`
`Basis
`
`Claims Challenged
`
`Berger,4 Eglen,5 Gibson,6 and PDR
`20017
`
`Tang,8 Gibson, and PDR 2001
`Tang, Berger, Gibson, and PDR 2001
`
`§ 103
`
`1–6, 10, and 11
`
`§ 103
`§ 103
`
`1–6, 10, and 11
`1–6, 10, and 11
`
`
`
`
`4 U.S. Patent No. 5,202,333, issued April 13, 1993 to Berger et al. (Ex.
`1006, “Berger”).
`5 R.M. Eglen et al., Pharmacological characterization of RS 25259-197, a
`novel and selective 5-HT3 receptor antagonist, in vivo, 114 British Journal of
`Pharmacology 860-66 (1995) (Ex. 1025, “Eglen”).
`6 PHARMACEUTICAL PREFORMULATION AND FORMULATION: A PRACTICAL
`GUIDE FROM CANDIDATE DRUG SELECTION TO COMMERCIAL DOSAGE FORM
`21, 34–35, 175–237, 295–355 (Mark Gibson ed., 2001) (Ex. 1007,
`“Gibson”).
`7 PHYSICIANS’ DESK REFERENCE 680–83, 1503–07, 3104–3106 (55th ed.
`2001) (Exs. 1011, 1009, 1010, respectively, collectively, “PDR 2001”).
`8 Jun Tang et al., The Efficacy of RS-25259, a Long-Acting Selective 5-HT3
`Receptor Antagonist, for Preventing Postoperative Nausea and Vomiting
`After Hysterectomy Procedures, 87 ANESTH. ANALG. 462–67 (1998) (Ex.
`1008, “Tang”)
`
`7
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`Patent 9,173,942 B2
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`
`II. ANALYSIS
`
`A. Eligibility for Post-Grant Review
`The post-grant review provisions set forth in Section 6(d) of the AIA9
`apply only to patents subject to the first-inventor-to-file (FITF) provisions of
`the AIA. See AIA § 6(f)(2)(A) (“The amendments made by subsection (d)
`. . . shall apply only to patents described in section 3(n)(1).”). Transitional
`provision AIA section 3(n)(1) is as follows:
`
`(n) EFFECTIVE DATE.—
`
`(1) IN GENERAL.—Except as otherwise provided in this
`section, the amendments made by this section shall take effect
`upon the expiration of the 18-month period beginning on the date
`of the enactment of this Act, and shall apply to any application
`for patent, and to any patent issuing thereon, that contains or
`contained at any time—
`(A) a claim to a claimed invention that has an effective
`filing date as defined in section 100(i) of title 35, United
`States Code, that is on or after the [March 16, 2013]
`effective date . . . ; or
`(B) a specific reference under section 120, 121, or 365(c)
`of title 35, United States Code, to any patent or application
`that contains or contained at any time such a claim.
`AIA § 3(n)(1), 125 Stat. 293.
`The term “effective filing date” for a claimed invention in a patent or
`application for patent means “the filing date of the earliest application for
`
`
`9 Leahy-Smith America Invents Act, Pub. L. No. 112-29, 125 Stat. 284
`(2011) (“AIA”).
`
`8
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`Patent 9,173,942 B2
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`which the patent is entitled, as to such invention, to a right of priority under
`section 119, 365(a), or 365(b) or to the benefit of an earlier filing date under
`section 120, 121, or 365(c).” 35 U.S.C. § 100(i)(1); see also AIA § 3(a),
`125 Stat. at 285 (amending 35 U.S.C. § 100).
`Entitlement to the benefit of an earlier date under §§ 119, 120, 121,
`and 365, is premised on disclosure of the claimed invention in the manner
`provided by § 112(a) 10 (other than the requirement to disclose the best
`mode) in the application for which the benefit of the earlier filing date is
`sought. See 35 U.S.C. §§ 119(e), 120.
`The ’942 patent issued on November 3, 2015 from U.S. Application
`No. 13/901,830 (“the ’830 application”), filed on May 24, 2013. Ex. 1001,
`[21], [22], [45]. The ’942 patent is a continuation of U.S. Application No.
`13/901,437 (“the ’437 application”), filed on May 23, 2013, now U.S. Patent
`No. 8,598,219 (“the ’219 patent”). Id. at [63]. The ’437 application, in turn,
`is a continuation-in-part of U.S. Application No. 13/087,012, filed on April
`14, 2011, now U.S. Patent No. 8,518, 981.11 Id. Petitioner contends that
`claim 9 of the ’437 application had support only in newly added Example 8
`
`
`10 Section 4(c) of the AIA redesignated 35 U.S.C. § 112 ¶ 1 as 35 U.S.C.
`§ 112(a). 125 Stat. at 296.
`11 In addition, U.S. Application No. 13/087,012 is a continuation of U.S.
`Application No. 11/186,311, filed on July 21, 2005, now U.S. patent No.
`7,947,724, which is a continuation of Application No. PCT/EP2004/000888,
`filed on January 30, 2004. Finally, Provisional Application No. 60/444,351
`was filed on January 30, 2003. Ex. 1001, [63], [64].
`9
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`of the ’437 application—i.e., claim 9 of the ’437 application was not
`disclosed in the manner provided by § 112(a) prior to May 23, 2013. Pet. 4–
`6. The record appears to support Petitioner’s contention, and Patent Owner
`does not dispute that the effective filing date of claim 9 of the ’437
`application is no earlier than May 23, 2013. See Ex. 1002 (Prosecution
`History of the ’830 application), 154–156 (Applicants of the ’942 patent
`discussing the AIA status of the ’830 and ’437 applications.). Under the
`provisions of AIA sections 3(n)(1)(A) and (B), then, both the ’219 patent
`and the ’942 patent (which claims benefit to the ’219 patent) are AIA first-
`inventor-to-file patents.
`An additional requirement for post-grant review eligibility is that “[a]
`petition for a post-grant review may only be filed not later than the date that
`is 9 months after the date of the grant of the patent.” 35 U.S.C. § 321(c); see
`37 C.F.R. § 42.202(a).
`The Petition was filed on February 5, 2016 (Paper 4, 1), within nine
`months of the grant of the ’942 patent. See 35 U.S.C. § 321(c). Petitioner
`further certifies that it has standing to seek a post-grant review of the ’942
`patent. Pet. 4.
`Accordingly, on this record, we determine that the ’942 patent is an
`AIA first-inventor-to-file patent and is eligible for post-grant review.
`
`B. Claim Construction
`In a post-grant review, the claims of an unexpired patent are
`interpreted using the broadest reasonable construction in light of the
`
`10
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`specification of the patent in which they appear. 37 C.F.R. § 42.200(b);
`Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131, 2144–46 (2016). Under
`that standard, claim terms are given their ordinary and customary meaning,
`as would be understood by one of ordinary skill in the art in the context of
`the entire disclosure. In re Translogic Tech., Inc., 504 F.3d 1249, 1257
`(Fed. Cir. 2007).
`We determine that no claim term requires express construction for
`purposes of deciding whether to institute a review in this case. See, e.g.,
`Wellman, Inc. v. Eastman Chem. Co., 642 F.3d 1355, 1361 (Fed. Cir. 2011)
`(“[C]laim terms need only be construed ‘to the extent necessary to resolve
`the controversy.’”) (quoting Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200
`F.3d 795, 803 (Fed. Cir. 1999)).
`
`C. The Prior Art
`
`1. Berger (Ex. 1006)
`Berger discloses a number of 5-HT3 receptor antagonists of formula I,
`as well as pharmaceutical compositions containing the compounds, or their
`pharmaceutically acceptable salts, admixed with excipients. Ex. 1006, 1:9–
`11; 3:14–18. The compounds of Formula I include palonosetron. See Ex.
`1001, 1:56–58.12
`Berger teaches that the compounds of Formula I exhibit utility in
`treating a broad range of diseases in animals, particularly humans, including
`
`
`12 Palonosetron is also referred to as RS 25259-197. See, e.g., Ex. 1025,
`Abstract.
`
`11
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`emesis induced by surgical anesthesia, or treatment for cancer with
`radiotherapy or chemotherapy with cytotoxic agents. Ex. 1006, 9:50–58,
`10:7–9. “In general, compounds of Formula I will be administered as
`pharmaceutical compositions by one of the following routes: oral, systemic
`(e.g., transdermal, intranasal or by suppository) or parenteral (e.g.,
`intramuscular, intravenous or subcutaneous).” Id. at 12:25–29.
`
`Berger teaches that “[t]herapeutically effective amounts of
`compounds of Formula I may range from approximately 1.0 nanogram per
`Kg (ng/Kg) body weight per day to 1.0 mg/Kg body weight per day.” Id. at
`12:11–15. “Preferably the amount will be approximately 10 ng/Kg/day to
`0.1 mg/Kg/day.” Id. at 12:14–16. “Therefore, a therapeutically effective
`amount for a 70 Kg human may range from 70 ng/day to 70 mg/day,
`preferably 700 ng/day to 7.0 mg/day.”13 Id. at 12:16–18.
`Berger further teaches “[i]n general, the final composition will
`comprise from 0.000001% w to 10.0% w with the remainder being [an]
`excipient or excipients.”14 Id. at 12:66–67.
`
`Example 13 of Berger discloses representative formulas for oral and
`intravenous administration, as well as a representative tablet form. Id. at
`
`
`13 According to Petitioner, “[c]onverted to the units claimed in . . . claim 2
`of the ’942 Patent, this preferred range of amounts formulated and delivered
`is 0.0007 mg to 7.0 mg.” Pet. 28 (citing Ex. 1012 ¶ 44; Ex. 1026 ¶ 34).
`14 According to Petitioner, “[t]he claimed concentration of 0.05 mg/ml,
`when converted to this weight scale, would be 0.005% w.” Pet. 30 (citing
`Ex. 1012 ¶ 67; Ex. 1026 ¶ 35).
`
`12
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`28:54–29:22. A representative formulation for intravenous administration is
`as follows.
`
`
`Id. at 28:1–11. Thus, Berger’s representative solution for intravenous
`administration contains a compound of Formula I at a concentration of 10–
`100 mg/ml.
`
`2. Eglen (Ex. 1025)
`Eglen discloses the results of a study to investigate the inhibitory
`effects of intravenously administered RS 25259-197, i.e., palonosetron, on
`cisplatin-induced emesis in ferrets and dogs. According to Eglen, the ferret
`and the dog “are well established animal models of emesis which respond to
`cancer chemotherapeutic agents in a manner similar to that observed in
`man.” Ex. 1025, 861.
`Intravenous doses of 1, 3, 10, and 30 μg/kg-1 (i.e., 10, 30, 100, and
`300 μg/kg) given to ferrets prior to cisplatin “produced [statistically]
`significant and dose-dependent reduction in the number of emetic episodes
`in ferrets.” Id. at 863, Fig. 5. In dogs, intravenous doses of 30, 100, and 300
`μg/kg-1 (i.e., 300, 1000, and 3000 μg/kg) produced a statistically significant
`13
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`and dose-dependent reduction in the number of emetic episodes induced by
`cisplatin, actinomycin D, etc. Doses of 3 and 10 μg/kg-1 (i.e., 30 and 100
`μg/kg) did not produce a statistically significant reduction in the number of
`emetic episodes. Id. at 863, Fig. 6.
`Eglen does not disclose the concentration of any of the palonosetron
`doses used in the study.
`
`3. Tang (Ex. 1008)
`Tang discloses the results of a study evaluating the safety and efficacy
`of RS-25259, i.e., palonosetron, for the prevention of postoperative nausea
`and vomiting (PONV) in 218 women undergoing hysterectomy procedures.
`Ex. 1008, Abstract.
`“Patients were randomized to one of six prophylactic treatment
`groups: placebo (saline) or 0.1, 0.3, 1.0, 3.0, or 30 μg/kg RS-25259.” Id. at
`463. The average weights of the six study groups ranged from 70 ± 14 kg to
`76 ± 18 kg. Id. at 464, Table 1.
` “Each dose of study medication was prepared by the hospital
`pharmacy in a total volume of 15 mL of isotonic sodium chloride solution
`and was administered IV over 30 s approximately 20–30 min before the end
`of surgery.” Id.
`The[] results suggest[ed] that smaller doses of RS-25259 are
`ineffective in preventing of PONV. Only the largest dose of
`RS-25259, 30 μg/kg IV, was effective in decreasing vomiting
`and the need for rescue antiemetic drugs during the first 24 h
`after major gynecologic surgical procedures. Unfortunately,
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`even the largest dose of RS-25259 did not reduce the severity
`of nausea during the early postoperative period.
`Id. at 466.
`
`4. Gibson (Ex. 1007)
`Gibson sets out a number of “Guiding Principles for Simple Parenteral
`Solutions,” and teaches, among other things, that “the excipient
`concentration, rate of administration and total daily dose [of parenteral
`solutions] should fall within the boundaries established by precedent in
`existing marketed products.” Ex. 1007, 332, 334–35.
`
`5. PDR 2001 (Exs. 1009–1011)
`PDR 2001 discloses intravenous formulations of medications used to
`prevent nausea and vomiting: Zofran (ondasetron) (Ex. 1009), Kytril
`(granisetron hydrochloride) (Ex. 1010), and Anzamet (dolasetron) (Ex.
`1011).
`
`D. Asserted Obviousness over Berger, Eglen, Gibson,
`and PDR 2001
`Petitioner contends that claims 1–6, 10, and 11 would have been
`
`obvious over the combined teachings of Berger, Eglen, Gibson, and PDR
`2001. Pet. 23–50. Patent Owner contends, in relevant part, that Petitioner
`has not established that the palonosetron concentration of 0.05 mg/mL
`required by all the claims would have been obvious over Berger and Eglen,
`especially when considered in light of Tang (Ex. 1008). Prelim. Resp. 18–
`53.
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`Petitioner contends that both Berger and Eglen disclose formulations
`
`of palonosetron for intravenous use in the treatment and/or prevention of
`emesis. Petitioner acknowledges, however, that neither reference “teaches
`the specific concentration, the pH range claimed, the use of mannitol instead
`of dextrose [as required by claim 1], or the specific amount of claim 2.” Pet.
`38. Nevertheless, Petitioner contends that Berger teaches concentrations and
`doses encompassing the claimed concentration of 0.05 mg/mL (claim 1–6,
`10, and 12), in an amount of 0.25 mg (claim 2). Id. at 28, 30. Petitioner
`contends that “a person of ordinary skill in the art would look at Eglen as
`furthering the work done in Berger,” and would turn to Eglen for guidance
`in narrowing the concentration and dose ranges. Id. at 33.
`Specifically, with respect to dose, Petitioner contends that:
`Berger discusses a range of possible doses of compounds,
`including palonosetron, that could be used as a therapeutically
`effective amount, including a range of 1.0ng/kg/day to
`1.0mg/kg/day based on body weight, and a preferred range of
`10ng/kg/day to 0.1mg/kg/day. As Berger explains, for a standard
`70kg human, the preferred dose range is from 700ng/day to
`7.0mg/day. . . . Converted to the units claimed in, for example,
`claim 2 of the ’942 Patent, this preferred range of amounts
`formulated and delivered is 0.0007mg to 7.0mg. This range
`encompasses the 0.25mg amount claimed in claim 2 of the ‘942
`Patent.
`Pet. 28 (citing Ex.1006, 12:11–18; Ex.1012 ¶ 44; Ex. 1026 ¶ 34).
`
`With respect to concentration, Petitioner contends that:
`Berger states that the amount of palonosetron or other compound
`of Formula I in the final dosage form preferably ranges from
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`0.00001% w to 1.0%w. . . . The claimed concentration of
`0.05mg/ml, when converted to this weight scale, would be
`0.005% w. . . . The concentration claimed in claim 1 of the ’942
`Patent also falls within this preferred concentration range.
`Pet. 30 (citing Ex. 1006, 12:66–67; Ex.1012 ¶ 67; Ex. 1026 ¶ 35).
`Petitioner contends that Eglen “reported a narrower dosage range for
`intravenous palonosetron.” Id. at 29. Specifically, “[d]oses of 1, 3, 10, and
`30μg/kg administered intravenously, showed an inhibitory effect against
`cisplatin induced emesis . . . in ferrets.” Id. (citing Ex. 1025, 863, Fig.5).
`“For a 70kg human subject, this dosage range corresponds to approximately
`amounts of palonosetron of 0.013, 0.04, 0.13, and 0.4mg, respectively,”15
`after dividing by a “known factor of 5.3 for ferrets.” Id. (citing Ex. 1025,
`863, Fig. 5; Ex. 1026 ¶¶ 31, 40); see also id. at 29 n.2 (citing Ex. 1026
`¶¶ 26–31).
`Eglen does not discuss the concentration of any of its dosages, but
`Petitioner contends that:
` [Eglen’s] “Vehicle control” was set at 1ml/kg for ferrets. . . .To
`a POSA, this means that the doses were diluted in a like fashion,
`and the resulting concentration ranged from 0.001–0.10mg/ml, a
`range that encompasses the claimed range. . . . The resulting
`calculated range tested for dogs was broader and resulted in a
`concentration range of 0.003–3.0mg/ml. Both of these ranges
`
`15 We note that the dosages disclosed in Eglen are actually reported as 1, 3,
`10, and 30 μg/kg-1 (i.e., 10, 30, 100, and 300 μg/kg), and the amounts for a
`70 kg human subject would be correspondingly larger, but the difference has
`no impact on our decision in this case.
`
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`17
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`fall within the range disclosed in Berger and encompass the
`0.05mg/ml concentration claimed.
`Id. at 30–31 (citing Ex. 1025, 861; Ex. 1026 ¶¶ 60-62; Ex. 1012 ¶ 71).
`Alternatively, Petitioner contends that “[c]oncentrations can also be
`determined for Eglen based on diluting the doses tested in Eglen in standard
`whole integer volumes used for injectable products in general and setrons
`specifically.” Id. at 31 (citing Ex. 1012 ¶¶ 68–71; Ex. 1026 ¶¶ 57–59).
`Petitioner contends “as the dose and concentration ranges disclosed in
`Eglen were narrower than, and encompassed by, the ranges of Berger, and
`because there was data establishing some level of efficiency, it would have
`been obvious to use Eglen’s ranges in connection with the formulation
`teachings of Berger.” Id. (citing Ex.1026 ¶ 42; Ex. 1012 ¶ 68).
`Petitioner contends essentially that Eglen’s concentration “range”
`brackets the claimed concentration, and “[i]n the absence of some
`compelling reason to the contrary . . . any concentration, but most assuredly
`those actually disclosed in the art, [is] obvious.” Id. at 40 (citing Ex. 1012 ¶
`72; Ex. 1026 ¶¶ 59, 62). Similarly, Petitioner contends, “[a]bsent
`unexpected results or teaching away from including those amounts in a
`formulation, the use of an amount 0.25mg of palonosetron in a formulation
`is obvious.” Id. at 44 (citing Ex. 1012 ¶ 87; 1026 ¶ 65). Finally, Petitioner
`contends that “[t]he remaining differences: the specific range of pH, the use
`of mannitol instead of dextrose, and the amount of mannitol used, are all
`obvious and constitute nothing more than minor variations of excipients and
`conditions known per se” and would have been obvious given the teachings
`18
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`of Gibson and the formulations of other setrons disclosed in PDR 2001. Id.
`at 45.
`
`We have carefully considered Petitioner’s contentions, but are not
`persuaded that Petitioner has shown sufficiently that one of ordinary skill in
`the art would have had a reason to formulate palonosetron as required by the
`claims, particularly at a concentration of 0.05 mg/mL.
`First, Eglen does not discuss the concentration of its formulations at
`all. Even assuming one of ordinary skill in the art could ascertain the
`concentration of Eglen’s formulations by making inferences about the
`dosage volumes, the result would be discrete concentrations—not a range.
`Petitioner has not shown that any of Eglen’s purported concentrations
`correspond to the claimed 0.05 mg/mL concentration.
`Second, Patent Owner argues, among other things, that “the most
`relevant prior art that a [person of ordinary skill in the art] would have
`considered was Tang [Ex. 1008], the only peer-reviewed, prior art
`publication reporting human efficacy data involving palonosetron.” Prelim.
`Resp. 33 (citing Ex. 2008, 34:22–35:5). Patent Owner contends that:
`The clinical trial reported in Tang [Ex. 1008] was designed as a
`“dose-ranging study” to determine the doses of palonosetron that
`may be effective to treat PONV. . . . As such—and unlike the
`other references on which [Petitioner] relies . . . Tang [Ex. 1008]
`was specifically designed to identify the doses that should be
`pursued as part of any palonosetron development program.
`Id. at 33–34 (citing Ex. 2005, 209:9–25; Ex. 2008, 37:2–6).
`
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`Patent Owner contends that the “doses studied in Tang were 0.1, 0.3,
`1.0, 3.0, and 30 μg/kg. Id. at 34 (citing Ex. 1008, 462). Patent Owner
`contends that only the largest dose, 30 μg/kg given intravenously, roughly
`2.1 mg based on a 70 kg patient,16 was effective in decreasing vomiting and
`the need for rescue antiemetic drugs during the first 24 hours after major
`gynecologic surgical procedures. Id. (citing Ex. 1008, 466; Pet. 29). Patent
`Owner contends that “this is consistent with the testimony of [Petitioner’s]
`expert, Dr. Frame, in [Helsinn Healthcare S.A. v. Dr. Reddy’s Labs., Ltd.,
`Civil Action Nos. 11-3962, involving the ’219 patent] that ‘the dose that
`Tang concluded . . . had efficacy to treat . . . [emesis]’ was 30 μg/kg, which
`is roughly 2.1 mg and over eight times higher than the claimed 0.25 mg
`dose.” Id. (citing Ex. 2005, 115:16–19; see also Ex. 2016, 4–17; Ex. 2017,
`435:20–436:7, 447:18–449:1, 520:2–7, 10–11). “Even then, the 30 μg/kg
`dose was only partially effective since ‘beyond 12 hours there wasn’t a
`significant reduction in vomiting’ . . . and none of the doses reduced
`nausea.” Id. (citing Ex. 2008, 48:20–24, 43:15–24).
`Patent Owner contends that Tang teaches away from the claimed
`invention, and that Petitioner “has not explained why a POSA, knowing that
`a 2.1 mg dose showed only partial efficacy . . . would have ever been
`
`
`16 As discussed above in section II.C.3, “[e]ach dose of study medication
`[in Tang] was prepared by the hospital pharmacy in a total volume of 15 mL
`of isotonic sodium chloride solution and was administered IV over 30 s
`approximately 20–30 min before the end of surgery.” Ex. 1008, 463. Thus,
`the concentration of the largest dose was approximately 0.14 mg/mL.
`20
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`motivated to pursue the 8–40 times lower doses required by the claims-at-
`issue (i.e., 0.05–0.25 mg).” Patent Owner further contends that it has been
`established through prosecution of the application that matured into the ’942
`patent, and prosecution of its parent applications, that palonosetron has an
`unusual property, “it is unexpectedly more stable at lower concentrations in
`solution,” “with greatest stability seen below 0.1 mg/ml.” Prelim. Resp. 9
`(citing Ex. 2012, 216:17–217–7; Ex. 1041, 12–13; Ex. 2072 ¶ 9). Prelim.
`Resp. 38.
`We agree with Patent Owner that a person of ordinary skill in the art
`would have considered Tang to be relevant to a “palonosetron development
`project.” Prelim. Resp. 33. Moreover, we are not persuaded by Petitioner’s
`argument that because the challenged claims “[do] not require administration
`to a human of any dose to reduce the likelihood of postoperative nausea and
`vomiting,” “Tang is not a teaching away from the alleged invention as
`actually claimed.” Pet. 18.
`We need not determine whether Tang actually teaches away from the
`claimed formulations—it is enough that we agree with Patent Owner that
`Tang would not have led a person of ordinary skill in the art to expect that a
`solution of palonosetron at a concentration of 0.05 mg/mL would be
`effective in treating emesis. Id. at 39 (citing Ex. 1008, 466). If anything,
`Tang would have suggested amounts and concentrations still higher than the
`highest dose and concentration evaluated by Tang.
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`Again, the relevant inquiry is whether one of ordinary skill in the art
`would have had a reason to select the claimed concentration from Berger’s
`disclosed concentration range, or Eglen’s purported range, given that the
`common objective of Berger and Eglen was to formulate and/or evaluate an
`intravenous solution for the treatment and prevention of emesis, and given
`Tang’s teaching that only the highest dose of palonosetron was effective—
`30 μg/kg (or approximately 2.1 mg for a 70 kg patient), at a concentration of
`approximately 1.4 mg/mL, nearly three times that claimed (see supra 19
`n.16).
`
`We agree with Patent Owner that Petitioner has not established that
`one of ordinary skill in the art would have had a reason to formulate a
`pharmaceutical
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