`Patent No. 8,729,094
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-012
`
`
`
`Patent No. 8,729,094
`Issue Date: May 20, 2014
`Title: LIQUID PHARMACEUTICAL FORMULATIONS OF PALONOSETRON
`____________________________
`
`Inter Partes Review No. IPR2015-01551
`
`__________________________________________________________________
`
`CORRECTED PETITION FOR INTER PARTES REVIEW OF
`CLAIMS 22-27 AND 30 OF U.S. PATENT NO. 8,729,094
`AND MANDATORY NOTICES UNDER 37 C.F.R. § 42.8
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`____________________________
`
`DR. REDDY’S LABORATORIES, LTD. and
`DR. REDDY’S LABORATORIES, INC.
`Requestors
`
`v.
`
`HELSINN HEALTHCARE S.A. and ROCHE PALO ALTO LLC
`Patent Owner
`
`
`
`
`
`Case IPR2015-01551
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-012
`
`
`TABLE OF CONTENTS
`
`Page
`
`TABLE OF AUTHORITIES ................................................................................... iii
`
`EXHIBIT LIST ........................................................................................................ iv
`
`STATEMENT OF REASONS FOR RELIEF REQUESTED ................................... 5
`
`I.
`
`II.
`
`INTRODUCTION AND SUMMARY OF ARGUMENT .............................. 5
`
`THE CLAIMS UNDER CONSIDERATION ................................................. 7
`
`III. THE SPECIFICATION AND PROSECUTION HISTORY OF THE
`‘094 PATENT .................................................................................................. 8
`
`A. The Specification Of The ‘094 Patent ...................................................... 8
`
`B. The Prosecution History Of The ‘094 Patent ......................................... 10
`
`IV. CLAIM CONSTRUCTION .......................................................................... 14
`
`A. Optionally ............................................................................................... 14
`
`B. Acute And Delayed ................................................................................. 15
`
`C. Chelating Agent ...................................................................................... 16
`
`V.
`
`CLAIMS 22-27 AND 30 OF THE ‘094 PATENT ARE OBVIOUS OVER
`BERGER (EXH.1010) WHEN TAKEN IN VIEW OF CHELLY
`(EXH.1012), TANG (EXH.1019), AVIS (EXH.1050), AND THE 2001
`PHYSICIANS’ DESK REFERENCE (EXHS.1015-1017) ............................. 16
`
`A. The Level Of Ordinary Skill In The Art ................................................. 18
`
`B. Scope And Content Of The Prior Art ..................................................... 20
`
`1. The “Treatment” Limitations Of Claim 22 ...................................... 20
`
`a.
`
`b.
`
`Dosing Unit Conversions ....................................................... 20
`
`Berger ..................................................................................... 22
`
`
`
`i
`
`
`
`Case IPR2015-01551
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-012
`
`
`c.
`
`Chelly ..................................................................................... 24
`
`d.
`
`e.
`
`Tang ....................................................................................... 25
`
`Berger, Chelly, And Tang Combined .................................... 29
`
`2. Dose Adjustments ............................................................................ 32
`
`3. A POSA’s Use Of Data To Select A Dose ...................................... 33
`
`4. The Product Recitations Of The Claims .......................................... 36
`
`C. Differences Between The Claims And The Prior Art ............................. 44
`
`D. Dependent Claims ................................................................................... 51
`
`1. Claim 23 ........................................................................................... 51
`
`2. Claim 24 ........................................................................................... 51
`
`3. Claim 25 ........................................................................................... 52
`
`4. Claim 26 ........................................................................................... 53
`
`5. Claim 27 ........................................................................................... 54
`
`6. Claim 30 ........................................................................................... 55
`
`E. Claim Chart ............................................................................................. 55
`
`VI. CONCLUSION .............................................................................................. 58
`
`
`
`
`
`ii
`
`
`
`
`
`Case IPR2015-01551
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-012
`
`
`
`CASES
`
`TABLE OF AUTHORITIES
`
`Page(s)
`
`3M v. Chemque, Inc.,
`303 F.3d 1294 (Fed. Cir. 2002) .......................................................................... 18
`
`In re Aller,
`220 F.2d 454 (C.C.P.A. 1955) ...................................................................... 45, 48
`
`Asyst Techs. Inc. v. Emtrak, Inc.,
`544 F.3d 1310 (Fed. Cir. 2008) .......................................................................... 46
`
`Atlas Powder Co. v. E. I. Du Pont de Nemours & Co.,
`750 F.2d 1569 (Fed. Cir. 1984) .......................................................................... 34
`
`In re Baxter Travenol Labs.,
`952 F.2d 388 (Fed. Cir. 1991) ............................................................................ 46
`
`In re Cuozzo Speed Techs., LLC,
`No. 2014-1301, Slip. Op. (Fed. Cir. Feb. 4, 2015) ............................................. 14
`
`Ericsson Inc. v. Intellectual Ventures II, LLC,
`IPR 2014-01412 (PTAB. Mar. 18, 2015) ........................................................... 15
`
`Galderma Labs., L.P. v. Tolmar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013) ...................................................................... 18, 46
`
`Graham v. John Deere Co.,
`383 U.S. 1 (1966) ................................................................................................ 17
`
`KSR Int'l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ............................................................................................ 17
`
`In re Merck & Co.,
`800 F.2d 1091 (Fed. Cir. 1986) .......................................................................... 34
`
`Mintz v. Dietz & Watson, Inc.,
`679 F.3d 1373 (Fed. Cir. 2012) ......................................................................... 18
`
`
`
`iii
`
`
`
`Case IPR2015-01551
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-012
`
`Oracle Corp. v. Thought, Inc.,
`IPR 2014-00118 (PTAB Apr. 25, 2014) ............................................................ 15
`
`Par Pharm. Inc. v. TWI Pharms., Inc.,
`773 F.3d 1186, No. 2014-1391, 2014 U.S. App.
`LEXIS 22737 (Fed. Cir. Dec. 3, 2014) ............................................................... 17
`
`Univ. of Rochester v. G.D. Searle & Co.,
`249 F. Supp. 2d 216 (W.D.N.Y. 2033) ............................................................... 20
`
`Takeda Pharm. Co. v. Mylan Inc.,
`Case No. 13-4001, 2014 U.S. Dist. LEXIS 159527
` (N.D. Cal. Nov. 11, 2014) .................................................................................. 20
`
` Warner Chilcott Co., LLC v. Lupin Ltd,
`Civ. Action Nos. 11-5048, 12-2928,
`2014 U.S. Dist. LEXIS 6228 (D.N.J. Jan. 17, 2014) .......................................... 19
`
`STATUTES, RULES & OTHER AUTHORITIES
`
`35 U.S.C. § 102 .................................................................................................passim
`
`35 U.S.C. § 103 .............................................................................................. 4, 11, 17
`
`37 C.F.R. § 42.100(b) .............................................................................................. 14
`
`
`
`
`
`iv
`
`
`
`Case IPR2015-01551
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-012
`
`
`EXHIBIT LIST
`
`
`Exhibit # Reference
`1001
`U.S. Patent No. 8,729,094
`1002
`U.S. Patent No. 7,947,724
`1003
`U.S. Patent No. 7,947,725
`1004
`U.S. Patent No. 7,960,424
`1005
`U.S. Patent No. 8,598,219
`1006
`Complaint for Patent Infringement, Helsinn Healthcare S.A. and
`Roche Palo Alto LLC v. Dr. Reddy’s Laboratories, Ltd. and
`Dr. Reddy’s Laboratories, Inc., U.S.D.C.N.J. Civil Action
`No. 3:14-cv-04274-MLC-DEA
`Complaints for Patent Infringement, Helsinn Healthcare S.A. and
`Roche Palo Alto LLC v. Dr. Reddy’s Laboratories, Ltd. and
`Dr. Reddy’s Laboratories, Inc., et al. U.S.D.C.N.J. Civil Action
`No. 3:11-cv-03962-MLC-TJB filed 7/8/2011; Helsinn Healthcare
`S.A. and Roche Palo Alto LLC v. Dr. Reddy’s Laboratories, Ltd.,
`Dr. Reddy’s Laboratories, Inc., et al., U.S.D.C.N.J. Civil Action
`Nos. 3:11-cv-05579-MLC-DEA filed 9/23/2011; Helsinn
`Healthcare S.A. and Roche Palo Alto LLC v. Dr. Reddy’s
`Laboratories, Ltd., Dr. Reddy’s Laboratories, Inc., et al.,
`3:13-cv-05815-MLC-DEA filed 12/27/2013; and Helsinn
`Healthcare S.A. and Roche Palo Alto LLC v. Dr. Reddy’s
`Laboratories, Ltd. & Dr. Reddy’s Laboratories, Inc., U.S.D.C.N.J.
`Civil Action No. 3:12-cv-02867-MLC-DEA filed 5/12/2012
`Serial No. 13/902,132 Final Rejection, Dec. 6, 2013
`Serial No. 13/902,132, Amendment After Final, Feb. 21, 2014
`U.S. Patent No. 5,202,333 (“Berger”)
`Eglen et al., Pharmacological characterization of RS 25259-197, a
`novel and selective 5-HT3 receptor antagonist, in vivo, 114 British
`J. Pharmacol. 860-66 (1985) (“Eglen”)
`Chelly et al., Oral RS-25259 Prevents Postoperative Nausea and
`Vomiting Following Laparoscopic Surgery, Abstracts of Scientific
`Papers 1996 Annual Meeting, 85 Anesthesiology, No. 34, A21
`(Sept. 1996) (“Chelly”)
`
`1007
`
`1008
`1009
`1010
`1011
`
`1012
`
`
`
`v
`
`
`
`1014
`
`1015
`
`1016
`
`1017
`
`1018
`
`1019
`
`1020
`
`Case IPR2015-01551
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-012
`
`Exhibit # Reference
`1013
`Gralla et al., Recommendations for the Use of Antiemetics:
`Evidence-Based, Clinical Practice Guidelines, 17 J. Clin.
`Oncology, No. 9, 2971-94 (Sept. 1999)
`Gibson, Parenteral Dosage Forms, Pharmaceutical Preformulation
`and Formulation, A Practical Guide from Candidate Drug Selection
`to Commercial Dosage Form 175-237, 295-354 (2001)
`ZOFRAN (2001). In Physician’s Desk Reference 1503-07 (55th
`ed.) Montvale, NJ: PDR Network
`KYTRIL (2001). In Physician’s Desk Reference 3104-06 (55th ed.)
`Montvale, NJ: PDR Network
`ANZEMET (2001). In Physician’s Desk Reference 680-83 (55th
`ed.) Montvale, NJ: PDR Network
`Gaia Piraccini et al., An Interesting 5-HT3 Receptor Antagonist
`Antiemetic for Patients Undergoing Chemotherapy-Based
`Conditioning Regimens, Abstract 5169, 98(11) J. of the American
`Society of Hematology 350b (Nov. 16, 2001)
`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.,
`462-7 (1998) (“Tang”)
`Lauri P. Cohen, Many Medicines Are Potent Years Past Expiration
`Dates, Wall St. J., March 28, 2000.
`1021
`Declaration of William McGuire, M.D.
`1022 William McGuire, M.D. curriculum vitae
`1023
`Declaration of David G. Frame, Pharm.D.
`1024
`David G. Frame, Pharm.D. curriculum vitae
`1025
`Tr. transcript Dr. Kirsch 19:12-20:23, June 5, 2015 (what is a
`POSA)
`Tr. transcript Dr. Candiotti 18:19-20:4, June 10, 2015 (what is a
`POSA)
`Gandara et al., Consensus Proposal for 5-HT3 Antagonists in the
`Prevention of Acute Emesis Related to Highly Emetogenic
`Chemotherapy, Support Care Cancer (1998) 6:237-243
`(“Gandara”)
`
`1026
`
`1027
`
`
`
`vi
`
`
`
`1029
`
`1030
`
`1031
`
`1032
`
`1033
`1034
`1035
`1036
`
`1037
`1038
`1039
`
`1040
`1041
`1042
`
`Case IPR2015-01551
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-012
`
`Exhibit # Reference
`1028
`Tr. transcript Dr. Frame direct 109:2-110:15, 121:18-123:3,
`124:20-128:4, June 8, 2015 (PONV to CINV)
`Tr. transcript Dr. Candiotti direct 82:12-83:15, June 10, 2015
`(PONV to CINV)
`Tr. Transcript Dr. Frame direct 107:14-108:25, June 8, 2015 (oral
`to IV)
`U.S. Food and Drug Administration. Estimating the safe starting
`dose in clinical trials for therapeutics in adult healthy volunteers
`(Draft Guidance Document) Center for Drug Evaluation and
`Research and Center for Biologics Evaluation and Research (Dec.
`2002)
`Tr. transcript Dr. Candiotti direct 108:21-109:20, June 10, 2015 (5
`ml volume)
`January 16, 2002 Helsinn Press Release
`October 3, 2001 Helsinn Press Release
`April 10, 2001 Helsinn Press Release
`Kibbe, Handbook of Pharmaceutical Excipients, Citric Acid
`191-94 (3rd ed. 2000)
`U.S. Patent No. 9,066,980
`Serial No. 13/902,132 Official Action, Aug. 8, 2013
`Serial No. 13/902,182 Applicants’ Amendment and Response to
`Office Action, Oct. 9, 2013
`Declaration of Dr. Patrick P. DeLuca
`Dr. Patrick P. DeLuca curriculum vitae
`Patrick P. DeLuca and James C. Boylan, 5 Formulation of Small
`Volume Parenterals, 1 Pharmaceutical Dosage Forms:Parenteral
`Medications, 173(2nd ed. rev. expanded Marcel Dekker, Inc. 1992)
`Tr. transcript Dr. Amidon direct156:15-165:9, June 15, 2015
`(K.I.S.S. 5ml, Golden Rule, Ex.13 commercially viable)
`Brown et al., The Effectiveness of a Single Intravenous Dose of
`Ondansetron, Oncology 1992;49:273-278
`Helsinn Healthcare S.A. et al. v. Dr. Reddy’s Laboratories,
`Ltd. et al., Civil Action No. 12-2867-MLC (D.N.J. Feb. 19, 2015)
`Markman Order (Dkt.91), Feb. 19, 2015
`
`1043
`
`1044
`
`1045
`
`
`
`vii
`
`
`
`1047
`
`1048
`
`1049
`
`1050
`
`Case IPR2015-01551
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-012
`
`Exhibit # Reference
`1046
`Tr. transcript Dr. Amidon direct 106:2-107:18, June 16, 2015
`(EDTA citric acid)
`Tr. transcript Dr. Candiotti cross-examination 141:15-143:25,
`June 10, 2015 (human dose based on animals)
`Prosecution History of U.S. Patent No. 7,947,724 (U.S. Ser.
`No. 11/186311), Amend. Resp., Apr. 6, 2009
`Mikawa et al., Optimal Dose of Granisetron for Prophylaxis
`Against Postoperative Emesis After Gynecological Surgery, 85
`Anesth. Analg., 652-6 (1997)
`Avis et al., 2 Parental Drug Administration: Routes, Precautions,
`Problems, Complications, and Drug Delivery Systems, 1
`Pharmaceutical Dosage Forms:Parenteral Medications 173(2nd ed.
`rev. expanded Marcel Dekker, Inc. 1992)
`Reproduction of Figure 5 of Eglen Exh.1011, at 863
`Reproduction of Figure 6a of Eglen Exh.1011, at 863
`Dose response curves for Chelly (Exh.1012) and Tang (Exh.1019)
`Approved KYTRIL Label, Aug. 16, 2002
`R.E. Leak and J.D. Woodford, Pharmaceutical Development of
`Ondansetron Injection, 25 (Suppl. 1) Eur. J. Cancer Clin.
`Oncol. 567-69 (1989)
`
`1051
`1052
`1053
`1054
`1055
`
`
`
`viii
`
`
`
`
`
`Dr. Reddy’s Laboratories, Ltd. and Dr. Reddy’s Laboratories, Inc. request
`
`inter partes review of claims 22-27 and 30 of U.S. Patent No. 8,729,094 (“the
`
`‘094 Patent”) (Exh.1001).
`
`NOTICE OF LEAD AND BACKUP COUNSEL
`
`Backup Counsel:
`William L. Mentlik
`(Reg. No. 27,108)
`WMentlik.ipr@ldlkm.com
`Postal and Hand-Delivery Address
`600 South Avenue West
`Westfield, NJ 07090
`Telephone: 908.518.6305
`Fax: 908.654.7866
`
`Thomas M. Palisi
`(Reg. No. 36,629)
`TPalisi.ipr@ldlkm.com
`Postal and Hand-Delivery Address
`600 South Avenue West
`Westfield, NJ 07090
`Telephone: 908.518.6366
`Fax: 908.654.7866
`
`Maegan A. Fuller
`(Reg. No. 71,596)
`MFuller.ipr@ldlkm.com
`Postal and Hand-Delivery Address
`600 South Avenue West
`Westfield, NJ 07090
`Telephone: 908.518.6324
`Fax: 908.654.7866
`
`
`Lead Counsel:
`Michael H. Teschner
`(Reg. No. 32,862)
`MTeschner.ipr@ldlkm.com
`Postal and Hand-Delivery Address
`600 South Avenue West
`Westfield, NJ 07090
`Telephone: 908.518.6313
`Fax: 908.654.7866
`
`
`
`
`
`
`
`
`
`
`
`Case IPR2015-01551
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-012
`
`
`NOTICE OF EACH REAL-PARTY-IN-INTEREST
`The Real-Parties-In-Interest for this Petition are Requestor, Dr. Reddy’s
`
`Laboratories, Ltd. (“DRL LTD”) an Indian company, and Dr. Reddy’s
`
`Laboratories, Inc. (“DRL Inc.”) a U.S. company, and wholly owned subsidiary of
`
`DRL LTD. (collectively referred
`
`to herein as “DRL,” “Petitioner,” or
`
`“Requestor”).
`
`NOTICE OF RELATED MATTERS
`Patent Owner asserted the ‘094 Patent in a civil action filed in the United
`
`States District Court for the District of New Jersey (Civ. Action No. 14- 4274), on
`
`July 7, 2014 (“the Litigation”). (Exh.1006.) Patent Owner has also filed lawsuits
`
`against Petitioner involving other members of the ‘094 Patent’s immediate family.
`
`These include: Civ. Action No. 11-3962, filed July 8, 2011, alleging infringement
`
`of U.S. Patent Nos. 7,947,724 and 7,947,725 (Exhs.1002, 1003, respectively); Civ.
`
`Action No. 11-5579, filed September 23, 2011, alleging infringement of U.S. Pat.
`
`No. 7,960,424 (Exh.1004); Civ. Action No. 13-5815, filed December 27, 2013,
`
`alleging infringement of U.S. Patent Nos. 8,518,981; 8,598,218; and 8,598,219
`
`(Exh.1005); Civ. Action No. 12- 2867 filed May 11, 2012, alleging infringement of
`
`U.S. Pat. No. 7,947,724 (Exh.1002.) All of these cases are before The Honorable
`
`Judge Cooper in the U.S. District Court for the District of New Jersey.
`
`2
`
`
`
`Case IPR2015-01551
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-012
`
`
`It is the undersigned’s understanding that the assertions of infringement of
`
`the ‘981 and ‘218 Patents were dismissed, and that some of the issues pled in the
`
`various complaints have been reorganized and in some cases consolidated. A trial
`
`was held before Judge Cooper on June 2-16, 2015, in Civ. Action No. 11-3962
`
`(“the Trial”) involving infringement and invalidity allegations for the ‘724, ‘725,
`
`‘424, and ‘219 Patents. (Exhs.1002-1005.) The undersigned is not a record counsel
`
`in any of these civil actions.
`
`Petitioner has filed three other IPR petitions concurrently on the same claims
`
`of
`
`the
`
`same patent under unique
`
`theories bearing attorney docket
`
`nos. REDDY 7.1R-010, REDDY 7.1R-011, and REDDY 7.1R-013.
`
`NOTICE OF SERVICE INFORMATION
`Please address all correspondence to the lead and backup counsel at the
`
`address
`
`shown above. Petitioner also consents
`
`to electronic
`
`service
`
`by
`
`
`at: MTeschner.ipr@ldlkm.com, WMentlik.ipr@ldlkm.com,
`
`TPalisi.ipr@ldlkm.com, and MFuller.ipr@ldlkm.com.
`
`GROUNDS FOR STANDING
`Petitioner certifies that the patent for which review is sought is available for
`
`inter partes review, and that Petitioner is not barred or estopped from requesting an
`
`inter partes review on the grounds identified in the petition. This petition is being
`
`filed within one year of the filing of the Complaint in the Litigation, which
`
`3
`
`
`
`Case IPR2015-01551
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-012
`
`occurred on July 7, 2014. (Exh.1006.) The petition is thus timely under 35 U.S.C.
`
`§ 315(b). The fee for this petition has been paid. However, the U.S. Patent and
`
`Trademark Office is hereby authorized to charge Deposit Account No. 12-1095 for
`
`any fees that may be due and owing in connection with this petition.
`
`STATEMENT OF PRECISE RELIEF REQUESTED
`Petitioner requests that claims 22-27 and 30 of the ‘094 Patent be held
`
`unpatentable based on the following ground: Claims 22-27 and 30 are obvious over
`
`Berger (Exh.1010), when taken in view of Chelly (Exh.1012), Tang (Exh.1019),
`
`AVIS
`
`(Exh.1050), and
`
`the 2001 Physicians’ Desk Reference
`
`(“PDR”)
`
`(Exhs.1015-1017). See 35 U.S.C. § 103.1
`
`THRESHOLD REQUIREMENT FOR INTER PARTES REVIEW
`This Petition meets the threshold requirement of 35 U.S.C. § 314(a). All of
`
`the elements of claims 22-27 and 30 of the ‘094 Patent are taught, either expressly
`
`or inherently, in the prior art, or are obvious in view of the prior art, as explained
`
`below in the grounds of unpatentability. The reasons to combine the cited
`
`references, where applicable, are established under 35 U.S.C. § 103(a).
`
`
`1 Despite being based on a provisional application filed January 30, 2003, the
`
`‘094 Patent is governed by the changes to 35 U.S.C. §§ 102 and 103, as amended
`
`by the AIA for prior art purposes. (See Exh.1009, at 17-19.)
`
`4
`
`
`
`Case IPR2015-01551
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-012
`
`
`I.
`
`STATEMENT OF REASONS FOR RELIEF REQUESTED
`INTRODUCTION AND SUMMARY OF ARGUMENT
`Assume you are a generic drug manufacturer and you want to further one of
`
`this country’s most important objectives: reducing health care costs by bringing a
`
`lower cost intravenous (“IV”) palonosetron product to market. Palonosetron is a
`
`5-HT3 receptor antagonist, known for its ability to treat people undergoing
`
`treatment for chemotherapy-induced nausea and vomiting (CINV). Cancer care is
`
`profoundly expensive, and anything that can lower its cost can make it available to
`
`people who might otherwise not benefit from it.
`
`Obviously, there are challenges. First, there is another company ahead of
`
`you in developing this drug, for this indication, via this route ____ the Patent Owner
`
`who had already patented palonosetron. But that patent, Berger, U.S. Patent
`
`No. 5,202,333 (Exh.1010), which also discloses palonosetron IV formulations and
`
`their use for treating CINV, is about to enter the public domain. So everyone will
`
`soon be free to practice it.
`
`Second, a product must be developed. You know that this can be done.
`
`Berger disclosed a palonosetron IV formulation that even one of Patent Owner’s
`
`experts admitted was “potentially commercial viable.” (Exh.1043, at 165:2-5.) And
`
`Patent Owner had made public statements about its success in preclinical and
`
`clinical trials. (Exh.1033.) In fact, it told the world that it was nearing the
`
`5
`
`
`
`Case IPR2015-01551
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-012
`
`completion of Phase III clinical trials in humans for CINV, and that it expected to
`
`file with the FDA for market approval within a year of that press release. So a
`
`manufacturer would have a reasonable expectation that a palonosetron IV
`
`formulation indeed can be developed.
`
`Moreover, clinical work demonstrating efficacy was already published. The
`
`Phase II data was consistent and encouraging. It pointed to very low doses of
`
`palonosetron being effective, and that efficacy plateaued somewhere between
`
`about 0.07 and 0.21mg in humans. (Chelly, Exh.1012; Tang, Exh.1019.) This was
`
`consistent with published statements about palonosetron’s high potency and
`
`binding efficiency. Better still, even at doses ten times higher than likely starting
`
`doses, and more, palonosetron was safe ____ yes there was an increase in headaches
`
`and constipation, but nothing unexpected.
`
`Formulation of parenteral drug products is often a fairly standard affair,
`
`using well-established excipients and procedures. And here, a manufacturer would
`
`know that successful formulations were possible, as evidenced by Patent Owner’s
`
`press releases and Berger patent. Arriving at the claimed formulation was thus the
`
`exercise of a formulator’s standard operating procedures. Sterility, tonicity, pH,
`
`concentration, and dose, are features of every IV product, and all would have
`
`6
`
`
`
`Case IPR2015-01551
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-012
`
`necessarily and always been evaluated and optimized. And maximizing stability, in
`
`particular, would have been a goal of every formulator.
`
`Indeed, stability might have presented the only arguable issue in an
`
`otherwise plain vanilla product development. The ‘094 Patent offered a
`
`characterization of Berger’s illustrative IV formulation in its Example 13, stating
`
`that it would have had a pH of 3.7 and a stability of less than about 1-2 years. That
`
`would still allow it to be marketed and used commercially. But, the fact that
`
`despite its use of a citrate, and Berger’s formulation having a pH of 3.7 (buffering
`
`at acidic pH was long known for drugs potentially at risk for instability), its shelf
`
`life was allegedly suboptimal. This would certainly clue formulators into the issue,
`
`making it inconceivable that a formulator would not address it.
`
`II. THE CLAIMS UNDER CONSIDERATION
`22. A method for reducing the likelihood of cancer chemotherapy-induced
`nausea and vomiting, comprising intravenously administering to a human in need
`thereof a pharmaceutical single-use, unit-dose formulation comprising a 5 mL
`sterile aqueous isotonic solution buffered at a pH of about 5.0+0.5, said solution
`comprising: about 0.05 mg/mL palonosetron hydrochloride based on the weight of
`its free base; and a tonicifying effective amount of mannitol; wherein said solution
`optionally comprises one or a combination of a citrate buffer and a chelating agent,
`wherein said formulation is stable at 24 months when stored at room temperature,
`and wherein said intravenous administration to said human occurs before the start
`of the cancer chemotherapy.
`23. The method of claim 22, wherein said intravenous administration to
`said human occurs over a period of time of 10 to 60 seconds.
`
`7
`
`
`
`Case IPR2015-01551
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-012
`
`
`24. The method of claim 22, wherein said intravenous administration
`reduces the likelihood of acute nausea and vomiting in said human.
`25. The method of claim 22, wherein said intravenous administration
`reduces the likelihood of delayed nausea and vomiting in said human.
`26. The method of claim 22, wherein said solution comprises a citrate
`buffer.
`27. The method of claim 22, wherein said solution comprises a chelating
`agent.
`30. The method of claim 22, wherein said solution comprises from about
`10 mg/mL to about 80 mg/mL mannitol.
`III. THE SPECIFICATION AND
`PROSECUTION HISTORY OF THE ‘094 Patent
`A. The Specification Of The ‘094 Patent
`The ‘094 Patent issued from U.S. Serial No. 13/902,132 on May 20, 2014,
`
`based on a string of applications dating back to January 30, 2003. In the Summary
`
`of the Invention, Patent Owner argued that it made a series of discoveries leading,
`
`allegedly, to “a surprisingly effective and versatile formulation for the treatment
`
`and prevention of emesis using palonosetron.” (Exh.1001 col.2 ll.65-67.) “These
`
`formulations are shelf stable for periods greater than 24 months at room
`
`temperature, and thus can be stored without refrigeration, and manufactured using
`
`non-aseptic, terminal sterilization processes.” (Id. col.3 ll.1-4.)
`
`That series of alleged discoveries
`
`included determining
`
`that
`
`low
`
`concentrations of palonosetron can be used because palonosetron requires, in some
`
`instances, only one-tenth the amount of other previously known compounds for
`
`8
`
`
`
`Case IPR2015-01551
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-012
`
`treating emesis. (See id. col.3 ll.5-11.) Of course, in the Background of the
`
`Invention section, applicants conceded that palonosetron was already known to be
`
`“an order of magnitude more potent than most existing 5-HT3 receptor
`
`antagonists.” (Id. col.1 ll.58-61.) Using one-tenth as much of something 10x more
`
`potent is hardly a surprise. Applicants also allegedly discovered that by adjusting
`
`the pH and/or excipient concentration, it was possible to increase stability, and that
`
`the addition of mannitol and a chelating agent enhanced stability as well. (See
`
`generally id. col.3 ll.17-41.) But using such techniques was also well known.
`
`The Detailed Description section tracked the theme set by the Summary.
`
`Examples 1-3 related to optimization studies, where “optimum” was based on the
`
`impact of an excipient or condition on stability rather than impact on the patient.
`
`(See generally id. col.7 ll.15-58.) The remaining examples recited specific
`
`formulations and stability testing.
`
`Given the nature of the claims of the ‘094 Patent, two aspects of the
`
`specification are curious. First, it contains surprisingly little description of a
`
`method of treatment. Aside from a brief discussion of the potential impact of lower
`
`dosages of IV palonosetron on the length of the administration time (see id. col.5
`
`ll.7-15), it contains no discussion of administration per se. And not even the few
`
`9
`
`
`
`Case IPR2015-01551
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-012
`
`uses of the terms “method,” “process,” and “treating” were accompanied by a
`
`description of a CINV treatment method.
`
`Second,
`
`the
`
`specification mentions
`
`only
`
`the
`
`one
`
`dose
`
`(5mlx0.05mg/ml=0.25mg), with no discussion of a dosing range. It never suggests
`
`that this dose is particularly unexpectedly better than any other.
`
`B.
`The Prosecution History Of The ‘094 Patent
`U.S. Serial No. 13/902,132 was filed on May 24, 2013 as a continuation of
`
`its parent, U.S. Patent No. 8,598,219 (“the ‘219 Patent”) (Exh.1005). The
`
`‘219 Patent was a continuation-in-part filed only a day earlier. The application was
`
`accompanied by a request for prioritized examination under 37 C.F.R. § 1.102(e).
`
`A nonfinal rejection was mailed on August 8, 2013. (See Exh.1038.) In pertinent
`
`part, the claims directed to palonosetron formulations were rejected pursuant to 35
`
`U.S.C. § 102(b) as being anticipated by Baroni et al., WO 2004/073714. Method
`
`claims 12 and 15 were rejected as obvious over Baroni. (Id.)
`
`On October 9, 2013, applicants filed a response and amendment. (See
`
`Exh.1039.) The product claims were canceled, and method claim 12 was amended
`
`to include many of the product limitations found in the claims as issued. A number
`
`of additional method claims were also added. Applicants argued that Baroni had an
`
`effective filing date of February 18, 2003, pursuant to 35 U.S.C. § 102(a)(2) (id.
`
`10
`
`
`
`Case IPR2015-01551
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-012
`
`at 10), and argued that the original claims 12-15 were fully supported by the
`
`priority application and thus entitled to an effective filing date of January 30, 2003,
`
`more than two weeks prior to Baroni.
`
`The application was finally rejected on December 6, 2013. (See Exh.1008.)
`
`The Examiner withdrew the prior rejections, and in their place rejected claims 12,
`
`14-16, 18-24, 26-33, and 35-41 under pre-AIA 35 U.S.C. § 103(a) over Berger,
`
`U.S. Patent No. 5,202,333 (Exh.1010), in view of a number of secondary
`
`references. (Exh.1008, at 4.) The Examiner noted that Berger taught a method of
`
`treating and/or reducing chemotherapy induced nausea and vomiting with a
`
`pharmaceutical solution comprising palonosetron in a pharmaceutically acceptable
`
`carrier, in a single unit dosage, for intravenous use. The Examiner argued further
`
`that Berger taught a concentration of palonosetron from about 0.000001%w to
`
`10% w, and the use of citric acid, which the Examiner concluded was a chelating
`
`agent. According to the Examiner, Berger made it obvious to formulate in any
`
`volume from 1ml-100ml, and volume selection was a “matter of optimizations
`
`within the purview of the skilled artisan.” (See generally id. at 4-5.)
`
`The Examiner further noted that administration occurring before the start of
`
`chemotherapy was found in the art, and that “wherein” clauses, such as the one
`
`reciting the long term stability, should not be given weight. (Id.) The Examiner
`
`11
`
`
`
`Case IPR2015-01551
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-012
`
`also noted that Berger fails to teach a formulation comprising a specifically
`
`claimed amount of EDTA, mannitol, and citric acid, and did not teach the pH. But
`
`the Examiner then discussed the teachings of the secondary references in
`
`combination to establish obviousness. A number of other rejections were
`
`discussed, including double patenting.
`
`Applicants responded on February 21, 2014 (see Exh.1009), noting the
`
`patenting of other members of the same family including, inter alia, U.S. Patent
`
`Nos. 7,947,724 (Exh.1002) and 8,598,219 (Exh.1005). While acknowledging that
`
`the current application differed from those patents because it claims a method,
`
`applicants argued that the method claims included, directly or indirectly, many of
`
`the same product features ____ including
`
`the dose of palonosetron and
`
`its
`
`concentration. (Exh.1009, at 7.) Applicants argued that those features were not
`
`considered obvious during the prosecution of related patents and implied that those
`
`features should support patentability of the methods claimed as well.