Paper No. ______
`Filed: May 18, 2016
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________
`
`DR. REDDY’S LABORATORIES, LTD. and
`DR. REDDY’S LABORATORIES, INC.,
`Petitioner
`
`v.
`
`HELSINN HEALTHCARE S.A.,
`Patent Owner
`
`______________________
`
`Case PGR2016-00007
`Patent 9,173,942
`
`______________________
`
`Patent Owner’s Preliminary Response
`to Petition for Post-Grant Review
`of U.S. Patent No. 9,173,942
`
`

`
`
`
`TABLE OF CONTENTS
`
`Case PGR2016-00007
`
`I.
`II.
`
`D.
`E.
`
`Introduction ..................................................................................................... 1
`Background ..................................................................................................... 5
`A. Aloxi® Is a Breakthrough Drug Product
`for Patients Suffering from CINV ........................................................ 5
`B. Helsinn’s Development of Palonosetron .............................................. 8
`C.
`The ’942 Patent Discloses Palonosetron
`Formulations for Treating Emesis ...................................................... 10
`Prosecution History of the ’942 Patent and Its Family Members ...... 12
`Related Litigations ............................................................................. 13
`1.
`The ANDA Action ................................................................... 14
`2.
`The 505(b)(2) Action ............................................................... 16
`3.
`The Second 505(b)(2) Action .................................................. 16
`III. DRL’s Obviousness Positions Should Be Rejected ..................................... 17
`A.
`The Petition Fails to Establish That It Is
`More Likely Than Not That the Claims Are Unpatentable ............... 18
`1.
`Based on the Prior Art, a POSA Would Not Have
`Selected Palonosetron for Development .................................. 19
`a.
`A POSA Would Not Have Pursued Palonosetron
`Since Enthusiasm for 5-HT3s Had Faded ...................... 23
`NK-1s Were the Antiemetics of Interest in 2003 .......... 27
`Real-World Facts Confirm That a POSA Would
`Not Have Developed a “Me Too” 5-HT3 ...................... 29
`Based on the Prior Art, A POSA Would Not Have
`Selected 0.25 mg or 0.05 mg/mL Palonosetron ....................... 32
`a.
`Tang 1998 Teaches Away from the Claimed
`Concentration and Dose ................................................. 33
`A POSA Would Not Pursue a 0.05 mg/mL Dose-
`Dependent Concentration or 0.25 mg Dose Based
`on the Berger ’333 Patent or Eglen 1995 ...................... 39
`DRL’s Remaining Arguments Lack Merit .................... 43
`
`b.
`c.
`
`2.
`
`b.
`
`c.
`
`i
`
`

`
`Case PGR2016-00007
`
`TABLE OF CONTENTS
`
`3.
`
`The Prior Art Does Not Render the ’942 Patent Claims
`Obvious in View of the Other Claimed Components .............. 46
`DRL Fails to Make an Adequate Prima Facie Showing ......... 51
`4.
`B. DRL Fails to Adequately Address
`Evidence of Secondary Considerations .............................................. 53
`1.
`Industry Skepticism ................................................................. 54
`2.
`Unexpected Results .................................................................. 55
`3.
`Commercial Success ................................................................ 56
`4.
`Failure of Others and Long-Felt, But Unsolved, Need ............ 57
`5.
`Industry Praise .......................................................................... 57
`6.
`Evidence of Copying ................................................................ 58
`IV. The Board Should Exercise Its Discretion
`under 35 U.S.C. § 325(d) and Deny the Petition .......................................... 58
`V. DRL’s Claim Constructions Are Unnecessary or Incorrect ......................... 61
`VI. DRL Advances Redundant Grounds of Rejection ....................................... 63
`VII. Conclusion .................................................................................................... 65
`
`ii
`
`

`
`TABLE OF AUTHORITIES
`
`Case PGR2016-00007
`
`Page(s)
`
`Cases
`
`Advanced Display Sys., Inc. v. Kent State Univ.,
`212 F.3d 1272 (Fed. Cir. 2000) .......................................................................... 58
`
`Am. Hoist & Derrick Co. v. Sowa & Sons,
`725 F.2d 1350 (Fed. Cir. 1984) .......................................................................... 59
`
`Apple Inc. v. ITC,
`725 F.3d 1356 (Fed. Cir. 2013) .......................................................................... 53
`
`Cheese Sys., Inc. v. Tetra Pak Cheese & Powder Sys., Inc.,
`725 F.3d 1342 (Fed. Cir. 2013) .......................................................................... 20
`
`Coal. For Affordable Drugs XI LLC v. Insys Pharma, Inc.,
`IPR2015-01800, Paper 9 (Mar. 10, 2016) .......................................................... 23
`
`In re Cyclobenzaprine Hydrochloride
`Extended-Release Capsule Patent Litig.,
`676 F.3d 1063 (Fed. Cir. 2012) .............................................................. 17, 32, 53
`
`Dynamic Drinkware v. Nat’l Graphics,
`800 F.3d 1375 (Fed. Cir. 2015) .......................................................................... 45
`
`Endo Pharms., Inc. v. Depomed, Inc.,
`IPR2014-00652, Paper 68 (Sept. 16, 2015) ........................................................ 22
`
`Excelsior Med. Corp. v. Lake,
`IPR2013-00494, Paper 10 (Feb. 6, 2014) ........................................................... 58
`
`Galderma Labs., L.P. v. Tolmar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013) ................................................................ 43, 45-46
`
`Graham v. John Deere Co. of Kan. City,
`383 U.S. 1 (1966) ................................................................................................ 17
`
`Hulu LLC v. Intertainer, Inc.,
`IPR2014-01456, Paper 8 (Mar. 6, 2015) ............................................................ 59
`
`iii
`
`

`
`TABLE OF AUTHORITIES
`(continued)
`
`Insite Vision Inc. v. Sandoz, Inc.,
`
`783 F.3d 853 (Fed. Cir. 2015) .......................................................... 17, 19, 22, 41
`
`Page(s)
`
`Intri-Plex Techs., Inc. v. Saint-Gobain
`Performance Plastics Rencol Ltd.,
`IPR2014-00309, Paper 83 (Mar. 23, 2015) ...................................... 17-18, 20, 54
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ............................................................................................ 17
`
`Leo Pharm. Prods., Ltd. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) ........................................................ 32, 33, 43, 48
`
`Liberty Mutual Insurance Co. v. Progressive Casualty Insurance Co.,
`CBM2012-00003, Paper 7 (Oct. 25, 2012) ............................................ 64, 64-65
`
`Monarch Knitting Mach. Corp. v. Sulzer Morat GmbH,
`139 F.3d 877 (Fed. Cir. 1998) ...................................................................... 19, 54
`
`Novartis Pharm. Corp. v. Par Pharm., Inc.,
`48 F. Supp. 3d 733 (D. Del. 2014) ...................................................................... 48
`
`Novo Nordisk A/S v. Caraco Pharm. Labs., Ltd.,
`719 F.3d 1346 (Fed. Cir. 2013) .......................................................................... 44
`
`Ortho-McNeil Pharm., Inc. v. Mylan Labs., Inc.,
`520 F.3d 1358 (Fed. Cir. 2008) ........................................................ 20, 32, 54, 55
`
`Panduit Corp. v. Dennison Mfg. Co.,
`774 F.2d 1082 (Fed. Cir. 1985) .......................................................................... 57
`
`Pfizer, Inv. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) .......................................................................... 32
`
`Prism Pharma Co. v. Choogwae Pharma Corp.,
`IPR2014-00315, Paper 14 (July 8, 2014) ........................................................... 59
`
`Purdue Pharma LP v. Depomed, Inc.,
`IPR2015-00378, Paper 73 (July 8, 2015) ........................................................... 22
`
`iv
`
`

`
`TABLE OF AUTHORITIES
`(continued)
`
`Standard Oil Co. v. Am. Cyanamid Co.,
`
`774 F.2d 448 (Fed. Cir. 1985) ............................................................................ 32
`
`Page(s)
`
`Star Sci., Inc. v. R.J. Reynolds Tobacco Co.,
`655 F.3d 1364 (Fed. Cir. 2011) .......................................................................... 53
`
`Syntex (USA) LLC v. Apotex, Inc.,
`407 F.3d 1371 (Fed. Cir. 2005) .......................................................................... 57
`
`Therasense, Inc. v. Becton, Dickinson & Co.,
`649 F.3d 1276 (Fed. Cir. 2011) .......................................................................... 60
`
`Warner Chilcott Co. v. Lupin Ltd.,
`No. 11-5048, 2014 WL 202659 (D.N.J. Jan. 17, 2014) ..................................... 38
`
`In re Zletz,
`893 F.2d 319 (Fed. Cir. 1989) ............................................................................ 62
`
`Statutes
`
`35 U.S.C.
`§ 103(a) ............................................................................................................... 17
`§ 325(d) ..................................................................................................... 5, 58, 61
`§ 326(b) ............................................................................................................... 64
`
`Regulations
`
`37 C.F.R.
`§ 42.1(b) .............................................................................................................. 64
`§ 42.200(b) .......................................................................................................... 62
`
`Other Authorities
`
`MPEP § 2144.05 ...................................................................................................... 41
`
`
`
`v
`
`

`
`Case PGR2016-00007
`
`LIST OF EXHIBITS
`
`Exhibit
`2001
`
`2002
`
`Description
`Excerpts from Trial Tr. (Calderari), Helsinn Healthcare, S.A. v. Dr.
`Reddy’s Labs., Ltd., No. 11-3962 (D.N.J. June 2, 2015).
`Excerpts from Trial Tr. (Calderari), Helsinn Healthcare, S.A. v. Dr.
`Reddy’s Labs., Ltd., No. 11-3962 (D.N.J. June 3, 2015).
`2003 RESERVED
`Excerpts from Trial Tr. (Kirsch), Helsinn Healthcare, S.A. v. Dr.
`2004
`Reddy’s Labs., Ltd., No. 11-3962 (D.N.J. June 5, 2015)
`Excerpts from Trial Tr. (Frame), Helsinn Healthcare, S.A. v. Dr. Reddy’s
`Labs., Ltd., No. 11-3962 (D.N.J. June 8, 2015).
`Excerpts from Trial Tr. (Marriott), Helsinn Healthcare, S.A. v. Dr.
`Reddy’s Labs., Ltd., No. 11-3962 (D.N.J. June 9, 2015).
`Excerpts from Trial Tr. (Benhamza), Helsinn Healthcare, S.A. v. Dr.
`Reddy’s Labs., Ltd., No. 11-3962 (D.N.J. June 9, 2015).
`Excerpts from Trial Tr. (Candiotti), Helsinn Healthcare, S.A. v. Dr.
`Reddy’s Labs., Ltd., No. 11-3962 (D.N.J. June 10, 2015).
`2009 RESERVED
`Excerpts from Trial Tr. (Saab), Helsinn Healthcare, S.A. v. Dr. Reddy’s
`2010
`Labs., Ltd., No. 11-3962 (D.N.J. June 12, 2015).
`Excerpts from Trial Tr. (Markman), Helsinn Healthcare, S.A. v. Dr.
`Reddy’s Labs., Ltd., No. 11-3962 (D.N.J. June 15, 2015).
`Excerpts from Trial Tr. (Amidon), Helsinn Healthcare, S.A. v. Dr.
`Reddy’s Labs., Ltd., No. 11-3962 (D.N.J. June 15, 2015)
`Excerpts from Trial Tr. (DeLuca), Helsinn Healthcare, S.A. v. Dr.
`Reddy’s Labs., Ltd., No. 11-3962 (D.N.J. June 16, 2015).
`Excerpts from Trial Demonstrative Ex. 12 (Kirsch) Helsinn Healthcare,
`S.A. v. Dr. Reddy’s Labs., Ltd., No. 11-3962 (D.N.J. June 5, 2015).
`Excerpts of Defendants’ Contested Facts, from Final Pretrial Order,
`Helsinn Healthcare, S.A. v. Dr. Reddy’s Labs., No. 11-3962 (D.N.J.
`Apr. 17, 2015).
`Excerpts from William McGuire Deposition Tr., Helsinn Healthcare,
`S.A. v. Dr. Reddy’s Labs., Ltd., No. 12-2867 (D.N.J. Apr. 16, 2016).
`Excerpts from Christopher Fausel Deposition Tr., Helsinn Healthcare,
`S.A. v. Dr. Reddy’s Labs., Ltd., No. 12-2867 (D.N.J. Apr. 15, 2016).
`2018 RESERVED
`2019 RESERVED
`
`2005
`
`2006
`
`2007
`
`2008
`
`2011
`
`2012
`
`2013
`
`2014
`
`2015
`
`2016
`
`2017
`
`vi
`
`

`
`Case PGR2016-00007
`
`LIST OF EXHIBITS
`(continued)
`
`2022
`
`2023
`
`2024
`
`2025
`
`2026
`
`2027
`
`2028
`
`2020 RESERVED
`Excerpts from Maurie Markman Deposition Tr., Helsinn Healthcare,
`2021
`S.A. v. Dr. Reddy’s Labs., Ltd., No. 11-3952 (D.N.J. Jan. 7, 2015).
`Excerpts from Markman Hearing Tr. (Schoneich) Helsinn Healthcare,
`S.A. v. Dr. Reddy’s Labs., Ltd., No. 12-2867 (D.N.J.Oct. 21, 2014).
`Excerpts from Rebuttal Expert Report of Tanios Bekaii-Saab, M.D.,
`with respect to U.S. Patent No. 8,598,219, Helsinn Healthcare, S.A. v.
`Dr. Reddy’s Labs., Ltd., No. 11-3962 (D.N.J. Sept. 15, 2014) (“Saab
`ANDA Action ’219 Report”).
`Excerpts from Rebuttal Expert Report of Tanios Bekaii-Saab, M.D.,
`Helsinn Healthcare, S.A. v. Dr. Reddy’s Labs., Ltd., No. 11-3962 (D.N.J.
`Oct. 25, 2013) (“Saab Initial ANDA Action Report”).
`Excerpts from Rebuttal Expert Report of Keith A. Candiotti, M.D. with
`respect to U.S. Patent Nos. 8,729,094 & 9,066,980, Helsinn Healthcare,
`S.A. v. Dr. Reddy’s Labs., Ltd., No. 12-2867 (D.N.J. Feb. 11, 2016)
`(“Candiotti 505(b)(2) Action Report”).
`Excerpts from Expert Report of David G. Frame, Helsinn Healthcare,
`S.A. v. Dr. Reddy’s Labs., Ltd., No. 11-3962 (D.N.J. Sept. 5, 2013)
`(“Frame ANDA Action Report”) (as submitted in prosecution of U.S.
`Patent Application No. 13/901,830).
`Excerpts from Expert Report of Lee Kirsch, Ph.D., Helsinn Healthcare,
`S.A. v. Dr. Reddy’s Labs., Ltd., No. 11-3962 (D.N.J. Sept. 9, 2013)
`(“Kirsch ANDA Action Report”) (as submitted in prosecution of U.S.
`Patent Application No. 13/901,830).
`Excerpts from Expert Report of Patrick P. DeLuca, Ph.D., Helsinn
`Healthcare, S.A. v. Dr. Reddy’s Labs., Ltd., No. 11-3962 (D.N.J. Sept. 9,
`2013) (“DeLuca ANDA Action Report”) (as submitted in prosecution of
`U.S. Patent Application No. 13/901,830).
`2029 RESERVED
`Excerpts from Expert Report of Dr. Joanne Broadhead, Helsinn
`2030
`Healthcare, S.A. v. Dr. Reddy’s Labs., Ltd., No. 12-2867 (D.N.J. Jan.6,
`2016) (“Broadhead 505(b)(2) Action Report”).
`Jeremy D. Gale et al., Tachykinin NK1 receptor antagonists for the
`control of chemotherapy-induced nausea and vomiting, 11(12) Expert
`Opin. Ther. Pat. 1837-47 (2001) (“Gale 2001”).
`2032 Approval Package for Zolfran® Injection (ondansetron), approved Apr.
`11, 2000.
`
`2031
`
`vii
`
`

`
`Case PGR2016-00007
`
`LIST OF EXHIBITS
`(continued)
`
`2034
`
`2037
`
`2033 R.M. Eglen & D.W. Bonhaus, 5-hydroxytryptamine (5-HT)3 receptors:
`molecular biology, pharmacology and therapeutic importance, 2 Curr.
`Pharm. Des. 367 (Aug. 1996) (“Eglen 1996”).
`Jean Latreille et al., Use of dexamethasone and granisetron in the
`control of delayed emesis for patients who receive highly emetogenic
`chemotherapy, 16 J. Clin. Oncol. 1174 (Mar. 1998) (“Latreille 1998”).
`2035 H. Tsukada et al., Randomised comparison of ondansetron plus
`dexamethasone with dexamethasone alone for the control of delayed
`cisplatin-induced emesis, 37 Eur. J. Cancer 2398 (2001) (“Tsukada
`2001”).
`2036 Andre N. Rizk & Paul J. Hesketh, Antiemetics for Cancer
`Chemotherapy-Induced Nausea and Vomiting: A Review of Agents in
`Development, 2 Drugs R&D 229 (Oct. 1999) (“Rizk 1999”).
`Peter S. Loewen, Anti-emetics in development, 11 Expert Opin. Investig.
`Drugs 801 (2002) (“Loewen 2002”).
`2038 Henry Grabowski, The Effect of Pharmacoeconomics on Company
`Research and Development Decisions, 11 Pharmacoecon. 389 (May
`1997) (“Grabowski 1997”).
`2039 Kelly B. Pendergrass, Options in the Treatment of Chemotherapy-
`Induced Emesis, 6 Cancer Prac. 276 (Sept.-Oct. 1998) (“Pendergrass
`1998”).
`2040 RESERVED
`2041 RESERVED
`Pamela Sauer, Generic Formulators Position for Profits, 260 Chem.
`2042
`Mkt. Rep. FR12 (Aug. 13, 2001) (“Sauer 2001”).
`2043 Anita Greil, Roche, Novartis Feed on GlaxoSmithKline Castoffs, Dow
`Jones Int’l News, Aug. 31, 2000 (“Greil 2000”).
`P.J. Hesketh et al., Randomized Phase II Study of the Neurokinin 1
`Receptor Antagonist CJ-11,974 in the Control of Cisplatin-Induced
`Emesis, 17 J. Clin. Oncol. 338 (Jan. 1999) (“Hesketh 1999”).
`Fausto Roila et al., Delayed Emesis: Incidence, Pattern, Prognostic
`Factors and Optimal Treatment, 10 Support Cancer Care 88 (2002)
`(“Roila 2002”).
`2046 RESERVED
`2047 RESERVED
`2048 RESERVED
`2049 RESERVED
`
`2044
`
`2045
`
`viii
`
`

`
`Case PGR2016-00007
`
`LIST OF EXHIBITS
`(continued)
`
`2056
`
`2062
`
`2063
`
`2050 RESERVED
`2051 RESERVED
`2052 RESERVED
`2053 Helsinn’s NDA 21-372 Submission Letter dated Sept. 26, 2002.
`2054 Highlights of Prescribing Information, ALOXI® (palonosetron HCl)
`Injection for Intravenous Use, revised Feb. 2008.
`2055 Approval letter from FDA to Helsinn for New Drug Application No. 21-
`372 (ALOXI®) (July 25, 2003).
`Product Monograph, ALOXI® (palonosetron hydrochloride), revised
`Mar. 12, 2012.
`5/5/99 Email from Zeneca to Helsinn.
`2057
`3/14/00 Letter from Chiron to Helsinn.
`2058
`5/31/00 Email from Ortho Biotech to Helsinn.
`2059
`3/13/2000 Letter from Amgen to Helsinn.
`2060
`2061 Collection of letters to Helsinn from Baxter, Bayer, Berlex, Bristol-
`Meyers Squibb, Cephalon, Chiron, Coulter, CTI, Eli Lilly, Forest,
`Fujisawa, Genzyme, Ilex, Ligand, Liposome, Merck, and TAP Pharma.
`Information Disclosure Sheet, filed Jan. 12, 2006, in U.S. Patent
`Application No. 11/186,311 (Signed on Aug. 7, 2006).
`Information Disclosure Sheet, filed Dec. 20, 2011, in U.S. Patent
`Application No. 13/087,012 (Signed on July 6, 2012).
`Information Disclosure Sheet, filed Dec. 20, 2012, in U.S. Patent
`Application No. 13/087,012. (Signed on Feb. 14, 2013).
`Information Disclosure Sheet, filed Oct. 2, 2013, in U.S. Patent
`Application No. 13/901,437 (Signed on Oct. 7, 2013).
`Information Disclosure Sheet, filed May 23, 2013, in U.S. Patent
`Application No. 13/901,437 (Signed on July 23, 2013).
`Information Disclosure Sheet, filed May 24, 2013, in U.S. Patent
`Application No. 13/901,830 (Signed on Nov. 7, 2013).
`Information Disclosure Sheet, filed Mar. 27, 2014, in U.S. Patent
`Application No. 13/901,830 (Signed Apr. 9, 2014).
`Information Disclosure Sheet, filed Mar. 5, 2015, in U.S. Patent
`Application No. 13/901,830 (Signed July 27, 2015).
`Information Disclosure Sheet, filed July 28, 2015, in U.S. Patent
`Application No. 13/901,830 (Signed July 29, 2015).
`2071 RESERVED
`
`2064
`
`2065
`
`2066
`
`2067
`
`2068
`
`2069
`
`2070
`
`ix
`
`

`
`Case PGR2016-00007
`
`LIST OF EXHIBITS
`(continued)
`
`2072 Declaration of Daniele Bonadeo, signed Feb. 9, 2009, in U.S. Patent
`Application No. 11/186,311 (“2/9/09 Bonadeo Decl.”).
`2073 RESERVED
`Petition, Dr. Reddy’s Labs. v. Helsinn Healthcare, S.A., IPR2015-01550,
`2074
`Paper 1 (P.T.A.B. July 3, 2015) (“7/3/15 DRL IPR”).
`2075 RESERVED
`Petition, Dr. Reddy’s Labs. v. Helsinn Healthcare, S.A., PGR2016-
`2076
`00008, Paper 1 (P.T.A.B. Feb. 5, 2016) (“DRL PGR2”).
`2077 RESERVED
`2078 RESERVED
`2079 RESERVED
`2080
`Email from Russell W. Faegenburg, of Lerner, David, Littenberg,
`Krumholz & Mentlik, LLP, to Dana R. Weir, of Paul Hastings, LLP
`(May 10, 2016).
`2081 Helsinn Healthcare S.A., v. Dr. Reddy’s Labs., Ltd., No. 11-3962, 2016
`WL 832089 (D.N.J. Mar. 3, 2016) (the “Supplemental ANDA
`Opinion”).
`2082 Complaint, Helsinn Healthcare S.A., v. Dr. Reddy’s Labs., Ltd., No. 12-
`2867 (D.N.J. May 11, 2012).
`2083 Complaint, Helsinn Healthcare S.A., v. Dr. Reddy’s Labs., Ltd., No. 14-
`4274 (D.N.J. July 7, 2014).
`2084 Amended Complaint, Helsinn Healthcare S.A., v. Dr. Reddy’s Labs.,
`Ltd., No. 14-4274 (D.N.J. Sep. 2, 2015).
`
`x
`
`

`
`
`
`I.
`
`Introduction
`
`
`
`Case PGR2016-00007
`
`The claims-at-issue of U.S. Patent No. 9,173,942 (“the ’942 patent”) cover
`
`Aloxi®, Patent Owner’s highly successful — and extensively copied — drug
`
`product indicated to prevent nausea and vomiting, or “emesis,” in patients
`
`receiving cancer chemotherapy. In its Petition, Dr. Reddy’s Laboratories, Ltd. and
`
`Dr. Reddy’s Laboratories, Inc. (collectively, “DRL” or Petitioner) improperly
`
`describe the claimed inventions as “palonosetron, sugar (mannitol), and water.”
`
`(Pet. at 8.) In doing so, DRL miscomprehends the claimed inventions and ignores
`
`the development obstacles that were overcome in arriving at the formulations
`
`covered by the ’942 patent claims.
`
`As described below, Patent Owner pursued palonosetron despite heavy
`
`skepticism in the industry concerning the development of “5-HT3s,”1 particularly
`
`given that, by 2003, 5-HT3 products had already been marketed for more than a
`
`decade and imminent generic competition was expected. Further complicating
`
`Patent Owner’s development efforts, palonosetron possesses a unique property: it
`
`becomes less stable at higher concentrations. One of Patent Owner’s challenges
`
`
`1 The term “5-HT3s” refers to a class of compounds, which includes palonosetron,
`
`that block 5-HT3 receptors and disrupt the serotonin pathway, which is implicated
`
`in emesis. (Ex. 2039 at 277.)
`
`1
`
`

`
`
`
`
`
`Case PGR2016-00007
`
`was therefore in finding a concentration that was low enough to provide sufficient
`
`stability, but high enough to prevent emesis. For example, the intravenous
`
`palonosetron formulation disclosed in the Berger ’333 Patent (Ex. 1006) was not
`
`stabile enough to meet regulatory requirements. (Ex. 1001, cols. 1:62-2:12.)
`
`Only after extensive testing did Patent Owner realize its objective of
`
`“provid[ing] a formulation of Palonosetron hydrochloride with increased
`
`pharmaceutical stability for preventing and/or reducing emesis.” (Ex. 1001, col.
`
`2:50-52.) Indeed, it discovered that it achieved even more than that. While several
`
`5-HT3s, including Aloxi®, have been FDA-approved to prevent “acute”
`
`chemotherapy-induced nausea and vomiting (“CINV”), Aloxi® is the only one
`
`approved to prevent “delayed” CINV.2 For this reason, DRL’s experts hail Aloxi®
`
`as “a wonderful product” (Ex. 2011, 6/10/15 (Markman) Trial Tr. at 8:2) that is
`
`
`2 Emesis occurring within 24 hours after the administration of chemotherapy is
`
`commonly referred to as “acute CINV,” while emesis occurring more than 24
`
`hours after the administration of chemotherapy is referred to as “delayed CINV.”
`
`(Ex. 2010, 6/12/15 (Saab) Trial Tr. at 18:16-19:5.)
`
`2
`
`

`
`
`
`
`
`Case PGR2016-00007
`
`“used most of the time” despite the availability of lower-priced, generic 5-HT3s
`
`(Ex. 2017, 4/15/16 (Fausel) Dep. Tr. at 279:8-280:1).3
`
`Applying a hindsight-driven analysis, DRL alleges that claims 1-6, 10, and
`
`11 (“the claims-at-issue”) of the ’942 patent are unpatentable for obviousness.
`
`DRL’s Petition is a rehash of arguments that were already vetted in district court
`
`litigation. After considering the same prior art references, the district court
`
`rejected DRL’s argument that claims of related patents were invalid based on, inter
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`alia, the finding that the same claim limitations present in the ’942 patent claims
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`would not have been obvious. (Ex. 1061, Memorandum Opinion at 5.) And for
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`good reason; DRL’s recycled obviousness arguments begin with the erroneous
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`premise that a person of ordinary skill in the art (“POSA”)4 would have selected
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`palonosetron for development. As discussed in Section III.A.1 below, only
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`through hindsight would a POSA have made that critical decision given that the
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`3 Certain exhibits submitted herewith have been excerpted to exclude confidential
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`information.
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`4 Patent Owner agrees with DRL that the definition of a POSA used in Civil Action
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`No. 11-3962 in the District of New Jersey (“the ANDA action”), which involves
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`the’942 patent’s parent and grandparent, should be used in these proceedings. (Pet.
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`at 27-28.)
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`industry shifted its focus by 2003 to new classes of compounds, including “NK-
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`1s,” which exhibited more promising results for delayed CINV.
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`DRL compounds the errors in its obviousness analysis by misinterpreting the
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`only peer-reviewed prior art reference disclosing palonosetron clinical data, Tang
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`1998 (Ex. 1008). Contrary to DRL’s assertions, a POSA would not have selected a
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`0.25 mg dose or a 0.05 mg/mL dose-dependent concentration5 of palonosetron for
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`development based on the results from Tang 1998, where even a 2.1 mg dose —
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`more than eight times greater than the highest dose covered by the claims-at-issue
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`— was only partially effective in treating emesis. (See § III.A.2, infra.)
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`Unsurprisingly, during prosecution, the Examiner agreed that Tang 1998
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`taught away from the claimed dose and dose-dependent concentration: “[Tang]
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`specifically teach[es] that . . . administering palonosetron . . . was effective only at
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`a higher dose. . . . Yes Tang teaches a [dose] of 3.0 µg/kg which is closest to the
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`dose recited, however, Tang also teaches that it fails to pr[event] or reduce the
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`5 As conceded by DRL’s expert declarant, Dr. Christopher Fausel, a POSA would
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`have sought to formulate an intravenous palonosetron solution “in 5mls or less.”
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`(See, e.g., Ex. 1026, 2/5/16 Fausel Decl. at ¶ 57.) Thus, the claimed 0.05 mg/mL
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`concentration is dose-dependent, and would be limited to doses of 0.05 mg
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`(corresponding to 1 mL) to 0.25 mg (corresponding to 5 mL).
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`post-operative vomiting.” (Ex. 1043 (Notice of Allowance) at 7-8 (emphasis
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`added).) The Examiner also properly considered and rejected the other prior art
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`references relied upon by DRL in its Petition, which were also of record during
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`prosecution of the ’942 patent’s parent, grandparent, and great-grandparent. Thus,
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`DRL’s challenges to the ’942 patent should be denied under 35 U.S.C. § 325(d).
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`(See § IV, infra.)
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`In addition to generalizing that it would have been “routine” to use the
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`claimed excipients in the required amounts, DRL’s Petition fails to adequately
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`address secondary considerations of nonobviousness. (See § III.B, infra.) As
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`found in the ANDA action, there is compelling objective evidence of commercial
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`success, long-felt but unsolved need, failure of others, and industry praise.
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`(Ex. 1061, Memorandum Opinion at 5.)
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`In sum, DRL has not demonstrated that it is more likely than not that any
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`claim-at-issue is unpatentable on any ground. Patent Owner therefore respectfully
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`submits that the Board should decline to institute a trial.
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`II. Background
`A. Aloxi® Is a Breakthrough Drug
`Product for Patients Suffering from CINV
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`Nausea and vomiting are the body’s natural responses to noxious stimuli,
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`and serve the critical function of expelling harmful substances from the body. (Ex.
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`2024, Saab Initial ANDA Action Report at ¶ 16.) Medications, such as
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`chemotherapy, can also stimulate these same physiologic pathways. (Id. at ¶ 17.)
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`The trauma to patients from CINV can be severe. As Patent Owner’s expert,
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`Dr. Tanios Bekaii-Saab, testified in the ANDA action, CINV has long been
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`recognized as one of its most dreaded side effects. (Ex. 2010, 6/12/15 (Saab) Trial
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`Tr. at 14:23-15:25.) In fact, the CINV symptoms were so severe for some patients
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`that they refused to continue chemotherapy. (Id.) And to the extent cancer that
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`was previously in remission returned, some patients were reluctant to restart
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`chemotherapy based on their past experiences. (Id.)
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`By 1991, a new form of treatment had been approved for patients suffering
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`from acute (i.e., within the first 24 hours following chemotherapy) CINV: 5-HT3s.
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`(Id. at 18:3-15.) According to Dr. Saab, the FDA-approved 5-HT3s “were effective
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`in helping with the acute episodes” of CINV and “a very welcome addition before
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`2003.” (Ex. 2010, 6/12/15 (Saab) Trial Tr. at 18:7-15.)
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`These 5-HT3s, however, did not effectively treat delayed CINV occurring
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`after 24 hours. Delayed CINV is a particularly debilitating condition given that the
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`patient has likely left the care of medical professionals when the symptoms first
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`arrive, and “will present with severe episodes of nausea and vomiting up to 20, 30
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`times.” (Id. at 19:12-17.) Because there is no cure for delayed emesis once
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`symptoms start, patients were kept in hospitals and supported with intravenous
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`fluids for up to a week until the symptoms subsided on their own. (Id.) As Dr.
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`Saab testified, before Aloxi®, “we didn’t have real good strategies at the time to
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`actually prevent or treat delayed emesis.” (Id. at 19:25-20:7.)
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`In July 2003, more than ten years after 5-HT3 started being approved, the
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`FDA approved Aloxi® for use in preventing acute and delayed CINV. (Id. at
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`65:11-67:7) To this day, Aloxi® is the only 5-HT3 approved for prevention of
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`delayed CINV. (Id. at 43:7-9, 67:1-7.) Major cancer-related professional society
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`guidelines identify Aloxi® as a preferred treatment for the management of
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`moderately emetogenic CINV. (Id. at 79:25-80:11.) With over $3.6 billion in U.S.
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`sales, Aloxi® has helped countless people cope with the side effects of
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`chemotherapy. (Ex. 2006, 6/9/15 (Marriott) Trial Tr. at 158:24-159:4.) Indeed,
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`Aloxi® was hailed as “a wonderful product” that “was effective for delayed CINV
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`where other setrons were not” by DRL’s own expert in the ANDA action. (Ex.
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`2011, 6/10/15 (Markman) Trial Tr. at 7:14-8:19, 9:20-10:6.) One of DRL’s PGR
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`declarants, Dr. Fausel, similarly testified in a related district court action that
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`Aloxi® is his group’s “workhorse” 5-HT3 antiemetic, i.e., the 5-HT3 antiemetic that
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`his group “use[s] most of the time,” despite the availability of less-expensive
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`generic 5-HT3s. (Ex. 2017, 4/15/16 (Fausel) Dep. Tr. at 279:8-280:1.)
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`B. Helsinn’s Development of Palonosetron
`Helsinn Healthcare S.A. acquired the rights to palonosetron from Roche
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`Palo Alto LLC in 1998. (Ex. 2081, Supplemental ANDA Opinion at *10.) Prior to
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`its acquisition, Roche had conducted Phase II clinical studies with a palonosetron
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`formulation in simple phosphate-buffered, pH 7.4 saline solutions (i.e., not the
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`formulations claimed by the ’942 patent). (Ex. 2002, 6/3/15 (Calderari) Trial Tr. at
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`10:9-16.) Based on unimpressive efficacy results, Roche abandoned its
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`palonosetron program. (Ex. 2081, Supplemental ANDA Opinion at *10, 12.)
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`Instead, Roche paid $1 billion to acquire rights to another 5-HT3, Kytril®. (Ex.
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`2002 6/3/15 (Calderari) Trial Tr. at 83:14-84:15.) By comparison, Helsinn paid
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`Roche $10 million for the rights to palonosetron, with further royalties due only if
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`a product was ever FDA-approved and launched. (Ex. 2002, 6/3/15 (Calderari)
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`Trial Tr. at 84:16-21, 158:16-22.) At the same time, Roche also shifted its research
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`and development efforts to developing an NK-1 antiemetic. (Id. at 85:14-86:6.)
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`By 1998, three 5-HT3s were already on the market: ondansetron,
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`granisetron, and dolasetron. (Ex. 2006 6/9/15 (Marriott) Trial Tr. at 155-56.)
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`Helsinn still chose to pursue Aloxi® because it was committed to entering the U.S.
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`market and a new field of research. (Ex. 2002, 6/3/15 (Calderari) Trial Tr. at
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`86:22-87:21.) Helsinn, however, faced significant hurdles. It had to design Phase
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`III trials and intravenous formulations for use in those trials, since certain Phase II
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`formulations having high palonosetron concentrations were not sufficiently stable.
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`(Id. at 118:24-119:16; Ex. 2001, 6/2/15 (Calderari) Trial Tr. at 121:15-122:14.)
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`The design of a formulation appropriate for clinical use proved challenging due to
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`palonosetron’s unusual property; it is unexpectedly more stable at lower
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`concentrations in solution. (Ex. 2012, 6/15/15 (Amidon) Trial Tr. at 216:17-
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`217:7.) For example, during prosecution of the ’942 patent, the Examiner was
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`referred to the February 9, 2009 Declaration of Daniele Bonadeo (Ex. 1041,
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`2/21/14 Office Action Response at 12-13), which included the table below
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`demonstrating that “the stability of [palonosetron] improves in this formulation as
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`its concentration decreased, with greatest stability seen below 0.1 mg/ml” (Ex.
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`2072, 2/9/09 Bonadeo Decl. at ¶ 9.)
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`Since bolus intravenous formulations like Aloxi® are limited to volumes of no
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`more than 5 mL (Ex. 1026, 2/5/16 Fausel Decl. at ¶ 57; Ex. 2008, 6/10/15
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`(Candiotti) Trial Tr. at 102:8-15), Helsinn needed to pinpoint a concentration that
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`was high enough to be efficacious, but low enough to be stable (Ex. 2002, 6/3/15
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`(Calderari) Trial Tr. at 40:8-21).
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`After extensive analysis and internal debate, Helsinn chose to pursue two
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`palonosetron doses in Phase III trials,