Opposition To Patent Owner’s Contingent Motion To Amend for Inter Partes
`Review of USPN 8,618,135
`
`Filed on behalf of Coalition for Affordable Drugs VIII, LLC
`By: Dr. Gregory Gonsalves
`Reg. No. 43,639
`2216 Beacon Lane
`Falls Church, Virginia 22043
`(571) 419-7252
`gonsalves@gonsalveslawfirm.com
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`COALITION FOR AFFORDABLE DRUGS VIII, LLC, Petitioner
`
`v.
`
`TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA,
`Patent Owner, based on Electronic Records of PTO
`U.S. Patent 8,618,135 to Rader
`Filing Date: March 11, 2011
`Issue Date: December 31, 2013
`TITLE: METHODS FOR TREATING DISORDERS OR DISEASES ASSOCIATED WITH
`HYPERLIPIDEMIA AND HYPERCHOLESTEROLEMIA WHILE MINIMIZING SIDE EFFECTS
`
`IPR Trial No. IPR2015-01835
`
`Petitioner’s Opposition To Patent Owner’s Contingent Motion To
`Amend
`
`
`
`
`
`
`
`
`
`
`Mail Stop "PATENT BOARD"
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
`
`
`
`
`
`
`Review of USPN 8,618,135
`
`Filed on behalf of Coalition for Affordable Drugs VIII, LLC
`By: Dr. Gregory Gonsalves
`Reg. No. 43,639
`2216 Beacon Lane
`Falls Church, Virginia 22043
`(571) 419-7252
`gonsalves@gonsalveslawfirm.com
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`COALITION FOR AFFORDABLE DRUGS VIII, LLC, Petitioner
`
`v.
`
`TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA,
`Patent Owner, based on Electronic Records of PTO
`U.S. Patent 8,618,135 to Rader
`Filing Date: March 11, 2011
`Issue Date: December 31, 2013
`TITLE: METHODS FOR TREATING DISORDERS OR DISEASES ASSOCIATED WITH
`HYPERLIPIDEMIA AND HYPERCHOLESTEROLEMIA WHILE MINIMIZING SIDE EFFECTS
`
`IPR Trial No. IPR2015-01835
`
`Petitioner’s Opposition To Patent Owner’s Contingent Motion To
`Amend
`
`
`
`
`
`
`
`
`
`
`Mail Stop "PATENT BOARD"
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
`
`
`
`
`
`
`
`Opposition To Patent Owner’s Contingent Motion To Amend for Inter Partes
`Review of USPN 8,618,135
`
`
`TABLE OF CONTENTS
`
`I.
`
`II.
`
`III.
`
`OVERVIEW OF WHY PATENT OWNER’S MOTION TO AMEND
`SHOULD BE DENIED ................................................................................... 1
`
`PATENT OWNER’S MOTION IS FACIALLY DEFICIENT
`BECAUSE IT LACKS THE REQUIRED CLAIM
`CONSTRUCTION. ......................................................................................... 1
`
`PATENT OWNER DID NOT ESTABLISH THAT THE ‘135
`PATENT IS ENTITLED TO CLAIM PRIORITY TO CERTAIN
`CLINICAL TRIALS. ....................................................................................... 2
`
`IV. PATENT OWNER HAS NOT DEMONSTRATED THAT THE
`SUBSTITUTE CLAIMS ARE PATENTABLE OVER THE PRIOR
`ART. ................................................................................................................ 4
`
`A.
`
`Substitute Claims 11-18 Are Obvious Over The Prior Art. .................. 5
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`Claims 1, 17 and 18 Are Obvious Over Wetterau In View
`Of ICH-E4, Chang, Guidance For Industry 2002,
`Reigner and the ‘653 Patent ......................................................11
`
`Substitute Claim 12 Is Obvious Over the Same Prior Art ........16
`
`Substitute Claims 13 and 14 Are Obvious Over the Same
`Prior Art ....................................................................................17
`
`Substitute Claim 15 Is Obvious Over the Same Prior Art ........17
`
`Substitute Claim 16 Is Obvious Over the Same Prior Art ........18
`
`B.
`
`There Is No Nexus Between The Alleged Indicia Of
`Nonobviousness And The Substitute Claims. .....................................18
`
`1.
`
`2.
`
`The Dosing Method That Was Alleged By Patent Owner
`To Have Unexpected Results Is Not Required By The
`Claims. ......................................................................................19
`
`The Long-Felt, But Unmet, Need Alleged By Patent
`Owner Has No Nexus To The Claimed Invention. ...................20
`
`
`
`i
`
`
`
`Opposition To Patent Owner’s Contingent Motion To Amend for Inter Partes
`Review of USPN 8,618,135
`
`
`3.
`
`4.
`
`5.
`
`The Failure Of Others Alleged By Patent Owner Has No
`Nexus To The Claimed Invention. ............................................22
`
`The Praise Of Others Alleged By Patent Owner Has No
`Nexus To The Claimed Invention. ............................................22
`
`The Alleged Commercial Success Of Juxtapid Has No
`Nexus To The Claimed Invention. ............................................23
`
`C.
`
`The Substitute Claims Are Not Patentable Over The
`Combinations Of Chang and The Pink Sheet Or Chang and
`Stein. ....................................................................................................24
`
`CONCLUSION. .............................................................................................25
`
`V.
`
`
`
`
`ii
`
`
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`Opposition To Patent Owner’s Contingent Motion To Amend for Inter Partes
`Review of USPN 8,618,135
`
`
`EXHIBIT LIST PURSUANT TO 37 C.F.R. § 42.63(e) AND
`TABLE OF ABBREVIATIONS
`
`
`
`iii
`
`
`
`Opposition To Patent Owner’s Contingent Motion To Amend for Inter Partes
`Review of USPN 8,618,135
`
`
`Ex. No.
`
`Description
`
`1001
`
`Certified U.S. Patent No. 8,618,135 to Rader.
`
`1002
`
`Declaration of Randall M. Zusman, M.D.
`
`1003
`
`Declaration of Michael Mayersohn, Ph.D.
`
`1004
`
`Affidavit of Christopher Butler, Office Manager, Internet Archive,
`authenticating Internet Archive URLs (June 16, 2015) (attaching as
`Ex. A:
`
`PPD News & IR Presentations (2004/04/15) (available at
`https://web.archive.org/web/20040415065142/http://ppdi.com/PPD_6
`_12.htm)).
`
`1005
`
`Affidavit of Christopher Butler, Office Manager, Internet Archive,
`authenticating Internet Archive URLs (June 12, 2015) (attaching as
`Ex. A:
`
`PPD News Releases(2004/02/13) (available at
`https://web.archive.org/web/20040213233245/http://www.ppdi.com/P
`PD_U6.htm?ID=126662);
`
`PPD News & IR Presentations(2003/12/12) (available at
`https://web.archive.org/web/20031212193444/http://ppdi.com/PPD_6
`_12.htm);
`
`PPD News & IR Presentations (2004/06/04) (available at
`https://web.archive.org/web/20040604203252/http://www.ppdi.com/P
`PD_6_12.htm)).
`
`1006
`
`Certified U.S. Provisional Patent Application No. 60/550,915.
`
`1007
`
`U.S. Patent No. 8,618,135 (highlighting dosing information not
`present in U.S. Provisional Patent Application No. 60/550,915).
`
`1008
`
`U.S. Patent Application No. 13/046,118.
`
`1009
`
`In re Application of: Rader, U.S. Patent Application No. 13/046,118,
`Amendment and Response to Oct. 2, 2012 Office Action (Mar. 4,
`2013).
`
`
`
`iv
`
`
`
`Opposition To Patent Owner’s Contingent Motion To Amend for Inter Partes
`Review of USPN 8,618,135
`
`
`1010
`
`1011
`
`1012
`
`1013
`
`1014
`
`1015
`
`1016
`
`1017
`
`In re Application of: Rader, U.S. Patent Application No. 13/046,118,
`Declaration of William Sasiela, Ph.D. (Apr. 8, 2010).
`
`In re Application of: Rader, U.S. Patent Application No. 13/046,118,
`Notice of Allowance (May 10, 2013).
`
`In re Application of: Rader, U.S. Patent Application No13/046,118,
`Notice of Allowance (Sept. 3, 2013).
`
`Bayer/PPD Implitapide Development Follows Zetia Model As Statin
`Add-On, 66 THE PINK SHEET 17 (Feb. 16, 2004).
`
`Evan Stein, CEO & President, MRL Int’l (Division of PPD),
`Presentation Given at PPD’s Analyst Day, Microsomal Triglygeride
`[sic] Transfer Protein (MTP) Inhibitor (implitapide) program (Feb. 5,
`2004).
`
`George Chang et al., Microsomal triglyceride transfer protein (MTP)
`inhibitors: Discovery of clinically active inhibitors using high-
`throughput screening and parallel synthesis paradigms, 5 CURRENT
`OPINION IN DRUG DISCOVERY & DEV. 562 (2002).
`
`Charles E. Chandler et al., CP-346086: an MTP inhibitor that lowers
`plasma cholesterol and triglycerides in experimental animals and in
`humans, 44 J. OF LIPID RES. 1887 (2003).
`
`FDA approves Zetia -- first new class to treat cholesterol since statins
`introduced, DRUGS.COM (Oct. 28, 2002),
`http://www.drugs.com/news/fda-approves-zetia-first-new-class-
`cholesterol-since-statins-introduced-3164.html (last visited July 22,
`2015).
`
`1018
`
`John R. Wetterau et al., An MTP Inhibitor That Normalizes
`Atherogenic Lipoprotein Levels in WHHL Rabbits, 282 SCI. 751
`(1998).
`
`1019
`
`U.S. Patent No. 5,712,279 to Biller et al.
`
`1020
`
`Evan Stein, OPPOSITION AGAINST EUROPEAN PATENT NO. 1 725 234
`B9 (filed Aug. 21, 2013).
`
`
`
`v
`
`
`
`Opposition To Patent Owner’s Contingent Motion To Amend for Inter Partes
`Review of USPN 8,618,135
`
`
`1021
`
`1022
`
`1023
`
`1024
`
`1025
`
`THOMPSON PDR, PHYSICIANS’ DESK REFERENCE 506-09, 1101-06,
`1813-21, 2036-41, 2126-31, 2547-51, 2729-31, 2865-68 (57th ed.
`2003) (excerpting product information for Tricor®, Pravachol®,
`Advicor®, Niaspan®, Mevacor®, Zocor®, Lipitor®, Colestid®, and
`Lescol®).
`
`THOMPSON PDR, PHYSICIANS’ DESK REFERENCE 2118-23, 3085-89
`(58th ed. 2004) (excerpting product information for Zetia®).
`
`U.S. FOOD & DRUG ASS’N, ESTIMATING THE MAXIMUM SAFE
`STARTING DOSE IN INITIAL CLINICAL TRIALS FOR THERAPEUTICS IN
`ADULT HEALTHY VOLUNTEERS: GUIDANCE FOR INDUSTRY (2005).
`
`Prices and coupons for 30 capsules of Juxtapid 5mg, 10mg, 20mg,
`30mg, 40mg and 60mg (brand), GOODRX.COM,
`http://www.goodrx.com/juxtapid (last visited July 16, 2015).
`
`Dan Mangan, ‘Fast Money’ faux pas: Firm draws FDA warning, DOJ
`subpoena, CNBC.COM (Jan. 13, 2014),
`http://www.cnbc.com/id/101327742 (last visited July 22, 2015).
`
`1026 Malcolm Rowland & Thomas N. Tozer, CLINICAL
`PHARMACOKINETICS: CONCEPTS AND APPLICATIONS 57 (3d ed. 1995).
`
`1027
`
`Curriculum Vitae of Randall M. Zusman, M.D.
`
`1028
`
`Documents considered by Randall M. Zusman, M.D.
`
`1029
`
`Curriculum Vitae of Michael Mayersohn, Ph.D.
`
`1030
`
`Documents considered by Michael Mayersohn, Ph.D.
`
`1031
`
`Third Report of the National Cholesterol Education Program (NCEP)
`Expert Panel on Detection, Evaluation and Treatment of High Blood
`Cholesterol in Adults (Adult Treatment Panel III) Final Report, 106
`CIRCULATION 3143 (2002).
`
`1032 Michael Mayersohn, Principles and Applications of
`Pharmacokinetics, in MEDICAL TOXICOLOGY 282 (Richard C. Dart
`ed., 3d ed. 2004).
`
`
`
`vi
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`Opposition To Patent Owner’s Contingent Motion To Amend for Inter Partes
`Review of USPN 8,618,135
`
`
`1033 Masashi Shiomi & Takashi Ito, MTP inhibitor decreases plasma
`cholesterol levels in LDL receptor-deficient WHHL rabbits by
`lowering the VLDL secretion, 431 EUR. J. OF PHARMACOLOGY 127
`(2001).
`
`1034
`
`Declaration of Jeffery A. Marx.
`
`1035
`
`1036
`
`Press Release, Cigna Corp., Cigna Announces Appearance at CIBC
`Healthcare Conference (Nov. 7, 2003),
`http://newsroom.cigna.com/article_display.cfm?article_id=236.
`
`Press Release, Gilead Scis., Gilead Sciences to Present at the 7th
`Annual Lehman Brothers Global Healthcare Conference on Friday,
`March 5th; Webcast Available Through Gilead Corporate Website
`(Mar. 4, 2004),
`http://gilead.com/news/press-releases/2004/3/gilead-sciences-to-
`present-at-the-7th-annual-lehman-brothers-global-healthcare-
`conference-on-friday-march-5th-webcast-available-through-gilead-
`corporate-website?mode=print.
`
`1037
`
`Press Release, PR Newswire, Dot Hill to Present at Robert W. Baird
`2004 Growth Stock Conference (May 4, 2004),
`http://www.prnewswire.com/news-releases/dot-hill-to-present-at-
`robert-w-baird-2004-growth-stock-conference-73777807.html.
`
`1038 Margaret A. McDowell et al., Anthropometric Reference Data for
`Children and Adults: U.S. Population, 1999-2002, CDC ADVANCE
`DATA FROM VITAL & HEALTH STATS. NO. 361 (2005).
`
`1039
`
`1040
`
`1041
`
`In re Application of: Rader, U.S. Patent Application No. 13/046,118,
`Amendment (Sept. 25, 2013).
`
`In re Application of: Rader, U.S. Patent Application No. 13/046,118,
`Supplemental Information Disclosure Statement (Sept. 25, 2013).
`
`In re Application of: Rader, U.S. Patent Application No. 13/046,118,
`Notice of Allowance (Oct. 29, 2013).
`
`1042
`
`Declaration of Randall M. Zusman, M.D. (served but not filed)
`
`
`
`vii
`
`
`
`Opposition To Patent Owner’s Contingent Motion To Amend for Inter Partes
`Review of USPN 8,618,135
`
`
`1043
`
`Affidavit of Christopher Butler, Office Manager, Internet Archive,
`authenticating Internet Archive URLs (April 1, 2016) (attaching as
`Ex. A:
`
`PPD News & IR Presentations (2004/04/15) (available at
`https://web.archive.org/web/20040415065142/http://ppdi.com/PPD_6
`_12.htm)). (served but not filed)
`
`1044
`
`Affidavit of Christopher Butler, Office Manager, Internet Archive,
`authenticating Internet Archive URLs (April 1, 2016) (attaching as
`Ex. A:
`
`PPD News Releases(2004/02/13) (available at
`https://web.archive.org/web/20040213233245/http://www.ppdi.com/P
`PD_U6.htm?ID=126662);
`
`PPD News & IR Presentations(2003/12/12) (available at
`https://web.archive.org/web/20031212193444/http://ppdi.com/PPD_6
`_12.htm);
`
`PPD News & IR Presentations (2004/06/04) (available at
`https://web.archive.org/web/20040604203252/http://www.ppdi.com/P
`PD_6_12.htm)). (served but not filed)
`
`1045
`
`1046
`
`1047
`
`Guidance for Industry 2002, Estimating the Safe Starting Dose in
`Clinical Trials for Therapeutics in Adult Healthy Volunteers (2002)
`(“Guidance For Industry 2002”)
`
`ICH-E4, Dose-Response Information to Support Drug Registration
`(1994) (“ICH-E4”)
`
`Bruno G. Reigner and Karen Smith Blesch., Estimating the starting
`dose for entry into humans: principles and practice, Eur J Clin
`Pharmacol (2002) 57: 835–845.
`
`
`
`viii
`
`
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`Opposition To Patent Owner’s Contingent Motion To Amend for Inter Partes
`Review of USPN 8,618,135
`
`
`TABLE OF ABBREVIATIONS
`
`Abbreviation
`
`‘915
`Provisional
`
`Definition
`
`U.S. Provisional Patent Application No. 60/550,915
`
`‘268 patent U.S. Patent No. 7,932,268
`
`‘923
`application
`
`U.S. Patent Application No. 10/591,923 (issued as ‘268 patent)
`
`‘135 patent U.S. Patent No. 8,618,135
`
`‘118
`application
`
`U.S. Patent Application No. 13/046,118 (issued as ‘135 patent)
`
`ApoB
`
`Apolipoprotein B
`
`CFAD
`
`Coalition For Affordable Drugs VIII, LLC
`
`Credes
`
`Hayman Credes Master Fund, L.P.
`
`HCM
`
`Hayman Capital Management, L.P.
`
`HCMF
`
`Hayman Capital Master Fund, L.P.
`
`HDL
`
`High density lipoprotein
`
`HeFH
`
`Heterozygous familial hypercholesterolemia
`
`HI
`
`Hayman Investments, L.L.C.
`
`HOF
`
`Hayman Orange Fund SPC – Portfolio A
`
`HoFH
`
`Homozygous familial hypercholesterolemia
`
`HOM
`
`Hayman Offshore Management, Inc.
`
`IDL
`
`Intermediate-density lipoprotein
`
`LDL
`
`Low density lipoprotein
`
`ix
`
`
`
`Opposition To Patent Owner’s Contingent Motion To Amend for Inter Partes
`Review of USPN 8,618,135
`
`
`Abbreviation
`
`Definition
`
`LDL-C
`
`Low density lipoprotein cholesterol
`
`Lp(a)
`
`Lipoprotein (a)
`
`Mayersohn
`
`Declaration of Michael Mayersohn, Ph.D. in Support of
`Coalition for Affordable Drug’s Petition for Inter Partes Review
`of U.S. Patent No. 8,618,135
`
`MTP
`
`Microsomal triglyceride transfer proteins
`
`TG
`
`Triglycerides
`
`Total-C
`
`Total cholesterol
`
`VLDL
`
`Very low density lipoprotein
`
`WHHL
`
`Watanabe-heritable hyperlipidemic
`
`Zusman
`
`Declaration of Randall M. Zusman, M.D. in Support of Coalition
`for Affordable Drug’s Petition for Inter Partes Review of U.S.
`Patent No. 8,618,135
`
`
`
`x
`
`
`
`Opposition To Patent Owner’s Contingent Motion To Amend for Inter Partes
`Review of USPN 8,618,135
`
`
`TABLE OF AUTHORITIES
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` PAGES
`
`Federal Cases
`
`Tyco Healthcare Grp. LP v. Mut. Pharm. Co.,
`642 F.3d 1370 (Fed. Cir. 2011) ...........................................................................5,6
`
`
`
`xi
`
`
`
`Opposition To Patent Owner’s Contingent Motion To Amend for Inter Partes
`Review of USPN 8,618,135
`
`OVERVIEW OF WHY PATENT OWNER’S MOTION TO AMEND
`SHOULD BE DENIED
`
`I.
`
`The Petitioner asks the Board to deny Patent Owner’s motion to amend (PO’s
`
`Motion). PO fails to meet its burden to show that it is entitled to the supplemental
`
`claims (see 37 C.F.R. § 42.20(e)). PO’s motion is facially defective because it i)
`
`does not construe important claim terms, ii) does not establish that the ‘135 patent is
`
`entitled to claim priority to certain clinical trials because the trials do not fall within
`
`the scope of the supplemental claims, and iii) does not address prior art known to the
`
`PO that would have taught to a person of ordinary skill of the art (POSA) the dosing
`
`scheme recited in the supplemental claims. PO’s arguments of secondary
`
`considerations of non-obviousness also fail because they are also not commensurate
`
`with the scope of the supplemental claims.
`
`For these reasons and the reasons set forth more fully below, the challenged
`
`claims are obvious and should be cancelled.
`
`II.
`
`PATENT OWNER’S MOTION IS FACIALLY DEFICIENT BECAUSE
`IT LACKS THE REQUIRED CLAIM CONSTRUCTION.
`
`Construction of new claim terms is a fundamental component of PO’s burden
`
`as the moving party seeking entry of substitute claims. See Idle Free Systems, Inc.
`
`v. Bergstrom, Inc., IPR2012-00027 (“Idle Free”), PN 26 at 7 (PTAB June 11, 2013).
`
`Proposed substitute independent claims 11, 17 and 18 recite “a first and a second
`
`dose level is 50% of the immediately following dose level” and “a third dose level
`
`
`
`1
`
`
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`Opposition To Patent Owner’s Contingent Motion To Amend for Inter Partes
`Review of USPN 8,618,135
`
`is about 0.2 to about 0.59 mg/kg/day.” PO failed to specify what it means by the
`
`qualifier “about.” Also, although the definite article “the” precedes the phrase
`
`“immediately following dose level” in claims 11, 17 and 18 and therefore, ostensibly
`
`refers to an earlier instance of that phrase, there is, in fact, no such earlier instance.
`
`In addition, although the definite article “the” also precedes the term “disorder” in
`
`claim 12 and therefore, ostensibly refers to an earlier instance of that term, there is,
`
`in fact, no such earlier instance.
`
`Nonetheless, PO provides no construction of any of this terminology. To the
`
`extent PO is asserting the plain and ordinary meaning of the terms in the
`
`supplemental claims, this is likewise inadequate given the additional claim
`
`limitations. See Xilinx, Inc. v. Intellectual Ventures I LLC, IPR2013-00029, Paper
`
`49 at 40-41 (PTAB Mar. 10, 2014) (holding argument for “plain and ordinary
`
`meaning” fails).
`
`III. PATENT OWNER DID NOT ESTABLISH THAT THE ‘135 PATENT
`IS ENTITLED TO CLAIM PRIORITY TO CERTAIN CLINICAL
`TRIALS.
`
`To establish reduction to practice, PO relies on a clinical trial protocol
`
`outlined (and presumably executed) by Dr. Rader, the inventor of the ‘135 patent:
`
`“starting patients at a dose of 0.03 mg/kg/day and upwardly titrating the compound
`
`in ½-log units — approximately tripling the dose at each dose level (0.03 mg/kg/day
`
`to 0.1 mg/kg/day to 0.3 mg/kg/day to 1.0 mg/kg/day)” (PO’s Motion, p. 12; see also
`
`
`
`2
`
`
`
`Opposition To Patent Owner’s Contingent Motion To Amend for Inter Partes
`Review of USPN 8,618,135
`
`Ex. 2077, 2079, and 2082). PO reasons that “Dr. Rader reduced his invention to
`
`practice no later than when the last patient was dosed on January 18, 2004” (id. at
`
`14). PO then asserts that the Pink Sheet (Ex. 1013) and Stein (Ex. 1014) are not prior
`
`art because they were published in the following month (i.e., February 2004).
`
`The proposed claimed dosage regimen, however, differs from, and is outside
`
`of, the actual dosing regimen used in Dr. Rader’s clinical trial. The substituted
`
`claimed dosage regimen requires doubling the previous dose of lomitapide at each
`
`subsequent dose level (PO’s Motion, p. 15 (“the specific method required by the
`
`substitute claims … requires each subsequent dose level to double in strength”)). In
`
`sharp contrast, the clinical trial required “tripling the dose at each dose level (0.03
`
`mg/kg/day to 0.1 mg/kg/day to 0.3 mg/kg/day to 1.0 mg/kg/day)” (id. at p. 12).
`
`Presented in tabular form, it can be seen that the starting dose of Dr. Rader’s actual
`
`trial is almost half of the lowest possible dose in the PO’s proposed claims:
`
`
`Substituted
`Amendments
`
`Dose 1
`50% of Dose 2
`
`Dose 2
`50% of Dose 3
`
`Converted to
`mg/kg/day
`Dr. Rader’s actual
`dosage regimen
`
`
`0.05 to 0.1475
`mg/kg/day
`0.03 mg/kg/day
`
`0.1 to 0.295
`mg/kg/day
`0.1 mg/kg/day
`
`Dose 3
`About 0.2 to about
`0.59 mg/kg/day
`based on a weight
`between 62.5 kg
`and 74.9 kg
`
`
`0.30 mg/kg/day
`
` As can be seen, the substituted claimed dosage regimen requires a third
`
`
`
`3
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`
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`Opposition To Patent Owner’s Contingent Motion To Amend for Inter Partes
`Review of USPN 8,618,135
`
`dosage level “from about 0.2 to about 0.59 mg/kg/day” (id. at Appendix A, p. 11).
`
`Therefore, the claimed first dosage level is from about 0.05 to about 0.1475
`
`mg/kg/day. As admitted by the PO, however, the first dosage level used in the
`
`clinical trial is 0.03 mg/kg/day (id. at p. 12), which is less than the claimed lower
`
`bound for the first dosage range of 0.05 mg/kg/day (id. at p. 12; see Ex. 2026 ¶ 37;
`
`Ex. 2077, p. 16 of 72). And as explained above, PO failed to provide a claim
`
`construction to show that 0.03 mg/day/day is about 0.05 mg/kg/day (supra § II).
`
`Accordingly, PO failed to show that the claimed invention was reduced to
`
`practice in January, 2004 and therefore, the Pink Sheet 2004 and Stein are prior art
`
`to the ’135 patent.
`
`IV. PATENT OWNER HAS NOT DEMONSTRATED THAT THE
`SUBSTITUTE CLAIMS ARE PATENTABLE OVER THE PRIOR
`ART.
`
`PO asserted that certain printed publications are the best prior art and that “the
`
`substitute claims are patentable over this prior art” (PO’s Motion, p. 14). But the
`
`PO omitted from its analysis other prior art references that are known to the PO and
`
`that are more material to patentability than the prior art that the PO addressed. These
`
`prior art references include: i) John R. Wetterau et al., An MTP Inhibitor That
`
`Normalizes Atherogenic Lipoprotein Levels in WHHL Rabbits, 282 SCI. 751 (1998)
`
`(“Wetterau,” Ex. 1018); ii) Guidance for Industry 2002, Estimating the Safe Starting
`
`Dose in Clinical Trials for Therapeutics in Adult Healthy Volunteers (2002)
`
`
`
`4
`
`
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`Opposition To Patent Owner’s Contingent Motion To Amend for Inter Partes
`Review of USPN 8,618,135
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`(“Guidance For Industry 2002,” Ex. 1045)1; iii) George Chang et al., Microsomal
`
`triglyceride transfer protein (MTP) inhibitors: Discovery of clinically active
`
`inhibitors using high-throughput screening and parallel synthesis paradigms, 5
`
`Current Opinion in Drug Discovery & Development 562 (2002) (Chang, Ex. 1015);
`
`iv) US 6,066,653 Richard E. Gregg, John R. Wetterau, METHOD OF TREATING
`
`ACID LIPASE DEFICIENCY DISEASES WITH AN MTP INHIBITOR AND
`
`CHOLESTEROL LOWERING DRUGS, published May 23, 2000 (“the ‘653
`
`patent,” Ex. 2095); v) ICH-E4, Dose-Response Information to Support Drug
`
`Registration (1994) (“ICH-E4,” Ex. 1046); and vi) Bruno G. Reigner and Karen
`
`Smith Blesch., Estimating the starting dose for entry into humans: principles and
`
`practice, Eur. J Clin. Pharmacol (2002) 57: 835–845 (“Reigner,” Ex. 1047).
`
` As explained in detail below, substitute claims 11-18 are obvious over the
`
`combination of Wetterau, Guidance For Industry 2002, Chang, the ‘653 patent,
`
`ICH-E4, and Reigner.
`
`A.
`
`Substitute Claims 11-18 Are Obvious Over The Prior Art.
`
`The core issue is whether it would have been obvious for one of ordinary skill
`
`to administer MTP inhibitors via an escalating dosing regimen falling anywhere
`
`within the claimed ranges to treat hyperlipidemia and/or hypercholesterolemia. See
`
`
`1 A 2005 version of this reference is of record as Ex. 1023.
`
`
`
`5
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`
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`Opposition To Patent Owner’s Contingent Motion To Amend for Inter Partes
`Review of USPN 8,618,135
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`Tyco Healthcare Grp. LP v. Mut. Pharm. Co., 642 F.3d 1370 (Fed. Cir. 2011)
`
`(claims to dosing “6 to 8 milligrams” and “7.5 milligrams” of temazepam obvious
`
`given prior art teaching doses of “5 to 15 mg”).
`
`The following claim chart demonstrates that this core limitation as well as all
`
`the other limitations of substitute claim 11 would have been taught by the
`
`combination of Wetterau, Guidance For Industry 2002, Chang, the ‘653 patent,
`
`ICH-E4, and Reigner:
`
`8,618,135 (Amended
`Claims)
`11. (Proposed
`substitute for original
`claim 1) A method of
`treating a subject
`suffering from
`hyperlipidemia or
`hypercholesterolemia,
`the method
`comprising
`
`administering to the
`subject an effective
`
`
`
`Prior Art
`
`Wetterau discloses a method of treating a subject
`suffering from hypercholesterolemia.
`
`“Patients with abetalipoproteinemia, a disease caused by
`defects in the microsomal triglyceride transfer protein
`(MTP), do not produce apolipoprotein B-containing
`lipoproteins...This molecule (compound 9) inhibited the
`production of lipoprotein particles in rodent models and
`normalized plasma lipoprotein levels in Watanabe-
`heritable hyperlipidemic ( WHHL) rabbits, which are a
`model for human homozygous familial
`hypercholesterolemia. These results suggest that
`compound 9, or derivatives thereof, has potential
`applications for the therapeutic lowering of atherogenic
`lipoprotein levels in humans.” Ex.1018, Abstract.
`
`“Fig. 4. Effect of compound 9 on plasma lipid levels in
`WHHL rabbits (a negative percentage indicates a
`decrease). Five rabbits were treated orally for 14 days
`with compound 9 (10 mg/kg).) Ex. 1018 Fig. 4, pg 753.
`
`Wetterau discloses administering to the subject an
`effective amount of an MTP inhibitor.
`
`6
`
`
`
`Opposition To Patent Owner’s Contingent Motion To Amend for Inter Partes
`Review of USPN 8,618,135
`
`amount of an MTP
`inhibitor, wherein said
`administration
`comprises at least
`three step-wise,
`increasing dose levels
`of the MTP inhibitor,
`
`
`“We performed a high-throughput screen of a large
`chemical library to identify inhibitors of MTP-mediated
`triglyceride transfer. … An extensive optimization [of
`one of the analogs] was performed by an automatic
`organic synthesis … which resulted in the identification
`of the 4'-CF,-biphenyl carboxamide, 9. This MTP
`inhibitor possesses subnanomolar potency in both the
`lipid transfer and HepG2 apoB secretion assays and
`inhibits lipoprotein secretion in fasted rats (Table 1).”
`Ex. 1018, pg, 751, third column and pg 752 first
`column.
`
`“We also investigated the effect of a 2-week treatment
`with compound 9 in homozygous Watanabe-heritable
`hyperlipidemic (WHHL) rabbits whose hepatic LDL
`receptor activity is <5% that of normal rabbits, resulting
`in dramatically elevated levels of apoB-containing
`lipoproteins. WHHL rabbits are a model for human
`homozygous familial hypercholesterolemia (FH) (16).”
`Ex. 1018, pg, 753, second column.
`
`ICH-E4 teaches administration of an effective
`compound that comprise a step-wise, increasing dose
`level.
`
`“A study design widely used to demonstrate
`effectiveness utilizes dose titration to some
`effectiveness or safety endpoint… In some cases,
`notably where an early answer is essential, the
`titration-to-highest-tolerable-dose approach is
`acceptable, because it often requires a minimum number
`of patients.” ICH-E4, pg 4.
`
`ICH-E4 further teaches that a forced titration is
`advantageous particularly for rare diseases like HoFH
`where fewer patients are available because forced
`titration requires fewer patients compared a to a parallel
`dose-response study.
`
`
`
`7
`
`
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`Opposition To Patent Owner’s Contingent Motion To Amend for Inter Partes
`Review of USPN 8,618,135
`
`
`
`“Forced Titration
`A forced titration study, where all patients move
`through series of rising doses…Compared to a parallel
`dose-response study, this design may use fewer patients,
`and by extending the study duration, can be used to
`investigate a wide range of doses, again making it a
`reasonable first study.” ICH-E4, pgs. 11-12.
`
`
`
`“For example, many studies titrate the dose upward for
`safety reasons. As most side effects of drugs occur
`early and may disappear with continued treatment,
`this can result in a spuriously higher rate of undesirable
`effects at the lower doses.” ICH-E4, pg 6. Emphasis
`added.
`
`“The fixed dose is the final or maintenance dose;
`patients may be placed immediately on that dose or
`titrated gradually (in a scheduled "forced" titration)
`to it if that seems safer.” ICH-E4, pg 9. Emphasis
`added.
`
`“A widely used, successful, and acceptable design, but
`not the only study design for obtaining population
`average dose-response data, is the randomized parallel,
`dose-response study with three or more dosage levels,
`one of which may be zero (placebo). From such a trial,
`if dose levels are well chosen, the relationship of drug
`dosage, or drug concentration, to clinical beneficial or
`undesirable effects can be defined.
`
`Several dose levels are needed, at least two in
`addition to placebo, but in general, study of more
`than the minimum number of doses is desirable.”
`ICH-E4, pg 14, emphasis added.
`Reigner teaches how to estimate doses for human
`clinical trials and in particular, that a first and a second
`
`8
`
`wherein a first and a
`second dose level is
`50% of the
`
`
`
`
`
`Opposition To Patent Owner’s Contingent Motion To Amend for Inter Partes
`Review of USPN 8,618,135
`
`immediately following
`dose level, and
`
`wherein a third dose
`level is from about 0.2
`to about 0.59
`mg/kg/day based on a
`weight between 62.5
`and 74.9 kg, and
`
`dose level is 50% of the immediately following dose
`level:
`
`“Doses in humans are usually escalated arithmetically
`by adding an equal amount of drug for each escalation
`(e.g., ×, 2×, 3×, 4×, 5×), geometrically by multiplying
`each dose by the same factor (e.g., ×, 2×, 4×, 8×, 16×),
`or according to a specific formula (e.g., the modified
`Fibonacci dose escalation scheme of ×, 2×, 3.3×, 5×,
`7×, 9×, 12×) [41].” Reigner, pg. 843, left column,
`emphasis added.
`
`
`Wetterau teaches that “[A]t a dose of 10 mg/kg of 9, the
`plasma levels of atherogenic, apoB-containing
`lipoprotein particles were essentially normalized (Fig.
`4) with no alteration in plasma AST or ALT (17).” Ex.
`1018, pg. 753.
`
`Wetterau also discloses that “…were treated once daily
`with doses of compound 9 of 1, 3, or 6 mg per kilogram
`of body weight (mg/kg) for 7 days.” Id., pg. 753.
`
`Wetterau teaches10 mg/kg of compound 9 has efficacy
`in WHHL rabbits. The efficacious dose of 10 mg/kg of
`compound 9 in Wetterau can be estimated as 0.32
`mg/kg/day based on a human weight of 60 kg using the
`conversion factor provided in Table 1 of Guidance for
`Industry 2002 (pgs 6-7) and a safety factor of 10 (pg. 4).
`This equates to a dosing of 19.2 mg/day in humans. The
`range of ranges claimed are from 12.5 mg/day to 36.8
`mg/day for the lower end of a subject of 62.5 kg and
`14.98 mg/day to 44.1 mg/day for the upper end of a
`subject of 74.9 kg. Hence the dosing of 19.2 mg/day is
`within the claimed ranges.
`
`If the form administered in Wetterau were the free base,
`then at a dosing of 19.2 mg/day for humans, the
`methanesulfonate salt of compound 9 (addressed later),
`if also administered at 10 mg/kg, would amount to an
`
`
`
`9
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`
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`Opposition To Patent Owner’s Contingent Motion To Amend for Inter Partes
`Review of USPN 8,618,135
`
`
`equivalent of about 17.45 mg/day for humans (MW of
`free base of compound 9 is 693.7, MW of
`methanesulfonate salt form of compound 9 is 789.8).
`17.45 mg/day weight between 62.5 and 74.9 kg (Ex.
`1049, ¶ 51).
`
`Wetterau discloses compound 9 having the following
`structure.
`
`
`
`
`Ex. 1018, pg. 752
`
`Based on the structure, compound 9 is N-(2,2,2-
`trifluoroethyl)-9-[4-[4-[[[4’ (trifluoromethyl)[1,1’-
`biphenyl]-2-yl] carbonyl] amino]-1-piperidinyl]butyl]-
`9H-fluorene-9-carboxamide.
`
`Chang identifies the compound 9 of I as BMS201038.
`
`
`
`wherein the MTP
`inhibitor is N-(2,2,2-
`trifluoroethyl)-9-[4-[4-
`[[[4’
`(trifluoromethyl)[1,1’-
`biphenyl]-2-yl]
`carbonyl] amino]-1-
`piperidinyl]butyl]-9H-
`fluorene-9-
`carboxamide,
`methanesulfonate, and
`
`Ex. 1015, pg. 565, Figure 2.
`
`
`
`
`
`
`10
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`
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`Opposition To Patent Owner’s Contingent Motion To Amend for Inter Partes
`Review of USPN 8,618,135
`
`
`The ‘653 Patent, issued to BMS, discloses formulations
`suitable for oral administration comprising BMS201038
`methane sulfonic acid salt, i.e., methanesulfonate.
`
` “Capsules containing 1 mg MTP inhibitor BMS
`201,038 (Example 1) and capsules containing 50 mg
`BMS 201,038 (Example 2) are produced from the
`following ingredients...In Example 1 this amount is
`expressed in terms of the amount of methane sulfonic
`acid salt per capsule at 100% potency.” Ex. 2095,
`30:65-31:25.
`
`Wetterau discloses that:
`
`“We also investigated the effect of a 2-week treatment
`with compound 9 in homozygous Watanabe-heritable
`hyperlipidemic (WHHL) rabbits whose hepatic LDL
`receptor activity is <5% that of normal rabbits, resulting
`in dramatically elevated levels of apoB-containing
`lipoproteins. WHHL rabbits are a model for human
`homozygous familial hypercholesterolemia (FH) (16).”
`Ex. 1018, pg, 753, second column.
`
`
`wherein each dose
`level is administered
`to the subject for
`about 1 to about 5
`weeks.
`
`
`
`1.
`
`Claims 1, 17 and 18 Are Obvious Over Wetterau In View Of
`ICH-E4, Chang, Guidance For Industry 2002, Reigner and
`the ‘653 Patent
`
`As shown in detail in the chart above, the prior art teaches all the limitations
`
`of substitute independent claim 11. Substitute independent claims 17 and 18 differ
`
`from substitute independent claim 11 only in that they further delineate subsequent
`
`treatment periods which are also taught in the prior art.
`
`
`
`11
`
`
`
`Opposition To Patent Owner’s Contingent Motion T
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