IN THE 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
`_____________________
`
`Inter Partes Review No.: IPR2015-01835
`
`
`
`Supplemental Declaration of Randall M. Zusman, M.D. in Support of
`Coalition for Affordable Drugs’ Petition
`for Inter Partes Review of U.S. Patent No. 8,618,135 and Opposition To
`Motion To Amend
`
`Exhibit 1049
`
`
`
`
`
`

`
`Declaration of Randall M. Zusman, M.D.
`Petition for Inter Partes Review of U.S. Patent No. 8,618,135
`
`
`TABLE OF CONTENTS
`
`I.
`
`INTRODUCTION ........................................................................................... 1
`
`II. MY EXPERIENCE AND QUALIFICATIONS ............................................. 1
`
`III.
`
`SUMMARY OF OPINIONS ........................................................................... 1
`
`IV. LIST OF MATERIALS CONSIDERED ........................................................ 2
`
`V.
`
`PERSON OF ORDINARY SKILL IN THE ART .......................................... 3
`
`VI. BACKGROUND ............................................................................................. 3
`
`VII. THE 135 PATENT .......................................................................................... 3
`
`A.
`
`The Clinical Trials Are Not A Reduction To Practice Of The
`Escalating Dose Titration Regimen Recited In The Substitute
`Claims .................................................................................................... 3
`
`VIII. COMPARISON BETWEEN THE 135 PATENT CLAIMS AND THE
`PRIOR ART .................................................................................................... 5
`
`A. Disclosures, Knowledge and Information Available in the Art............ 5
`
`1. Wetterau (Ex. 1018) .................................................................... 5
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`ICH-E4 (Ex. 1018) ...................................................................... 5
`
`Guidance for Industry 2002 (Ex. 1045) ...................................... 6
`
`Reigner (Ex. 1047) ...................................................................... 6
`
`The ‘653 patent (Ex. 2095) ......................................................... 6
`
`The ‘653 patent (Ex. 2095) ......................................................... 6
`
`Chang .......................................................................................... 6
`
`Stein 2004 ................................................................................... 7
`
`The Pink Sheet ............................................................................ 7
`
`B.
`
`C.
`
`The Legal Parameters of Obviousness .................................................. 7
`
`Obviousness of the 135 Patent Substitute Claims: Wetterau In
`View Of ICH-E4, Chang, Guidance For Industry 2002, Reigner
`And The ‘653 Patent ............................................................................. 7
`
`1.
`
`Subject matter claimed by the 135 Patent substitute claim
`
`ii
`
`

`
`Declaration of Randall M. Zusman, M.D.
`Petition for Inter Partes Review of U.S. Patent No. 8,618,135
`
`
`1 would have been obvious to the person of ordinary skill ........ 8
`
`(a)
`
`(b)
`
`(c)
`
`(d)
`
`(e)
`
`“A method of treating a subject suffering from
`hyperlipidemia or hypercholesterolemia, the
`method comprising administering to the subject an
`effective amount of an MTP inhibitor, wherein
`said administration comprises …” ................................... 9
`
`“administering to the subject an effective amount
`of an MTP inhibitor, wherein said administration
`comprises at least three step-wise, increasing dose
`levels of the MTP inhibitor,” .......................................... 10
`
`“wherein a first and a second dose level is 50% of
`the immediately following dose level, and” ................... 13
`
`“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.” ................................................... 13
`
`“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” .................................................. 15
`
`(f) wherein each dose level is administered to the
`subject for about 1 to about 5 weeks. ............................. 16
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`135 Patent Substitute Claim 12 ................................................. 17
`
`135 Patent Substitute Claim 13 ................................................. 18
`
`135 Patent Substitute Claim 4 ................................................... 19
`
`135 Patent Substitute Claim 15 ................................................. 20
`
`135 Patent Substitute Claim 16 ................................................. 21
`
`135 Patent Substitute Claim 17 ................................................. 22
`
`135 Patent Substitute Claim 18 ................................................. 23
`
`D. Obviousness of the 135 Patent Substitute Claims Over Pink
`Sheet and Chang Or Stein And Chang ................................................ 24
`
`E.
`
`Obviousness of 135 Patent Claims: The Pink Sheet in view of
`Chang .................................................................................................. 26
`
`iii
`
`

`
`Declaration of Randall M. Zusman, M.D.
`Petition for Inter Partes Review of U.S. Patent No. 8,618,135
`
`
`F.
`
`G.
`
`Obviousness of 135 Patent Claims: Stein in view of Chang .............. 48
`
`THERE IS NO NEXUS BETWEEN THE ALLEGED
`INDICIA OF NONOBVIOUSNESS AND THE CLAIMS ............... 51
`
`CONCLUSION ........................................................ Error! Bookmark not defined.
`
`
`
`
`
`iv
`
`

`
`Declaration of Randall M. Zusman, M.D.
`Petition for Inter Partes Review of U.S. Patent No. 8,618,135
`
`
`TABLE OF EXHIBITS
`
`Exhibit Title
`
`1001
`
`1003
`
`1005
`
`1006
`
`1007
`
`1009
`
`1010
`
`1013
`
`1014
`
`1015
`
`U.S. Patent No. 8,618,135
`
`Declaration of Michael Mayersohn, Ph.D.
`
`Declaration of Christopher Butler, dated June 12, 2015,
`authenticating Internet Archive URLs attached as Ex. A:
`
`PPD News Releases(2/13/2004) (available at
`https://web.archive.org/web/20040213233245/http://www.pp
`di.com/PPD_U6.htm?ID=126662);
`
`PPD News & IR Presentations(12/12/2003) (available at
`https://web.archive.org/web/20031212193444/http://ppdi.co
`m/PPD_6_12.htm);
`
`PPD News & IR Presentations(6/4/2004) (available at
`https://web.archive.org/web/20040604203252/http://www.pp
`di.com/PPD_6_12.htm) (“PPD Screenshot”)
`
`U.S. Provisional Patent Application No. 60/550,915
`
`Highlighted 135 Patent identifying new dosing information not
`included in the 915 Provisional
`
`135 Patent File History, March 4, 2013 Amendment and
`Response
`
`135 Patent File History, Declaration of William Sasiela (“Sasiela
`Declaration”)
`
`Bayer/PPD Implitapide Development Follows ZETIA Model As
`Statin Add-On, 66 THE PINK SHEET 17 (Feb. 16, 2004) (“Pink
`Sheet”)
`
`Evan Stein, Microsomal Triglygeride [sic] Transfer Protein
`(MTP) Inhibitor (implitapide) program (Feb. 5, 2004) (“ Stein
`2004”)
`
`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”)
`
`v
`
`

`
`Declaration of Randall M. Zusman, M.D.
`Petition for Inter Partes Review of U.S. Patent No. 8,618,135
`
`1016
`
`Chandler et al., CP-346086: an MTP inhibitor that lowers plasma
`cholesterol and triglycerides in experimental animals and in
`humans, 44 J. LIPID RESEARCH 1887 (2003) (“Chandler”)
`
`1017
`
`1021
`
`1022
`
`1027
`
`1028
`
`1031
`
`1038
`
`FDA approves ZETIA – first new class to treat cholesterol since
`statins introduced, (Oct. 28, 2002) (available at
`http://www.drugs.com/news/fda-approves-ZETIA-first-new-class-
`cholesterol-since-statins-introduced-3164.html) (“ZETIA
`Article”)
`TRICOR®, PRAVACHOL®, ADVICOR®, NIASPAN®,
`MEVACOR®, ZOCOR®, LIPITOR®, COLESTID®, LESCOL®,
`57 PHYSICIANS’ DESK REFERENCE 506, 1101, 1813, 2036, 2126,
`2547, 2729, 2865 (2003) (“PDR 2003”)
`ZETIA®, 58 PHYSICIANS’ DESK REFERENCE 2118, 3085 (2004)
`(“PDR 2004”)
`
`Curriculum Vitae
`
`Documents Considered
`
`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) (“NCEP 2002”)
`
`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).
`(“CDC 2005 Anthropometric Reference Data”)
`
`1039
`
`In re Application of: Rader, U.S. Patent Application No.
`13/046,118, Amendment (Sept. 25, 2013).
`
`1040
`
`1041
`
`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)
`
`vi
`
`

`
`Declaration of Randall M. Zusman, M.D.
`Petition for Inter Partes Review of U.S. Patent No. 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)
`
`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.
`
`Baillie Deposition Transcript
`
`Supplemental Declaration Of Dr. Zusman
`
`FDA Label for Crestor
`
`FDA Label for Vytorin
`
`vii
`
`1045
`
`1046
`
`1047
`
`1048
`
`1049
`
`1050
`
`1051
`
`

`
`Declaration of Randall M. Zusman, M.D.
`Petition for Inter Partes Review of U.S. Patent No. 8,618,135
`
`
`1052
`
`1053
`
`1054
`
`1055
`
`1056
`
`1057
`
`1058
`
`1059
`
`FDA Label for Zocor
`
`FDA Label for Caduet
`
`FDA Label for Lipitor
`
`FDA Label for Zetia
`
`Kimball Deposition Transcript
`
`Gregg Deposition Transcript
`
`Sacks Deposition Transcript
`
`Rader Deposition Transcript
`
`
`
`
`
`viii
`
`

`
`Declaration of Randall M. Zusman, M.D.
`Petition for Inter Partes Review of U.S. Patent No. 8,618,135
`
`
`TABLE OF ABBREVIATIONS
`
`Abbreviation
`
`Definition
`
`268 Patent
`
`135 Patent
`
`U.S. Patent No. 7,932,268
`
`U.S. Patent No. 8,618,135
`
`915 Provisional U.S. Provisional Patent Application No. 60/550,915
`
`923 Application U.S. Patent Application No. 10/591,923
`(issued as the 268 Patent)
`
`118 Application U.S. Patent Application No. 13/046,118
`(issued as the 135 Patent)
`
`MTP
`
`CHD
`
`FH
`
`HeFH
`
`HoFH
`
`LDL
`
`LDL-C
`
`HDL
`
`VLDL
`
`apoB
`
`Total-C
`
`PDR
`
`Microsomal triglyceride transfer protein
`
`Coronary Heart Disease
`
`Familial hypercholesterolemia
`
`Heterozygous familial hypercholesterolemia
`
`Homozygous familial hypercholesterolemia
`
`Low density lipoprotein
`
`Low density lipoprotein cholesterol
`
`High density lipoprotein
`
`Very low density lipoprotein
`
`Apolipoprotein B
`
`Total cholesterol
`
`Physician’s Desk Reference
`
`ix
`
`

`
`Declaration of Randall M. Zusman, M.D.
`Petition for Inter Partes Review of U.S. Patent No. 8,618,135
`
`I.
`
`INTRODUCTION
`
`1.
`
`I, Randall M. Zusman, M.D., am over the age of eighteen (18) and
`
`otherwise competent to make this Declaration. I have personal knowledge of the
`
`facts set forth in this Declaration and am competent to testify to the same.
`
`2.
`
`I have been retained by counsel for the Coalition For Affordable
`
`Drugs (“CFAD” or “Petitioner”) in connection with the above-captioned inter
`
`partes review (“IPR”) Petition. Specifically, I have been asked to prepare this
`
`Supplemental Declaration to address the Patent Owner’s Motion to Amend and the
`
`Patent Owner’s Response as well as their exhibits including the expert
`
`declarations. I understand that this Declaration will be used to support
`
`unpatentability in any trial proceedings initiated in connection with these grounds.
`
`II. MY EXPERIENCE AND QUALIFICATIONS
`
`3. My experience and qualification are set forth in initial declaration
`
`(Exhibit 1002).
`
`III. SUMMARY OF OPINIONS
`
`4.
`
`I have reviewed and considered the 135 Patent, its file history and
`
`related applications, including the 915 Provisional from which the 135 Patent
`
`claims priority. I have also reviewed the Patent Owner’s Motion to Amend and the
`
`Patent Owner’s Response, as well as their corresponding expert declarations, and
`
`the information regarding the clinical trials that are alleged to be a reduction to
`
`1
`
`

`
`Declaration of Randall M. Zusman, M.D.
`Petition for Inter Partes Review of U.S. Patent No. 8,618,135
`
`practice of the substitute claims. The opinions listed here are in addition to the
`
`opinions set forth in my initial declaration (Ex. 1002).
`
`5.
`
`In my opinion, the clinical trials relied up by the Patent Owner do not
`
`establish reduction to practice of the specific set of escalating doses recited in the
`
`substitute claims of the 135 Patent.
`
`6.
`
`In my opinion, methods encompassed by claims 1-10 of the 135
`
`Patent and substitute claims 11-18 would have been obvious to the person of
`
`ordinary skill in the art, as defined herein, in view of the prior art as it existed
`
`before: (a) January 2004 (the priority date alleged in Patent Owner’s Motion to
`
`Amend) (b) March 5, 2004 (the 915 Provisional filing date); (c) March 7, 2005 (the
`
`filing date for the non-provisional application leading to the 135 Patent). This is
`
`because the claims encompass subject matter that, in turn, reflects nothing more
`
`than applying a known escalating dose titration regimen to achieve known and
`
`reasonably expected clinical results associated with a known MTP inhibitor drug.
`
`IV. LIST OF MATERIALS CONSIDERED
`
`7.
`
`In formulating my opinions, I have considered the ’135 Patent and its
`
`prosecution history, the documents listed in Exhibit 1028, the Patent Owner’s
`
`Reply and Motion to Amend as well as their corresponding expert declarations,
`
`and the Petitioner’s Opposition to the Motion To Amend and Reply, as well as
`
`their exhibits. In arriving at my opinions, I have relied upon my experience in the
`
`2
`
`

`
`Declaration of Randall M. Zusman, M.D.
`Petition for Inter Partes Review of U.S. Patent No. 8,618,135
`
`relevant art and have considered the point of view of a person of ordinary skill in
`
`the art as to the 135 Patent, as defined in my initial Declaration.
`
`V.
`
`PERSON OF ORDINARY SKILL IN THE ART
`
`8.
`
`A discussion of the person of ordinary skill in the art is set forth in my
`
`initial declaration.
`
`VI. BACKGROUND
`
`9.
`
`A discussion of background information is set forth in my initial
`
`declaration.
`
`VII. THE 135 PATENT
`
`10. A discussion of the 135 patent, its file history, the provisional
`
`application, and the meaning of certain claim terms is set forth in my initial
`
`declaration.
`
`A. The Clinical Trials Are Not A Reduction To Practice Of The
`Escalating Dose Titration Regimen Recited In The Substitute
`Claims
`
`11.
`
`I understand that the Patent Owner has attempted to claim priority to
`
`certain clinical trials as an alleged reduction to practice of the substitute claims.
`
`12.
`
`I have been asked to review the clinical trials and to offer my opinion
`
`regarding whether a person of ordinary skill in the art would understand that they
`
`were a reduction to practice of the substitute claims of the 135 Patent. After
`
`3
`
`

`
`Declaration of Randall M. Zusman, M.D.
`Petition for Inter Partes Review of U.S. Patent No. 8,618,135
`
`reviewing the information on these clinical trials, it is my opinion that they are not
`
`a reduction to practice of the substitute claims.
`
`13. Specifically, the dosage ranges used in the clinical trials do not
`
`provide adequate support for the particular numerical ranges and across the full
`
`scope of those ranges in the 135 Patent’s claimed series of escalating doses.
`
`14.
`
`In its attempt to establish reduction to practice, the Patent Owner
`
`relied on the clinical trial protocol performed 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). 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).
`
`15. The claimed dosage regimen, however, is different than the clinical
`
`trials. The dosage regimen recited in the substitute claims requires doubling the
`
`dose at each 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, Dr. Rader’s clinical trial requires “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).
`
`16. The dosage regimen recited in the substitute claims requires a third
`
`4
`
`

`
`Declaration of Randall M. Zusman, M.D.
`Petition for Inter Partes Review of U.S. Patent No. 8,618,135
`
`dosage level “from about 0.2 to about 0.58 mg/kg/day” (id. at Appendix A, p. 11).
`
`Accordingly, the claimed first dosage level is from about 0.05 (0.2 x 0.5 x 0.5) to
`
`about 0.1475 mg/kg/day (0.58 x 0.5 x 0.5). But as stated by the Patent Owner, the
`
`first dosage level of the clinical trials is 0.03 mg/kg/day (id. at p. 12), which is less
`
`than the claimed lower bound for the claimed first dosage range of 0.05 mg/kg/day.
`
`
`
`VIII. COMPARISON BETWEEN THE 135 PATENT CLAIMS AND THE
`PRIOR ART
`
`A. Disclosures, Knowledge and Information Available in the Art
`
`17. The information on the disclosures, knowledge and information
`
`available in the art supplements the information set forth in my initial declaration.
`
`The prior art references used in my obviousness analyses of the issued and
`
`substitute claims of the 135 patent are listed below.
`
`1. Wetterau (Ex. 1018)
`
`18.
`
`John R. Wetterau et al., An MTP Inhibitor That Normalizes
`
`Atherogenic Lipoprotein Levels in WHHL Rabbits, 282 SCI. 751 (1998). Wetterau
`
`was already of record in this proceeding at Ex. 1018.
`
`2.
`
`ICH-E4
`
`19. Dose-Response Information to Support Drug Registration (1994)
`
`5
`
`

`
`Declaration of Randall M. Zusman, M.D.
`Petition for Inter Partes Review of U.S. Patent No. 8,618,135
`
`
`3. Guidance for Industry 2002 (Ex. 1045)
`
`20. Estimating the Safe Starting Dose in Clinical Trials for Therapeutics
`
`in Adult Healthy Volunteers (2002). A 2005 version of this reference was already
`
`of record in the proceeding as Ex. 1023.
`
`4.
`
`Reigner (Ex. 1047)
`
`21. 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.
`
`5.
`
`The ‘653 patent (Ex. 2095)
`
`22. 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. This
`
`reference was already of record in this proceeding at Exhibit 2095.
`
`6.
`
`The ‘653 patent (Ex. 2095)
`
`23. 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. This
`
`reference was already of record in this proceeding at Exhibit 2095.
`
`7.
`
`Chang
`
`24. A discussion of Chang appears in my initial declaration.
`
`6
`
`

`
`Declaration of Randall M. Zusman, M.D.
`Petition for Inter Partes Review of U.S. Patent No. 8,618,135
`
`
`8.
`
`Stein 2004
`
`25. A discussion of Stein appears in my initial declaration.
`
`9.
`
`The Pink Sheet
`
`26. A discussion of the Pink Sheet appears in my initial declaration.
`
`B.
`
`The Legal Parameters of Obviousness
`
`27.
`
`I discussion of the legal parameters of obviousness appears in my
`
`initial declaration.
`
`C. Obviousness of the 135 Patent Substitute Claims: Wetterau In
`View Of ICH-E4, Chang, Guidance For Industry 2002, Reigner
`And The ‘653 Patent
`
`28. The person of ordinary skill in the art would have been taught,
`
`suggested and motivated from the existing prior art to dose lomitapide in an
`
`escalating dose titration regimen in patients suffering from hyperlipidemia or
`
`hypercholesterolemia, such as FH, within the dosage range as recited in the
`
`substitute claims by at least: (a) January 2004 (the priority date alleged in Patent
`
`Owner’s Motion to Amend); (b) March 5, 2004 (the 915 Provisional filing date);
`
`(c) March 7, 2004 (one year before the filing date for the non-provisional
`
`application for the 135 Patent); and (d) March 7, 2005 (the filing date for the
`
`priority non-provisional application for the 135 Patent). They would have done so
`
`with a reasonable expectation of success.
`
`29. As of January, 2004, the person of ordinary skill in the art would have
`
`7
`
`

`
`Declaration of Randall M. Zusman, M.D.
`Petition for Inter Partes Review of U.S. Patent No. 8,618,135
`
`been motivated
`
`from hyperlipidemia or
`
`to dose patients
`
`suffering
`
`hypercholesterolemia using lomitapide as taught by Wetterau in view of ICH-E4,
`
`Chang, Guidance For Industry 2002, Reigner and the ‘653 Patent and would have
`
`done so with a reasonable expectation of success.
`
`30.
`
`If the alleged clinical trial does not apply to establish an earlier
`
`priority date, the person of ordinary skill in the art would have been likewise
`
`motivated as of March 5, 2004, to dose patients suffering from hyperlipidemia or
`
`hypercholesterolemia using lomitapide as taught by Wetterau in view of ICH-E4,
`
`Chang, Guidance For Industry 2002, Reigner and the ‘653 Patent. Again, they
`
`would have done so with a reasonable expectation of success.
`
`1.
`
`Subject matter claimed by the 135 Patent substitute claim
`11 would have been obvious to the person of ordinary skill
`
`31. Substitute claim 11 of the 135 Patent is reproduced below:
`
`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 amount
`of an MTP inhibitor, wherein said administration comprises at least
`three step-wise, increasing dose levels of the MTP inhibitor, wherein a
`first and a second dose level is 50% of the 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
`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
`wherein each dose level is administered to the subject for about 1 to
`about 5 weeks.
`
`
`
`8
`
`

`
`Declaration of Randall M. Zusman, M.D.
`Petition for Inter Partes Review of U.S. Patent No. 8,618,135
`
`
`32.
`
`In my opinion, and as discussed in further detail below, substitute
`
`claim 11 would have been obvious to a person of ordinary skill in the art as of
`
`April 2004 or March 2004 over Wetterau in view of ICH-E4, Chang, Guidance For
`
`Industry 2002, Reigner and the ‘653 Patent.
`
`(a)
`
`“A method of treating a subject suffering from
`hyperlipidemia or hypercholesterolemia, the method
`comprising administering to the subject an effective
`amount of an MTP inhibitor, wherein said
`administration comprises …”
`
`33. 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.
`
`34.
`
`“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.
`
`9
`
`

`
`Declaration of Randall M. Zusman, M.D.
`Petition for Inter Partes Review of U.S. Patent No. 8,618,135
`
`
`(b)
`
`“administering to the subject an effective amount of
`an MTP inhibitor, wherein said administration
`comprises at least three step-wise, increasing dose
`levels of the MTP inhibitor,”
`
`35. Wetterau discloses administering to the subject an effective amount of
`
`an 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.
`
`36.
`
`“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.
`
`37. A POSA would have been motivated to further investigate compound
`
`9 in human HoFH patients in view of the successful animal model results of
`
`Wetterau and would have further consulted ICH-E4 because it provides a guideline
`
`10
`
`

`
`Declaration of Randall M. Zusman, M.D.
`Petition for Inter Partes Review of U.S. Patent No. 8,618,135
`
`for industry on dose-response information required by regulation agencies to
`
`support a drug registration.
`
`38.
`
`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.
`
`39.
`
`ICH-E4 further teaches that a forced titration may use fewer patients
`
`compared a to parallel dose-response study. “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.
`
`40.
`
`It was well known at the time that HoFH is a rare disease and hence
`
`there would have been an expectation that a “minimum number of patients” would
`
`have been expected to enroll in any clinical trial. For example previous clinical
`
`trials addressing HoFH had enrollment numbers or expected enrollment numbers
`
`in the single digits.
`
`41. Given the limited patient population available for clinical trials, it
`
`11
`
`

`
`Declaration of Randall M. Zusman, M.D.
`Petition for Inter Partes Review of U.S. Patent No. 8,618,135
`
`would have been obvious to POSA that a forced titration/dose escalation scheme as
`
`taught by ICH-E4 would have been preferred when designing a clinical trial for
`
`HoFH.
`
`42. Moreover, a forced titration is safer for the patients, which would
`
`have further motivated a POSA to adopt this clinical dosing regimen.
`
`43.
`
`“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.
`
`44.
`
`“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.
`
`45.
`
`It would also have been obvious that at least three step-wise,
`
`increasing dose levels would have been preferred because such a regimen requires
`
`a minimum number of data points to derive a meaningful dose response curve, as
`
`taught by ICH-E4. 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
`
`12
`
`

`
`Declaration of Randall M. Zusman, M.D.
`Petition for Inter Partes Review of U.S. Patent No. 8,618,135
`
`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.
`
`(c)
`
`“wherein a first and a second dose level is 50% of the
`immediately following dose level, and”
`
`46. Reigner teaches a first and a second 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.
`
`47.
`
`It would have been obvious to POSA to combine the teachings of
`
`Reigner, ICH-E4 and Wetterau because Reigner specifically discloses how to
`
`estimate doses to enter human clinical trials.
`
`(d)
`
`“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.”
`
`48. 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.
`
`13
`
`

`
`Declaration of Randall M. Zusman, M.D.
`Petition for Inter Partes Review of U.S. Patent No. 8,618,135
`
`
`49. Wetterau does not specify whether the 10mg/kg dose is a daily dose.
`
`However, in the same document where Wetterau discusses the animal studies, the
`
`authors specify 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. As once
`
`daily dosing was well known and practiced in the art at the time of the invention,