Reply To Patent Owner’s Response 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 Reply for Inter Partes Review of U.S. Patent No. 8,618,135
`
`
`
`
`
`
`
`
`
`
`Mail Stop "PATENT BOARD"
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
`
`
`
`
`
`

`
`Reply To Patent Owner’s Response for Inter Partes Review of USPN 8,618,135
`
`
`TABLE OF CONTENTS
`
`I.
`
`INTRODUCTION ........................................................................................... 1
`
`II.
`
`THE LEVEL OF ORDINARY SKILL IN THE ART. ................................... 2
`
`III. CLAIM CONSTRUCTION STATEMENT (37 C.F.R.
`§ 42.104(B)(3)). ............................................................................................... 3
`
`IV. GROUND 1: CLAIMS 1-10 ARE OBVIOUS IN VIEW OF THE
`PINK SHEET 2004 AND CHANG. ................................................................. 6
`
`A.
`
`B.
`
`C.
`
`The Protocol Proposed In The Pink Sheet Is Fundamentally The
`Same As The Claimed Invention. ......................................................... 6
`
`A POSA Would Have Been Motivated To Develop Lomitapide
`In March 2005. ...................................................................................... 8
`
`A POSA Would Have Had A Reasonable Expectation Of
`Success In Using the Pink Sheet Protocol With Lomitapide. .............12
`
`V. GROUND 2: CLAIMS 1-10 ARE OBVIOUS IN VIEW OF STEIN
`AND CHANG. ...............................................................................................15
`
`A.
`
`Stein Is Prior Art. .................................................................................15
`
`B.
`
`A POSA Would Have Been Motivated To Combine Chang and
`Stein And Would Have Had A Reasonable Expectation Of
`Success. ...............................................................................................17
`
`VI. THERE IS NO NEXUS BETWEEN THE ALLEGED INDICIA OF
`NONOBVIOUSNESS AND THE CLAIMS. ...............................................18
`
`The Dosing Method That Was Alleged By Patent Owner To
`Have Unexpected Results Is Not Required By The Claims. ..............18
`
`The Long-Felt, But Unmet, Need Alleged By Patent Owner Has
`No Nexus To The Claimed Invention. ................................................19
`
`The Failure Of Others Alleged By Patent Owner Has No Nexus
`To The Claimed Invention. .................................................................20
`
`i
`
`A.
`
`B.
`
`C.
`
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`Reply To Patent Owner’s Response for Inter Partes Review of USPN 8,618,135
`
`
`D.
`
`E.
`
`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
`
`VII. CONCLUSION. .............................................................................................24
`
`
`
`
`ii
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`Reply To Patent Owner’s Response for Inter Partes Review of USPN 8,618,135
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`
`EXHIBIT LIST PURSUANT TO 37 C.F.R. § 42.63(e) AND
`TABLE OF ABBREVIATIONS
`
`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.
`
`
`
`iii
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`Reply To Patent Owner’s Response for Inter Partes Review of USPN 8,618,135
`
`
`1009
`
`1010
`
`1011
`
`1012
`
`1013
`
`1014
`
`1015
`
`1016
`
`1017
`
`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).
`
`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.
`
`
`
`iv
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`

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`Reply To Patent Owner’s Response for Inter Partes Review of USPN 8,618,135
`
`
`1020
`
`1021
`
`1022
`
`1023
`
`1024
`
`1025
`
`Evan Stein, OPPOSITION AGAINST EUROPEAN PATENT NO. 1 725 234
`B9 (filed Aug. 21, 2013).
`
`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).
`
`
`
`v
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`Reply To Patent Owner’s Response for Inter Partes Review of USPN 8,618,135
`
`
`1032 Michael Mayersohn, Principles and Applications of
`Pharmacokinetics, in MEDICAL TOXICOLOGY 282 (Richard C. Dart
`ed., 3d ed. 2004).
`
`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).
`
`vi
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`Reply To Patent Owner’s Response for Inter Partes Review of USPN 8,618,135
`
`
`1042
`
`Declaration of Randall M. Zusman, M.D. (served but not filed)
`
`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 Æ Karen Smith Blesch., Estimating the starting
`dose for entry into humans: principles and practice, Eur J Clin
`Pharmacol (2002) 57: 835–845.
`
`1048
`
`Baillie Deposition Transcript
`
`1049
`
`Supplemental Declaration Of Dr. Zusman
`
`1050
`
`FDA Label for Crestor
`
`
`
`vii
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`Reply To Patent Owner’s Response for Inter Partes Review of USPN 8,618,135
`
`
`1051
`
`FDA Label for Vytorin
`
`1052
`
`FDA Label for Zocor
`
`1053
`
`FDA Label for Caduet
`
`1054
`
`FDA Label for Lipitor
`
`1055
`
`FDA Label for Zetia
`
`1056
`
`Kimball Deposition Transcript
`
`1057
`
`Gregg Deposition Transcript
`
`1058
`
`Sacks Deposition Transcript
`
`1059
`
`Rader Deposition Transcript
`
`
`
`viii
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`Reply To Patent Owner’s Response for Inter Partes Review of USPN 8,618,135
`
`
`TABLE OF ABBREVIATIONS
`
`Definition
`
`U.S. Provisional Patent Application No. 60/550,915
`
`Abbreviation
`
`‘915
`Provisional
`
`‘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
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`Reply To Patent Owner’s Response for Inter Partes Review of USPN 8,618,135
`
`
`Abbreviation
`
`Definition
`
`LDL-C
`
`Low density lipoprotein cholesterol
`
`Lp(a)
`
`Lipoprotein (a)
`
`Mayersohn
`
`in Support of
`Declaration of Michael Mayersohn, Ph.D.
`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
`
`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
`
`Zusman
`
`
`
`x
`
`

`
`Reply To Patent Owner’s Response for Inter Partes Review of USPN 8,618,135
`
`
`TABLE OF AUTHORITIES
`
`
`
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` PAGES
`
`Federal Cases
`
`In re Klopfenstein,
`380 F.3d 1345 (Fed. Cir. 2004) ............................................................................15
`
`Merck & Co., Inc. v. Biocraft Labs., Inc.,
`874 F.2d 804 (Fed. Cir. 1989) ................................................................................ 8
`
`Federal Statutes
`
`35 U.S.C. § 102 ........................................................................................................17
`
`Federal Regulations
`
`37 C.F.R. § 42.100(b) ................................................................................................ 3
`
`xi
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`Reply To Patent Owner’s Response for Inter Partes Review of USPN 8,618,135
`
`
`I.
`
`INTRODUCTION
`
`Patent Owner’s (PO’s) arguments must fail because
`
`they are not
`
`commensurate with the scope of any of the challenged claims. PO based its
`
`arguments on a claim construction that requires (i) “a forced dose titration
`
`regimen” (PO’s Response, p. 8), and (ii) that “[i]n the claimed regimen … patients
`
`continue receiving higher doses of lomitapide notwithstanding the presence of side
`
`effects at the lower dose” (id. at p. 36), (iii) to “permit the body to adapt to the
`
`therapy, resulting in improved tolerability and reduced toxicity” (id. at p. 24).
`
`But the challenged claims do not require any such forced dosing method
`
`notwithstanding the presence of side effects at lower doses for the purpose of
`
`improving tolerability (infra, § III). Rather, the claims require only stepwise
`
`increasing dose levels of lomitapide (id.), which are taught by the prior art (infra,
`
`§§ IV and V).
`
`PO also argued that the Pink Sheet required testing doses that are lower than
`
`those of the “ ’135 claims, which relate to administration of does that are higher
`
`than the 25 mg/day dose that led to [BMS’s] discontinuation of lomitapide
`
`development” (PO’s Response, p. 37). This argument, however, is also not
`
`commensurate with the scope of the claims because each of the independent claims
`
`1, 9, and 10 requires a maximum dose as low as 10 mg (infra, § III).
`
`PO also argued that “[t]he prior art thus does not teach the entire range in
`
`
`
`1
`
`

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`Reply To Patent Owner’s Response for Inter Partes Review of USPN 8,618,135
`
`
`claim 8” (PO’s Response, p. 55). But this argument is also not commensurate with
`
`the scope of the claims because it is well-settled law that “where there is a range
`
`disclosed in the prior art, and the claimed invention falls within that range, there is
`
`a presumption of obviousness.” Iron Grip Barbell Co. v. USA Sports, Inc., 392
`
`F.3d 1317, 1322 (Fed. Cir. 2004); accord Lazare Kaplan Int’l, Inc. v. Photoscribe
`
`Techs., Inc., 628 F.3d 1359, 1380-81 (Fed. Cir. 2010).
`
`Indeed, PO’s arguments with respect to each of the two instituted grounds of
`
`rejection and
`
`the secondary considerations of non-obviousness are not
`
`commensurate with the scope of the challenged claims 1-10. For these and the
`
`others reasons set forth below, the challenged claims are obvious.
`
`
`
`II. THE LEVEL OF ORDINARY SKILL IN THE ART.
`
`Petitioner set forth a definition for a person of ordinary skill in the art
`
`(POSA) as a M.D. or non-M.D. having, inter alia, a high level of education in “a
`
`pertinent discipline such as medicine, medicinal chemistry, pharmacology,
`
`pharmacokinetics, or drug development and delivery” and experience in the
`
`cardiovascular/cardiac field (Petition, pp. 28-29, Ex. 1002, ¶¶ 28-32; Ex. 1003,
`
`¶ 26). PO disagreed with Petitioner’s definition because it requires “that the POSA
`
`consults PINK SHEET and remains abreast of pharmaceutical companies” (PO’s
`
`Response, pp. 9-10). PO argued that most treating physicians do not read a Pink
`
`Sheet or attend investor presentations for drug companies (id. at p. 10).
`
`
`
`2
`
`

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`Reply To Patent Owner’s Response for Inter Partes Review of USPN 8,618,135
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`But Petitioner’s POSA definition is not limited to a M.D (Petition, pp. 28-
`
`29). And Dr. Baillie, PO’s expert, testified that Petitioner’s definition is “perfectly
`
`acceptable” (Ex. 1048, p. 24). In addition, another one of PO’s experts, Dr.
`
`Kimball, testified that a POSA is a person who has the knowledge of an entire drug
`
`development team:
`
`A. So POSA, the POSA in the context of drug development is a team
`
`and it's a team that's comprised of basic scientists, chemistry,
`
`pharmacology, toxicology, all the way through the medical doctor …
`
`it's a composite and everyone works together on that team and
`
`informs each other.
`
`Ex. 1056, p. 19, l. 2 – p. 20, l. 3 (emphasis added). Certainly, one or more
`
`members of this drug discovery team would attend investor presentations for
`
`drug companies and read the Pink Sheet (Ex. 1002, ¶28). Thus, a POSA
`
`would have known of the Pink Sheet as well as the other prior art in this
`
`proceeding (i.e., Stein, Chang).
`
`III. CLAIM CONSTRUCTION STATEMENT (37 C.F.R. § 42.104(B)(3)).
`
`Under 37 C.F.R. § 42.100(b), the claim terms of the ‘135 patent are
`
`presumed to take on their ordinary and customary meaning based on the broadest
`
`reasonable interpretation (“BRI”) of the claim language in light of the
`
`specification. The Patent Owner, however, asserted that “[t]he claims should be
`
`construed according to the same standard applicable in district court” (PO’s
`
`
`
`3
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`

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`Reply To Patent Owner’s Response for Inter Partes Review of USPN 8,618,135
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`Response, p. 7) and that the Board’s BRI “standard is legally impermissible” (id.).
`
`PO then proposed a construction of the claims to require “a forced dose titration
`
`regimen” (id. at p. 8). More particularly, PO asserted that “[i]n the claimed
`
`regimen … patients continue receiving higher doses of lomitapide notwithstanding
`
`the presence of side effects at the lower dose” (id. at p. 36) to “permit the body to
`
`adapt to the therapy, resulting in improved tolerability and reduced toxicity” (id. at
`
`p. 24). And PO’s experts repeatedly rely on this interpretation of the claims in
`
`forming their opinions on obviousness (Ex. 1058, pp. 24, 88; Ex. 1056, p. 181; Ex.
`
`1048, p.59).
`
`But the Supreme Court has unanimously held that it is legally permissible
`
`for the Board to use the BRI standard in IPRs. Cuozzo Speed Techs., LLC v. Lee,
`
`No. 15-446. According to the Supreme Court, the BRI “regulation represents a
`
`reasonable exercise of the rulemaking authority that Congress delegated to the
`
`Patent Office,” which “encourages the applicant to draft [claims] narrowly,” has
`
`been used by the PTO “for more than 100 years,” and is “not unfair to the patent
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`holder in any obvious way.” Id. at 17-19.
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`Under the BRI standard, the PO’s proposed claim construction is wrong for
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`three separate reasons. First, there is no suggestion in the claims that they are
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`restricted to a forced dosing method notwithstanding the presence of side effects at
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`lower doses for the purpose of improving tolerability, as conceded by PO’s own
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`Reply To Patent Owner’s Response for Inter Partes Review of USPN 8,618,135
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`expert:
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`Q. Do you know, does that term, "forced-dose titration regimen,"
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`appear in the claims at all?
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`A. I don't recall seeing that in the claim.
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`(Ex. 1058, p. 24, ll. 10-14; see also Ex. 1056, p. 182, ll. 1-5).
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`Second, it is impermissible to import limitations from the specification into
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`the claims. Superguide Corp. v. DirecTV Enterprises, Inc., 358 F.3d 870, 875, 69
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`USPQ2d 1865, 1868 (Fed. Cir. 2004) (“Though understanding the claim language
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`may be aided by explanations contained in the written description, it is important
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`not to import into a claim limitations that are not part of the claim”).
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`Third, PO neglected to provide any reasons whatsoever as to why its
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`proposed construction is proper (PO’s Response, p. 8). For these reasons, the
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`claims should be construed under the BRI to encompass any method that treats a
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`subject within the claimed stepwise increasing dose ranges of lomitapide.
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`Also, PO did not disagree with any of the proposed constructions by the
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`Petitioner for “a subject suffering hyperlipidemia or hypercholesterolemia,”
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`“effective amount,” “about”, “piperidine N-oxide thereof,” “severe,” and “control
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`levels” (PO’s Response, p. 7 (stating that it “does not contest any of the specific
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`constructions proposed by CFAD for the claim terms”)). Thus, Petitioner’s
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`constructions of those terms should be adopted as well.
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`Reply To Patent Owner’s Response for Inter Partes Review of USPN 8,618,135
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`IV. GROUND 1: CLAIMS 1-10 ARE OBVIOUS IN VIEW OF The PINK
`SHEET 2004 AND CHANG.
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`A POSA would have had motivation to combine teachings from Pink Sheet
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`2004 with Chang, and reasonably expect success. No non-obvious differences exist
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`between either combination and the claimed subject matter.
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`A. The Protocol Proposed In The Pink Sheet Is Fundamentally The
`Same As The Claimed Invention.
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`PO asserted that the ‘135 patent “is directed to a forced dose titration
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`regimen … in order to ameliorate the tolerability and side effects associated with
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`the compound” (id. at 36). PO then argued based on this claim construction that
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`the “claimed dosing regimen, is, therefore, fundamentally different from Pink
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`Sheet’s dose finding study” (id.) and dose titration used with statins (id. at 37).
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` But this argument is not commensurate with the scope of the claims because
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`nothing in the claims requires performing the method for one particular purpose
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`(e.g., improved tolerability) (supra § III). Therefore, even if the protocols in the
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`Pink Sheet and the statin dose titration were interpreted to be dose-finding studies
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`as alleged by PO, they would, nonetheless, not differ from the claimed invention.
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`Indeed, PO’s expert Dr. Sacks conceded that the Pink Sheet teaches the claimed
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`dosing schedule:
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`Q. So does the dosing schedule, does the first three doses in claim 1 fit
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`with the dose escalating -- the dose titration of the Pink Sheet?
`
`A. Yes.
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`6
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`Reply To Patent Owner’s Response for Inter Partes Review of USPN 8,618,135
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`(Ex. 1058, p. 136, ll. 2-6; see also, id. at p. 138, l. 11 – p. 139, l. 13 and Ex. 1048,
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`p. 96, ll. 12-23).
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` PO also argued that the claims require “patients [to] continue receiving
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`higher doses of lomitapide notwithstanding the presence of side effects at the lower
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`dose” (id.). But nothing in the claims requires forcing higher doses of lomitapide
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`into a patient after the patient experiences side effects (supra § III). The claimed
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`treatment method is not restricted to patients who experience side effects after the
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`first or second dose; it also applies to subjects that do not experience side effects.
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`PO failed to even attempt to explain how the protocol of the Pink Sheet as applied
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`to the latter group of subjects, would differ from the claimed method (PO’s
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`Response, § V.B; Ex. 1058, p. 144, ll. 19-20). In addition, the clinical trials relied
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`upon by PO for its alleged reduction to practice, called for lowering the dose (Ex.
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`2077, p. 21) and actually reduced the dosage in one patient (Ex. 2004, p. 7). Thus,
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`even the PO itself tacitly acknowledged that the claims are not so limited.
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`The PO also argued that the “protocol [of the Pink Sheet] relates to testing
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`doses lower than doses that exhibit toxicity, which is entirely different from the
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`‘135 claims, which relate to administration of doses that are higher than the 25
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`mg/day doses” (PO’s Response, p. 37). But the claims do not, in fact, require
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`doses higher than 25 mg/day; they instead require significantly less than 25
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`mg/day. The highest dose range required by independent claims 1, 9, and 10 (i.e.,
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`7
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`Reply To Patent Owner’s Response for Inter Partes Review of USPN 8,618,135
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`the third dose level) as well as claims 2-7 dependent therefrom “is from about 10 to
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`about 50 mg/day” (Ex. 1001, col. 19, ll. 45-50). Thus, even under PO’s incorrect
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`interpretation of the Pink Sheet, it would still not differ from the claimed invention
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`because dose ranges less than 25 mg/day are encompassed by the claims (Ex. 1048,
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`pp. 63-64; Ex. 1058, p. 133, ll. 12-17).
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`PO further attempted to distinguish the Pink Sheet by stating that it discloses
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`a “very slow increase in dosing amounts (5 mg)” (Ex. 2023 (Sacks) ¶128). But this
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`argument is also not commensurate with the scope of the claims of the ‘135 patent
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`because the claims encompass a dose increment as little as 3 mg (from 2 mg of a
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`first dose to 5 mg of a second dose as recited in Claims 1, 9 and 10) that are even
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`smaller than those of the Pink Sheet.
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`B. A POSA Would Have Been Motivated To Develop Lomitapide In
`March 2005.
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`PO argued that a POSA would not have been motivated to substitute
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`lomitapide for implitapide because “Chang describes at least 6 other MTP
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`inhibitors” (PO’s Response, p. 30). But as explained by the Board, “[t]he fact that
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`Chang discloses MTP inhibitors other than lomitapide, does not, by itself, make the
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`selection of lomitapide any less obvious” (Institution Decision, Paper No. 7, pp.
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`17-18, citing Merck & Co., Inc. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed.
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`Cir. 1989). In Merck, the Federal Circuit held that the prior art’s disclosure of a
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`multitude of combinations failed to render any particular formulation less obvious.
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`8
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`Reply To Patent Owner’s Response for Inter Partes Review of USPN 8,618,135
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`Id. Moreover, the Federal Circuit has rejected “the notion that one of [14 listed]
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`ingredients cannot anticipate because it appears without special emphasis in a
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`longer list.” Perricone v. Medicis Pharm. Corp., 432 F.3d 1368, 1376 (Fed. Cir.
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`2005). Thus, PO’s identification of merely 6 other MTP inhibitors in Chang is not
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`nearly enough to show that the selection of lomitapide from the list would not have
`
`been obvious. Also, there would have been a reason for a POSA to select
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`lomitapide because implitapide and lomitapide are specifically described in Chang
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`as having similar successful efficacy in humans (Ex. 1058, p. 84, ll. 5-9). As noted
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`by the Board, a POSA would have been motivated to substitute lomitapide for
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`implitipide because “implitapide and lomitapide are from the same class of
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`therapeutics, that is MTP inhibitors, and that they are known to have similar
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`clinical efficacy” (Institution Decision, p. 18).
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`PO also asserted that a POSA would have been dissuaded from lomitapide
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`because “development of lomitapide had been halted [by BMS] … due to toxicity
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`in phase I and II clinical trials” (PO’s Response, p. 27). But the proper inquiry is
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`whether a POSA would have been motivated to develop lomitapide as of the
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`effective filing date of the ‘135 patent (i.e., March, 2005), not at the time that
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`Chang was published. 35 U.S.C. 103(a). And as explained by the Board, a POSA
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`would have understood in March, 2005 that the toxicity in the clinical trials was
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`due to the high doses, not the lower doses required by the claims:
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`9
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`Reply To Patent Owner’s Response for Inter Partes Review of USPN 8,618,135
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`Chang was published in 2002, and reflected the understanding of the
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`use of MTP inhibitors as monotherapy at that time. Pink Sheet,
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`which was published February 16, 2004, acknowledges that MTP
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`inhibitors had been pursued by a number of companies, but that the
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`toxicity seen was most likely related to the high doses used during
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`trials. Ex. 1013.
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`(Institution Decision, pp. 18-19).
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`PO also asserted that a POSA would have been dissuaded from lomitapide
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`because of concern “about off-target toxicity, notably phospholipidosis and hERG,
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`due to lomitapide’s structure” (PO’s Response, p. 29). But BMS clearly
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`demonstrated that PO’s assertion is wrong because it was aware of lomitapide’s
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`structure and nonetheless, pursued development of lomitapide for many years and
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`did not discontinue the development because of off-target toxicity (Ex. 1056, p. 38,
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`l. 10 – p. 39, l. 3; p. 163, ll. 19-24). In addition, PO’s expert, Dr. Kimball,
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`admitted that there was nothing in the public domain at the time of the effective
`
`filing date of the ‘135 patent to indicate that either implitapide or lomitaide
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`exhibited off-target toxicity:
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`Q. Now were either of these compounds lomitapide and implitapide
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`known … in the 2004-2005 time frame to exhibit off-target toxicity?
`
`A. There was nothing in the public domain at that point in time that
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`I'm aware of.
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`(Ex. 1056, p. 103, ll. 15-24; see also, id. at p. 163; Ex. 1048, p. 50). Similarly, Dr.
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`Kimball admits that an article (Ex. 2020) by BMS specifically addressing
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`10
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`Reply To Patent Owner’s Response for Inter Partes Review of USPN 8,618,135
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`lomitapide and its development of MTP inhibitors fails to even mention either
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`phospolipidosis or hERG inhibition as a possibility (Ex. 1056, p. 163, ll. 16-22).
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`As also noted by the Board, a POSA would have been motivated to use an MTP
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`inhibitor like lomitapide as an add-on therapy to statins: “Pink Sheet, which
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`reflects the state of the art at the time of invention, suggests using the MTP
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`inhibitor as an add-on therapy to statins, in which safety and efficacy would be
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`studied using escalating doses” (Institution Decision, p. 19, citing Ex. 1013).
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`Indeed, PO admits that a POSA would have known to use MTP inhibitors as an
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`add-on therapy to stains because “the concepts of add-on therapy to statins was not
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`new” (PO’s Response, p. 29). Accordingly, “a POSA would have been motivated
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`to apply this knowledge about MTP-inhibitors as an add-on therapy to statins to the
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`development of lomatipide for this purpose” (Ex. 1049, ¶ 119).
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`The Board also found that a POSA would have known based on the
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`disclosure of the Technology Donation Agreement (Ex. 2001) and the Pink Sheet,
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`that both lomatipide and implitipide could be used to treat certain rare disorders
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`such as homozygous and severe heterozygous familial hypercholesterolemia
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`(Institution Decision, p. 19; see also, Ex. 1048, pp. 33, 101). Moreover, the
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`Technology Donation Agreement indicates that BMS abandoned lomitapide for
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`business reasons: “While it was not commercially feasible for BMS to develop the
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`compound for such use, Uni