IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`Mylan Pharmaceuticals Inc., Petitioner
`
`v.
`
`Nissan Chemical Industries Ltd.
`Patent Owner
`
`U.S. Patent No. 5,856,336 to Fujikawa et al.
`Issue Date: January 5, 1999
`Title: Quinoline Type Mevalonolactones
`
`_____________________
`
`Inter Partes Review No.: IPR2015-01069
`
`Declaration of Roger F. Newton, Ph.D. in Support of
`Mylan Pharmaceuticals Inc.’s Petition
`for Inter Partes Review of U.S. Patent No. 5,856,336
`
`
`
`Mylan Exhibit 1008, Page 1
`
`
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`Mylan Pharmaceuticals Inc., Petitioner
`
`v.
`
`Nissan Chemical Industries Ltd.
`Patent Owner
`
`U.S. Patent No. 5,856,336 to Fujikawa et al.
`Issue Date: January 5, 1999
`Title: Quinoline Type Mevalonolactones
`
`_____________________
`
`Inter Partes Review No.: IPR2015-01069
`
`Declaration of Roger F. Newton, Ph.D. in Support of
`Mylan Pharmaceuticals Inc.’s Petition
`for Inter Partes Review of U.S. Patent No. 5,856,336
`
`
`
`Mylan Exhibit 1008, Page 1
`
`
`
`I.
`
`INTRODUCTION
`
`1.
`
`I am over the age of eighteen (18) and otherwise competent to make
`
`this Declaration.
`
`2.
`
`I have been retained as an expert witness on behalf of Petitioner for
`
`the above-captioned inter partes review (“IPR”). I am being compensated for my
`
`time in connection with this IPR at my standard consulting rate, which is $700 per
`
`hour. My compensation does not depend in any way on the outcome of this IPR.
`
`3.
`
`It is my understanding that the Petition for IPR in this matter involves
`
`U.S. Patent No. 5,856,336 to Fujikawa et al. (“the ’336 patent”) (EX1001).
`
`It is
`
`also my understanding that the records of the USPTO indicate that the current
`
`owner of the ’336 patent is Nissan Chemical Industries Ltd. (“Nissan”).
`
`4.
`
`Claim 1 of the ’336 patent depicts a compound, which has a 4-
`
`fluorophenyl group, a quinoline ring scaffold, and what I have been informed the
`
`Patent Owner claims is a cyclopropyl substituent at the 2 position represented by
`
`“Δ.”1 This compound, which is in its calcium salt form, is also known as
`
`pitavastatin calcium salt. Claim 1 is reproduced below:
`
`1 Solely for the purpose of this Declaration and my analysis of the prior art, I will
`
`accept the Patent Owner’s interpretation.
`
`LEGAL02/35493234v1
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`1
`
`
`
`
`
`Mylan Exhibit 1008, Page 2
`
`
`
`1.
`
`A compound of the formula,
`
`Z = —CH(OH)—CH2—CH(OH) —CH2—COO.1/2Ca.
`
`(The ’336 patent (EX1001) at col. 32, ll. 21-36).
`
`Claim 1 is not directed to any particular optical isomer. Rather, a person of
`
`ordinary skill in the art as to the ’336 patent (“POSA”) would understand that all
`
`optical isomers and mixtures thereof are encompassed by the claim.
`
`5.
`
`Claim 2 is drawn to methods of using the compound of Claim 1 to
`
`reduce hyperlipidemia, hyperlipoproteinemia, or atherosclerosis and is reproduced
`
`below:
`
`hyperlipidemia,
`reducing
`for
`A method
`2.
`hyperlipoproteinemia or atherosclerosis, which comprises
`administering an effective amount of the compound of
`formula A as defined in Claim 1.
`
`(The ’336 patent (EX1001) at col. 32, ll. 37-40).
`
`6.
`
`In preparing this Declaration, I have reviewed the ’336 patent and its
`
`prosecution history as well as each of the documents cited in this Declaration and
`
`cited in the IPR Petition.
`
`In arriving at my opinions, I have relied upon my
`
`LEGAL02/35493234v1
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`2
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`Mylan Exhibit 1008, Page 3
`
`
`
`experience in the relevant art and have considered the point of view of a POSA, as
`
`defined below.
`
`7.
`
`It is my opinion that, during the relevant time period, a POSA would
`
`have selected the prior art compound shown below as the lead compound:
`
`(U.S. Patent No. 4,739,073 (“the Kathawala ’073 patent”) (EX1010) filed March
`
`4, 1985, and published April 19, 1988, at col. 52, ll. 27-40).
`
`8.
`
`This compound is also known as fluvastatin. The prior art at the
`
`relevant time showed that fluvastatin possessed excellent in vitro activity.
`
`(See
`
`“the Kathawala ’073 patent” (EX1010) at col. 33, ll. 11-43). This compound also
`
`demonstrated relatively high activity for
`
`in vivo cholesterol biosynthesis
`
`inhibition. Id. The compound was disclosed as lowering several lipid parameters
`
`in animals and was reported to be in human clinical trials by at least 1987.
`
`(See
`
`the Kathawala Abstract, EX1009, available at
`
`the University of Michigan
`
`Chemistry Library on July 29, 1987; the Engstrom Abstract, EX1011, first library
`
`stamp December 22, 1987.
`
`LEGAL02/35493234v1
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`3
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`
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`Mylan Exhibit 1008, Page 4
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`
`
`9.
`
`In addition, competing researchers recognized fluvastatin as one of
`
`only 5 HMG-CoA reductase inhibitors that had proceeded to clinical trials and
`
`was “particularly interesting.”
`
`(Tobert, EX1012, available at University of
`
`Minnesota Biomedical Library September 11, 1987, pages 534-535; Lee, EX1013,
`
`available at the National Library December 2, 1987, page 444 (“particularly
`
`interesting”)). The POSA also would have understood that fluvastatin was many
`
`times more active than two of the other four HMG-CoA reductase inhibitors in
`
`clinical trials in vivo. (See the Kathawala ’073 patent, col. 32, l. 53-col. 33, l. 11;
`
`col. 33, ll. 50-62).
`
`10.
`
`It was known by 1987 that HMG-CoA reductase inhibitors were
`
`useful in lowering cholesterol, a risk factor in coronary artery disease. Several
`
`major pharmaceutical groups were actively researching these compounds. Thus,
`
`the prior art would have motivated a POSA to select fluvastatin as a lead
`
`compound for further modification.
`
`11.
`
`In considering further modifications,
`
`the POSA would have
`
`considered the logical structural avenues available to further optimize the
`
`compound. Within fluvastatin, both the 4-fluorophenyl group (boxed in green)
`
`and isomeric side chain (boxed in blue) reflected the product of prior efforts to
`
`optimize structural groups in comparison to the early-generation statin molecules
`
`(i.e., compactin and mevinolin):
`
`LEGAL02/35493234v1
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`4
`
`
`
`Mylan Exhibit 1008, Page 5
`
`
`
`F
`
`N
`
`OH
`
`R
`
`OH
`
`S
`
`CO2Na
`
`Fluvastatin
`
`12.
`
`The prior art also taught advantages to incorporating nitrogen-
`
`containing ring systems in the molecule’s core. The POSA would have been
`
`motivated to further optimize the ring system with structural analogs of the
`
`fluvastatin’s 6,5 indole ring system; a 6,6 quinoline ring would have been an
`
`obvious structural modification expected to work (and indeed, such rings were in
`
`fact proposed for use in the relevant time frame in statin compounds).
`
`13.
`
`Likewise, the prior art had taught interchangeable options for the
`
`isopropyl group, including cyclopropyl. The art further taught a limited range of
`
`salt structures suitable for use with statins, including a calcium salt. Applying
`
`these known strategies to fluvastatin necessarily would have led the skilled artisan
`
`to the subject matter purportedly claimed by the ’336 patent.
`
`14.
`
`The indole-quinoline modification is a simple structural modification
`
`involving a single carbon atom addition. As discussed below, in light of the prior
`
`art, this would have been an obvious modification. Likewise, it was known in the
`
`art at the relevant time that a cyclopropyl and isopropyl groups are very similar.
`
`LEGAL02/35493234v1
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`5
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`
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`Mylan Exhibit 1008, Page 6
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`
`
`Indeed, this selection would have been so obvious that it would have been the next
`
`logical, and an analogous compound. Knowing that an isopropyl is an acceptable
`
`substituent, POSAs would have readily arrived at the selection of cyclopropyl
`
`group.
`
`15.
`
`I understand that the Patent Owner alleged during the prosecution of
`
`the ’336 patent that the claim compound, which contains a cyclopropyl substituent,
`
`had unexpected potency over the isopropyl substituent. (See Kitahara Declaration
`
`(“Kitahara Dec.”) dated May 25, 1992 (EX1032)). I have reviewed the data in the
`
`Kitahara Declaration, and the difference was within the range the POSA would
`
`have expected when replacing isopropyl with its close analog cyclopropyl.
`
`(See
`
`Suh published January 1985 (EX1029)).
`
`Further, a POSA would not have
`
`understood or recognized that
`
`this difference in in vitro potency would be
`
`clinically significant.
`
`16.
`
`Having made these two structural modifications, the POSA would
`
`have then considered salt options, which the POSA would have understood needed
`
`to be a positive cation, as discussed below.
`
`In view of the prior art, and his/her
`
`knowledge and experience, a POSA would have had a reasonable expectation of
`
`success that the calcium salt would have maintained potent HMG-CoA reductase
`
`inhibitory activity.
`
`In addition, these cation options would have been limited,
`
`given that there were only a few pharmaceutically acceptable cations that were
`
`LEGAL02/35493234v1
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`6
`
`
`
`Mylan Exhibit 1008, Page 7
`
`
`
`approved by the U.S. Food and Drug Administration (“FDA”) at the time of the
`
`invention. The POSA therefore would have recognized selecting a calcium cation
`
`as a routine design choice that would have been obvious to try.
`
`17.
`
`It is my opinion that each of the modifications described above
`
`would not have been synthetically challenging, but rather would have been routine
`
`and well within the skill set of a POSA. Having made these modifications, as I
`
`explain in detail below, a POSA would have arrived at the compound of Claim 1 of
`
`the ’336 patent with a reasonable expectation of success.
`
`18. Moreover, given the disclosures of the prior art with regard to
`
`biological activity, it is my opinion that a POSA would have reasonably expected
`
`that such a compound would be effective in reducing hyperlipidemia and
`
`hyperlipoproteinemia, as recited in Claim 2.
`
`II.
`
`LIST OF MATERIALS CONSIDERED
`
`19.
`
`In formulating my opinions, I have considered the documents cited
`
`and referenced in this declaration and the documents cited in the IPR Petition
`
`itself.
`
`III. MY EXPERIENCE AND QUALIFICATIONS
`
`20.
`
`I am an expert in the field of medicinal chemistry and drug discovery,
`
`and I have been an expert in this field since prior to 1987. In forming my opinions,
`
`I have relied on my knowledge, training, and experience in the relevant art. I have
`
`LEGAL02/35493234v1
`
`7
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`
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`Mylan Exhibit 1008, Page 8
`
`
`
`provided a copy of my current curriculum vitae, which describes my education and
`
`experience first as a synthetic and physical organic chemist and finally a medicinal
`
`chemist. (EX1007). In this later role, I led Glaxo’s chemical research team when
`
`it was the foremost pharmaceutical company in the world. I am well versed in the
`
`chemical structures and structure activity relationships of HMG-CoA reductase
`
`inhibitors.
`
`21.
`
`As an expert in the field since before 1987, I am qualified to offer
`
`opinions regarding what a POSA would have known or understood as of
`
`August 20, 1987, which I understand to be the earliest foreign application to which
`
`Patent Owners have claimed priority for the ’336 patent.2
`
`22.
`
`Since 1968, I have gained significant experience in the field of
`
`medicinal chemistry and drug delivery.
`
`I have a Ph.D. in synthetic and physical
`
`organic chemistry and a B.Sc. in chemistry and biology from the University of
`
`London.
`
`2 I have been made aware that there is some dispute regarding the exact priority
`
`date of Claims 1 and 2 of the ’336 patent. Regardless of what the ultimate priority
`
`date is determined to be, the opinions of a POSA as provided in this Declaration
`
`during any of those time frames would remain the same.
`
`LEGAL02/35493234v1
`
`8
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`
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`Mylan Exhibit 1008, Page 9
`
`
`
`23.
`
`From 1971-1996, I was employed by Allen & Hanburys and Glaxo
`
`Group Research Ltd.
`
`Initially, I served as a senior research chemist, then as a
`
`research leader, and eventually as the Head of
`
`the Exploratory Research
`
`Department, Head of the Chemical Research Department, Director of Chemistry,
`
`and Director of the Chemical Research Division.
`
`24. While at Glaxo Group Research Ltd., I also served as Chairman of
`
`the
`
`respiratory research management
`
`committee, Vice-Chairman of
`
`the
`
`cardiovascular research management committee and Vice-Chairman of the anti-
`
`infective research management committee. While at Allen & Hanburys and Glaxo
`
`Group Research Ltd., I was involved in the research for drugs to treat pain,
`
`congestive heart failure and hypertension, anti-emetics, anti-asthmatics, migraine,
`
`gastric ulcers, cardiac infarction, hyperlipidemia and viral and bacterial infections.
`
`During this time, Glaxo discovered and successfully launched the anti-emetic
`
`Zofran, the first drug specifically designed for the treatment of migraine, Imigran,
`
`Salmeterol the first long acting selective 2 stimulant for asthma, the influenza
`
`drug Relenza and an HIV protease inhibitor. While at Glaxo, I oversaw the statins
`
`research program, as well as programs to develop drugs for targeting other stages
`
`of cholesterol biosynthesis for the treatment of hyperlipidemia.
`
`25.
`
`Between 1998 and 2006, I served as a consultant for a number of
`
`pharmaceutical companies including Johnson & Johnson Pharmaceuticals, USA
`
`LEGAL02/35493234v1
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`9
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`Mylan Exhibit 1008, Page 10
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`
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`(1998-2004), Sun Pharma Ltd, Mumbai, India (2000), Sumitomo Chemicals Ltd,
`
`Osaka, Japan (2001-2006), Roche Pharmaceuticals, Switzerland (2002-2004),
`
`Novartis Institutes for BioMedical Research Inc. (2005-2006) and Celltech (2003-
`
`2004). As a consultant, I advised these companies regarding their medicinal
`
`chemistry programs. I also conducted scientific due diligence on their behalf into a
`
`number of biotechnology companies and advised as to the quality and relevance of
`
`their research to a possible partnership in specific areas of joint interest.
`
`26.
`
`Between 1992 and 2001, I served as a Director or Non-executive
`
`Director for a number of pharmaceutical companies.
`
`These included Non-
`
`executive Director of Glaxochem Ltd. (1992-1994), Non-executive Director of
`
`Cerebrus Ltd. (1995-1999), Non-executive Director of Cambridge Molecular
`
`Technologies (1997-1999), Founder, Director, and Non-executive Director of
`
`Cambridge Genetics Ltd. and Chairman of the scientific advisory board (1998-
`
`2001), and Non-executive Director of Syngenix Ltd. (1999-2001).
`
`27.
`
`I also served as a member of the scientific affairs boards of Celltech
`
`(1998-2003) and PanTherix (1999-2003), and as Chairman of the scientific
`
`advisory board of Amedis Ltd. (2002-2004).
`
`28.
`
`In 1997, I led the management buy in/buy out of the chemical
`
`company Maybridge PLC and served as chairman and then director of science until
`
`I retired in 2006. During this time and in collaboration with the biotechnology
`
`LEGAL02/35493234v1
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`10
`
`
`
`Mylan Exhibit 1008, Page 11
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`
`
`company Kudos we discovered the novel anti-cancer PARP-inhibitor Olaparib.
`
`This medicine was approved in the United States and Europe in 2014, and is now
`
`the property of AstraZeneca.
`
`29.
`
`I have held academic appointments at a number of universities.
`
`Between 1976 and 2005, I held appointments at the University of Sheffield (1976-
`
`1982), the University of Warwick (1984-1995), the University of Salford (1984-
`
`1989), Kings College, University of London (1984-1998), University College of
`
`North Wales, Bangor (1985-1990),
`
`the University of Bath (1994-1996),
`
`the
`
`University of Southampton (1991-1994), the University of Leeds (1995-1997), the
`
`University of St. Andrews (1993-1997), the University of Sussex (1996-2010) and
`
`the University of Cambridge (1996-2005).
`
`30.
`
`In 1995, I was awarded the Royal Society of Chemistry award for
`
`Medicinal Chemistry.
`
`In 1996, I was awarded the Royal Society of Chemistry
`
`Biological and Medicinal Chemistry Sector Award.
`
`31.
`
`Since 1966, I have been a joint author of 139 referred research
`
`papers, seven reviews, joint editor of one book chapter, joint author of two book
`
`LEGAL02/35493234v1
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`11
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`
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`Mylan Exhibit 1008, Page 12
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`
`
`chapters and author of three others, mostly concerned with synthetic organic
`
`chemistry. I have also been a joint inventor of 12 patents.3
`
`32.
`
`I have reviewed the ’336 patent and its claims.
`
`I believe I am an
`
`expert in the subject matter described, but have considered the issues discussed
`
`herein from the perspective of a POSA, as discussed further below.
`
`IV.
`
`POSA
`
`33.
`
`I understand that a POSA is a hypothetical person who is presumed
`
`to be aware of all pertinent art, follows conventional wisdom in the art, and is a
`
`person of ordinary creativity.
`
`34. With respect to the ’336 patent, the POSA would have held an
`
`advanced degree, such as an M.S. or a doctorate in one of the fields of medicinal or
`
`synthetic chemistry, pharmacology, pharmacy or medicine, with several years of
`
`experience in one of the fields of medicinal or synthetic chemistry, pharmacology,
`
`pharmacy or medicine.
`
`In addition, the POSA would have either personally
`
`possessed, or had access to, knowledge and skills from medicinal and/or synthetic
`
`chemists, as well as biologists, pharmacists and/or clinicians, including possessing
`
`3 I reserve the right to further explain my background and qualifications in
`
`deposition where needed.
`
`LEGAL02/35493234v1
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`12
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`
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`Mylan Exhibit 1008, Page 13
`
`
`
`knowledge of statins,
`
`their mechanisms of actions, and other cholesterol
`
`treatments.
`
`35.
`
`I understand that a POSA typically would have consulted with one or
`
`more members of a team of experienced professionals in the relevant field in order
`
`to solve a particular problem.
`
`36.
`
`The testimony that
`
`I provide in this Declaration is from the
`
`perspective of a POSA (as defined herein) during the relevant time period.4
`
`V.
`
`HISTORY OF STATINS
`
`37.
`
`By the late 1980s, researchers had shown that most cholesterol is
`
`manufactured by the human body in the liver. It was also known at that time that
`
`the enzyme HMG-CoA reductase plays a critical role in regulating cholesterol
`
`biosynthesis. HMG-CoA reductase was known to be the rate-controlling enzyme
`
`4 This Declaration contains the opinions that a POSA would have known or
`
`understood as of August 20, 1987, which I understand to be the earliest date of
`
`priority for the ’336 patent.
`
`I have been made aware that there is some dispute
`
`regarding the exact priority date of Claims 1 and 2 of the ’336 patent. Regardless
`
`of what the ultimate priority date is determined to be, the opinions of a POSA as I
`
`have described them in this Declaration would remain the same.
`
`LEGAL02/35493234v1
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`13
`
`
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`Mylan Exhibit 1008, Page 14
`
`
`
`of the mevalonate pathway, the metabolic pathway that leads to the production of
`
`cholesterol in the body.
`
`(See generally, Alberts published July 1980 (EX1022);
`
`Brown published August 27, 1981 (EX1030)).
`
`38.
`
`At the time of the claimed invention of the ’336 patent, a class of
`
`drugs called HMG-CoA reductase inhibitors – more commonly known as “statins”
`
`– were disclosed in the art and known to a POSA. Statins are competitive
`
`inhibitors of HMG-CoA reductase. By targeting the rate-limiting enzyme of
`
`cholesterol biosynthesis,
`
`these drugs ultimately lower cholesterol
`
`levels;
`
`this
`
`activity makes statins beneficial in the prevention or treatment of cardiovascular
`
`disease. (See Alberts (EX1022) and Brown (EX1030)).
`
`39.
`
`The properties of statins were well understood by August 1987, and
`
`large-scale clinical trials had confirmed that lovastatin was effective in lowering
`
`cholesterol. In fact, lovastatin was the first statin to receive FDA approval in 1987.
`
`40.
`
`As I will explain in more detail below, fluvastatin was another statin
`
`that was the subject of significant research at the time that the first application that
`
`led to the ’336 patent was filed. The properties of fluvastatin made it a natural
`
`choice for further research and development.
`
`VI. THE ’336 PATENT
`
`41.
`
`I have reviewed and considered the ’336 patent in view of the general
`
`knowledge in the relevant field from the perspective of a POSA relevant to the
`
`LEGAL02/35493234v1
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`14
`
`
`
`Mylan Exhibit 1008, Page 15
`
`
`
`’336 patent, as defined herein.
`
`I conclude that Claims 1 and 2 of the ’336 patent
`
`are obvious in view of the prior art. The ’336 patent issued on January 5, 1999,
`
`from U.S. Application Serial Number 883,398.
`
`(EX1001). The specification of
`
`the ’336 patent purports to describe mevalonolactone compounds having a
`
`quinoline ring that exhibit HMG-CoA reductase inhibitory activity.
`
`A.
`
`42.
`
`The Applications Leading to the ’336 Patent
`
`It
`
`is my understanding that
`
`the ’336 patent
`
`issued from U.S.
`
`Application Serial Number 883,398 (“the ’398 application”), filed May 15, 1992,
`
`and that the ’398 application was a divisional of U.S. Application Serial Number
`
`631,092 (“the ’092 application”), filed December 19, 1990.
`
`43.
`
`It is also my understanding that the ’092 application issued as U.S.
`
`Patent Number 5,872,130 (“the ’130 patent”)
`
`(EX1002) and that
`
`the ’092
`
`application itself was a continuation of U.S. Application Serial Number 233,752
`
`(“the ’752 application”) (EX1003), which was abandoned.
`
`44.
`
`I understand that the ’336 patent, the ’130 patent, and the ’752
`
`application all claim of priority to three foreign documents:
`
`
`
`
`
`Japanese Patent Application Number JP 62-207224 “JP 62-207224”
`
`(EX1004), filed August 20, 1987;
`
`Japanese Patent Application Number JP 63-15585 “JP 63-15585”
`
`(EX1005), filed January 26, 1988; and
`
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`15
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`Mylan Exhibit 1008, Page 16
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`
`
`Japanese Patent Application Number JP 63-193606 “JP 63-193606”
`
`(EX1006), filed August 3, 1988.
`
`45.
`
`I have been asked to review the certified English translations of these
`
`three Japanese Patent Applications and to offer my opinion regarding whether a
`
`POSA would understand any of these documents to provide support for the two
`
`issued claims of the ’336 patent.
`
`46.
`
`After reviewing the three Japanese patent applications listed above, I
`
`have concluded that neither JP 62-207224 (EX1004) nor JP 63-15585 (EX1005)
`
`provides support for the two claims of the ’336 patent. I will explain the basis for
`
`my opinion more fully in the following paragraphs:
`
`B.
`
`JP 62-207224 Does Not Provide Adequate Support
`Cyclopropyl Substituents the Challenged Claims Require
`
`for 2-
`
`47.
`
`I have concluded that the earliest filed priority document, JP 62-
`
`207224 (EX1004), does not provide adequate support
`
`for 2-cyclopropyl
`
`substituents. Initially, JP 62-207224 provides no examples directed to pitavastatin
`
`calcium, and no data justifying its selection or use as a stand-alone species. JP 62-
`
`207224 provides only one (1) aspirational species example that even includes a
`
`cyclopropyl substituent at the 2 position on the quinoline ring. That aspirational
`
`species is not pitavastatin calcium or a pitavastatin salt, but rather a carboxylic acid
`
`LEGAL02/35493234v1
`
`16
`
`
`
`Mylan Exhibit 1008, Page 17
`
`
`
`version of that compound.
`
`(See JP 62-207224, at page 12, Table 1,
`
`last
`
`compound).
`
`48.
`
`None of the approximately 50 examples of compounds for which
`
`melting points or oil status are described in JP 62-207224 have a cyclopropyl
`
`substituent. Additionally, none of the compounds that were tested biologically
`
`have a cyclopropyl substituent. Furthermore, the only compound utilized in the
`
`formulation examples has an isopropyl group (not cyclopropyl) at the 2 position.5
`
`49.
`
`In summation, a POSA would conclude that JP 62-207224 (EX1004)
`
`does not disclose any species of compounds with both a cyclopropyl group at the 2
`
`position and a salt at the end of the side chain, and its broad and generic disclosure
`
`would not suggest to a POSA that the applicants were in possession of the much-
`
`narrower species in Claims 1 and 2 of the ’336 patent.
`
`5 JP 62-207224 (EX1004) also does not disclose any species of compounds with
`
`both a cyclopropyl group at the 2 position and a salt at the end of the side chain.
`
`LEGAL02/35493234v1
`
`17
`
`
`
`Mylan Exhibit 1008, Page 18
`
`
`
`C.
`
`JP 62-207224 and JP 63-15585 Do Not Provide Adequate Support
`for Pitavastatin Calcium in the ’336 Patent
`
`50.
`
`I have further concluded that neither JP 62-207224 (EX1004) nor JP
`
`63-15585 (EX1005)6 provide support for a species directed to the calcium salt of
`
`pitavastatin or its isomers—the structure of which the Patent Owner insists is
`
`recited in Claim 1 of the ’336 patent.
`
`51.
`
`Initially, like JP 62-207224, JP 63-15585 provides no examples
`
`directed to pitavastatin calcium, and no data justifying its selection or use as a
`
`stand-alone species. The genuses disclosed in JP 62-207224 and JP 63-15585 do
`
`not even list calcium salts by name.
`
`Instead, when discussing possible
`
`substituents at the end of the side chain in the genus, JP 63-15585 and JP 62-
`
`207224 state “[w]herein M is NH4, a metal capable of forming a salt which is
`
`pharmaceutically acceptable or an amine H.” (JP 63-15585 (EX1005) at 4, ll. 11-
`
`12; JP 62-207224 (EX1004) at 4, ll. 4-5). M is further defined as “a metal capable
`
`of forming a pharmaceutically acceptable salt, and it includes, for example,
`
`sodium and potassium.” (JP 63-15585 at 5, ll. 17-19; JP 62-207224 at 5, ll. 1-3).
`
`6 Like the disclosure of JP 62-207224, the disclosure of JP 63-15585 (EX1005) is
`
`also very broad, and a POSA would understand that the generic description of the
`
`application includes thousands of compounds.
`
`LEGAL02/35493234v1
`
`18
`
`
`
`Mylan Exhibit 1008, Page 19
`
`
`
`The only salt species described, made, tested or put into formulation in JP 62-
`
`207224 and JP 63-15585 are sodium salts.
`
`52. Unlike JP 62-207224, JP 63-15585 (EX1005) does disclose some
`
`species examples of compounds with a cyclopropyl group. These include the
`
`compound I-520, which is a pitavastatin sodium salt, and the compound I-120,
`
`which is structurally similar to pitavastatin, but further modified with an ethyl
`
`group at the end of the side chain (JP 63-15585 at 56-57, Table 11, 47-48, Table
`
`10). While data is provided showing that I-120 has activity (id. at 23, Table 2-2),
`
`no biological data is provided for compound I-520 or for any pitavastatin salts, or
`
`for that matter any salt of a compound with a cyclopropyl group.
`
`53.
`
`The only compound put into a formulation in JP 63-15585 has an
`
`isopropyl substituent at the 2-position rather than a cyclopropyl substituent, and is
`
`a sodium salt. Preferred examples for the ’336 patent are not listed until the later-
`
`filed, third priority document, JP 63-193606. (See, e.g., the ’336 patent at col. 4, l.
`
`59-col. 5, l. 47).
`
`54.
`
`Although a POSA would have understood that calcium generally was
`
`a “pharmaceutically acceptable salt,” the only salts disclosed in JP 62-207224 and
`
`JP 63-15585 are sodium and potassium salts.
`
`55.
`
`Thus, in my opinion, the disclosures of JP 62-207224 and JP 63-
`
`15585 do not provide support to a POSA for the selection of a calcium salt from
`
`LEGAL02/35493234v1
`
`19
`
`
`
`
`
`Mylan Exhibit 1008, Page 20
`
`
`
`among the “pharmaceutically acceptable salts” in the context of the claimed
`
`invention.
`
`VII. OBVIOUSNESS OF CLAIMS 1 AND 2 OF THE ’336 PATENT
`
`56.
`
`I have been informed that there are generally two relevant inquiries in
`
`determining whether a new chemical compound would have been obvious over
`
`known compounds in the prior art: first, whether a POSA would have chosen the
`
`prior art compound as a starting point for additional development, and second,
`
`whether the prior art provided some reason or motivation to a POSA to change the
`
`lead compound to the claimed compound with a reasonable expectation of success.
`
`A.
`
`State of the Art Concerning HMG-CoA Reductase Inhibitors
`
`1.
`
`Discovery of the Mechanism and Structure Activity
`Relationship for HMG-CoA Reductase
`
`57.
`
`The enzyme known as 3-hydroxy-3-methylglutaryl-coenzyme A
`
`reductase (HMG-CoA reductase) catalyses the conversion of HMG-CoA into
`
`mevalonic acid. This was known by 1980 to be a major rate-limiting step in
`
`cholesterol
`
`biosynthesis,
`
`and
`
`thus
`
`a
`
`prime
`
`target
`
`for
`
`reduction
`
`of
`
`hypercholesterolemia, which in turn is a risk factor in coronary artery disease. (See
`
`Alberts (EX1022) at 3957).
`
`58.
`
`The first HMG-CoA reductase inhibitor was the natural product
`
`compactin. Compactin’s activity in inhibiting cholesterol synthesis in vitro as well
`
`as in rats was reported by Endo in 1976.
`20
`
`LEGAL02/35493234v1
`
`(Endo, EX1014, published December
`
`Mylan Exhibit 1008, Page 21
`
`
`
`1976, at 1347). The disclosure of the activity of an alkyl-substituted version called
`
`mevinolin followed in 1980.
`
`(See id., Endo). These compounds are fungal
`
`metabolites isolated from fungal broths.
`
`R = H, R1 = H
`Compactin
`Mevinolin = Lovastatin R = CH3, R1 = H
`Simvastatin
`R = CH3, R1 = CH3
`
`O
`
`O
`
`CH3
`
`*
`
`*
`
`OH
`
`*
`
`H
`
`* *
`
`O
`
`1
`
`*
`
`O R
`
`CH3
`
`*
`
`R
`
`*
`
`59.
`
`After the initial disclosure of compactin (mevastatin) and mevinolin
`
`(lovastatin), many companies,
`
`including Merck, Warner-Lambert and Sandoz
`
`began developing new synthetic compounds based on these core structures with
`
`enhanced activity. Before JP 62-207224 was filed, this work began to reveal
`
`patterns for a structure-activity relationship (“SAR”) between the compounds and
`
`expected activity. As the art developed, it confirmed potent HMG-CoA reductase
`
`inhibition activity was retained across a variety of nitrogen ring scaffolds, so long
`
`as a pharmacophore containing a lactone ring or an open heptenoic acid side chain
`
`was flanked on one side by a 4-fluorophenyl group, and on the other side by an
`
`alkyl group.
`
`LEGAL02/35493234v1
`
`21
`
`
`
`Mylan Exhibit 1008, Page 22
`
`
`
`F
`
`side chain
`
`alkyl
`
`Initially, it was soon found that compounds in which the hexa-hydro naphthalene
`
`scaffold part of the molecule in compactin and mevinolin (i.e., the 6,6 ring
`
`scaffold) could be replaced with simple achiral lipophilic aromatic substituents
`
`and retained activity. This suggested that the hexa-hydro naphthalene was binding
`
`to the HMG-CoA enzyme receptor via hydrophobic interactions and presenting
`
`the lactone or side chain to the active site of the enzyme, and that a wide variety of
`
`scaffolds which retained activity should be possible. (See generally G.E. Stokker
`
`et al., 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase Inhibitors. 1. Structural
`
`Modification of 5-Substituted 3,5-Dihydroxypentanoic Acids and Their Lactone
`
`Derivatives, 28 J. MEDICINAL CHEMISTRY 347 (1985) (“Stokker I”) (EX 1040);
`
`G.E. Stokker et al., 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase Inhibitors
`
`3. 7-(3,5-Disubstituted [1,1’-biphenyl]-2-yl)-3,5-dihydroxy-6-heptenoic Acids and
`
`Their Lactone Derivatives, 29 J. MEDICINAL CHEMISTRY 170, 175 (1986)
`
`(“Stokker II”) (EX 1041)). Stokker also demonstrated that it was shown that the
`
`HMG-CoA reductase enzyme is very sensitive to the stereochemistry of the side
`
`chain.
`
`(Stokker I at Abstract, 348, 349 and 351). Virtually all of the biological
`
`LEGAL02/35493234v1
`
`22
`
`
`
`Mylan Exhibit 1008, Page 23
`
`
`
`activity was found to reside in the 3(R)-5(S) hydroxy acid (the 4(R)-trans-lactone)
`
`enantiomer present in the natural products. (Id.). The cis- isomers were shown to
`
`be entirely devoid of activity and the 3(S)-5(R)-trans-enantiomer had very little
`
`activity. (Id.).
`
`60.
`
`U.S. Patent No. 4,647,576 (“the Hoefle ’576 patent”) (EX1016),
`
`assigned to Warner-Lambert, was filed December 10, 1984, and published on
`
`March 3, 1987. The Hoefle ’576 patent explained that compounds of the invention
`
`“are potent inhibitors of cholesterol biosynthesis by virtue of their ability to inhibit
`
`the enzyme 3-hydroxy-3-methyl-glutarylcoenzyme A reductase (HMG-CoA
`
`reductase).” (The Hoefle ’576 patent at col. 1, ll. 65-68). This patent preserved
`
`the compactin/mevanolin’s lactone ring, but also modified it by (a) preparing the
`
`compound with an open lactone ring as a side chain; (b) changing the ring system
`
`to a single 5-membered aromatic nitrogen-containing ring; and (c) changing the
`
`side groups:
`
`(See the Hoefle ’576 patent; see generally cols. 2-4).
`
`61.
`
`Compounds highly potent to inhibiting cholesterol synthesis resulted;
`
`the most potent compounds contained 4-fluorophenyl groups and isopropyl groups
`23
`
`LEGAL02/35493234v1
`
`
`
`Mylan Exhibit 1008, Page 24
`
`
`
`flanking the lactone ring/side chain location.
`
`(See the Hoefle ’576 patent
`
`(EX1016) at Table 1, cols. 19-20).
`
`62.
`
`U.S. Patent No. 4,613,610 (“the Wareing ’610 patent”) (EX1018),
`
`assigned to Sandoz, was filed on June 6, 1985, and published on September 23,
`
`1986. The Wareing ’610 patent also asserted the disclosed compounds can be used
`
`for “inhibiting cholesterol biosynthesis and lowering the blood cholesterol level
`
`and, therefore, in the treatment of hyperlipoproteinemia and atherosclerosis.” (The
`
`Wareing ’610 patent at col. 2, ll. 1- 4). Wareing’s compounds differ from Hoefle
`
`’576 patent’s in that Wareing’s 5-membered aromatic nitrogen ring has an
`
`additional nitrogen atom added.
`
`(See the Wareing ’610 patent Cols. 62, 66-67, 80-81).
`
`63.
`
`The Wareing ’610 patent also confirmed to the POSA that the most
`
`potent compounds possessed a 4-fluorophenyl group and an alkyl in the form of an
`
`isopropyl group flanking the open heptenoic acid side chain.
`
`(The Wareing ’610
`
`patent (EX1018) at cols. 53-54 (Test B), 62, 66, 80-81) (showing Examples 3, 7,
`
`LEGAL02/35493234v1
`
`24
`
`
`
`Mylan Exhibit 1008, Page 25
`
`
`
`and 14 were more active than mevinolin). This is, again, consistent with the
`
`pharmacophore noted above.
`
`64.
`
`The European patent 0114027 (“EP ’027
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