Case 1:14-cv-02758-PAC Document 117 Filed 12/19/16 Page 1 of 304
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`UNITED STATES DISTRICT COURT
`SOUTHERN DISTRICT OF NEW YORK
`
`Kowa Company, Ltd., et al.,
`
`Plaintiffs,
`
`v.
`
`Amneal Pharmaceuticals, LLC
`
`Defendant.
`
`Kowa Company, Ltd., et al.,
`
`Plaintiffs,
`
`v.
`
`Zydus Pharmaceuticals (USA) Inc., et al.,
`
`Defendants.
`
`Kowa Company, Ltd., et al.,
`
`Plaintiffs,
`
`v.
`
`Orient Pharma Co., Ltd.,
`
`Defendant.
`
`Kowa Company, Ltd., et al.,
`
`Plaintiffs,
`
`v.
`
`Sawai USA, Inc., et al.,
`
`Defendants.
`
`Civil Action No. 14-CV-2758 (PAC)
`
`Civil Action No. 14-CV-2760 (PAC)
`
`Civil Action No. 14-CV-2759 (PAC)
`
`Civil Action No. 14-CV-5575 (PAC)
`
`

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`Case 1:14-cv-02758-PAC Document 117 Filed 12/19/16 Page 2 of 304
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`Kowa Company, Ltd., et al.,
`
`Plaintiffs,
`
`v.
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`Apotex, Inc., et al.,
`
`Defendants.
`
`Kowa Company, Ltd., et al.,
`
`Plaintiffs,
`
`v.
`
`Lupin Ltd., et al.,
`
`Defendants.
`
`Civil Action No. 14-CV-7934 (PAC)
`
`Civil Action No. 15-CV-3935 (PAC)
`
`PLAINTIFFS’ PROPOSED FINDINGS OF FACT AND CONCLUSIONS OF LAW
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`

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`Case 1:14-cv-02758-PAC Document 117 Filed 12/19/16 Page 3 of 304
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`PLAINTIFFS’ PROPOSED FINDINGS OF FACT
`AND CONCLUSIONS OF LAW
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`[Plaintiffs are surmising, based on discovery, what Defendants’ arguments will be. Plaintiffs
`
`reserve the right to change, amend and/or supplement these proposed findings and conclusions in
`
`light of Defendants’ submissions.]
`
`I.
`
`FINDINGS OF FACT AND CONCLUSIONS OF LAW REGARDING
`INFRINGEMENT OF CLAIMS 1 AND 2 OF THE ‘336 PATENT
`
`1. The ‘336 patent is asserted against the
`
`defendants.
`
`Neither the
`
`defendants filed a 21 U.S.C. §355(j)(2)(b)(vii)(IV) (“Paragraph
`
`IV”) certification with respect to the ‘336 patent.
`
`II.
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`CLINICAL BACKGROUND RELEVANT TO LIVALO®
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`3. The pharmaceutical which all the defendants have initiated the ANDA procedure in order
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`to copy is a compound called pitavastatin calcium, which Kowa markets in the United States
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`under the trademark Livalo®. Livalo® is a drug which inhibits the production of cholesterol by
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`the body by inhibiting the enzyme called HMG-CoA reductase. That enzyme participates in a
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`key step in the synthesis of cholesterol. Livalo® is indicated for treatment of patients as an
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`adjunct therapy to diet to reduce elevated total cholesterol (TC), low-density lipoprotein
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`1
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`Case 1:14-cv-02758-PAC Document 117 Filed 12/19/16 Page 4 of 304
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`cholesterol (LDL-C), apolipoprotein B (Apo B), and triglycerides (TG), and to increase high-
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`density lipoprotein cholesterol (HDL-C).
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`4.
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`In other words, Livalo® reduces levels of “bad” cholesterol (LDL-C) and triglycerides in
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`the blood, as well as other undesirable materials, such as Apo B, while increasing the level of
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`“good” cholesterol (HDL-C). LDL-C is considered bad, because it carries cholesterol to tissues
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`in the body, particularly to the arteries, where it can build up. HDL-C is considered good
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`because it carries cholesterol from the body tissues to the liver, where it is removed.
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`5.
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`Livalo® is a unique statin, with a unique structure which is different from the
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`other statins being marketed, and with unique advantageous properties which makes it
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`particularly useful in treating a variety of different types of patients.
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`6.
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`Pitavastatin calcium, the active ingredient in Livalo®, has the following structure:
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`7. Livalo® has a unique structure, comprising a cyclopropyl group attached to a quinoline
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`core. Livalo® remains the only statin product ever approved by the FDA with a quinoline core,
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`as well as the only statin ever approved by the FDA with a cyclopropyl substituent. The fact that
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`Livalo® is in the form of the calcium salt also provides a number of benefits over other forms.
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`The differences in compound structure leads to surprising advantages provided by Livalo® in
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`treatment of patients.
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`III.
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`SCIENTIFIC BACKGROUND RELEVANT TO THE ‘336 PATENT
`
`2
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`8. Both Plaintiffs (through Dr. Stephen Byrn and Dr. William Roush) and Defendants
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`(through Dr. Milton Brown and Dr. Anthony Palmieri) presented expert testimony regarding the
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`‘336 patent. These experts essentially agreed about certain background scientific concepts of
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`organic and medicinal chemistry as they would have been understood by a person of ordinary
`
`skill in the art (“POSA”) in August 1987 (the priority date advocated by Plaintiffs for the ‘336
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`patent) or August 1988 (the priority date advocated by Defendants for the ‘336 patent).
`
`A.
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`Organic Molecules
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`9. Compounds for pharmaceutical use developed by medicinal chemists are typically
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`organic molecules. In general, organic molecules are carbon-based. In addition to carbon (C),
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`organic molecules typically also contain hydrogen (H), nitrogen (N), oxygen (O), and may also
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`contain other types of atoms.
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`10. When drawing chemical structures, chemists generally omit the “C,” which denotes a
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`carbon atom. Instead, organic and medicinal chemists represent carbon through the terminus or
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`apex of a straight-line drawing. The hydrogen atoms attached to these carbons are also omitted
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`from these drawings. Because carbon forms four bonds, each terminus is assumed to contain the
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`appropriate number of bonded hydrogens to satisfy each carbon’s four-bond requirement.
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`11. Organic molecules often include “substituents” as part of their overall structure. A
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`substituent is an atom, or group of atoms, that is substituted in place of a hydrogen atom on the
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`carbon backbone of an organic molecule, as shown in the hypothetical molecule below:
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`3
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`12. Another shorthand technique used by chemists is to depict single, double, and triple
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`chemical bonds by single, double, and triple lines, respectively.
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`13. The total structure of the organic molecule – which consists of the carbon backbone, the
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`substituents, and the orientation of these components in space relative to one another (referred to
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`as molecular configuration) – determines how the molecule will act in a biological system. The
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`substituents are therefore a critical element of the organic molecule, particularly in medicinal
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`chemistry applications.
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`B.
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`Stereochemistry
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`14. “Stereochemistry” is a branch of chemistry dealing with the configuration of molecules in
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`three-dimensional space.
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`15. Organic chemists use the following terms to describe the structural characteristics of
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`compounds: (a) “isomers” are chemical compounds that have the same molecular formula but
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`different structures (i.e., the number and type of atoms are the same, but the way the atoms are
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`connected to each other is different); (b) “stereoisomers” are chemical compounds that have the
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`same number and type of atoms and identical atomic connectivity but differ in the way in which
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`the atoms are oriented in three-dimensional space; (c) “enantiomers” are pairs of stereoisomers
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`that are non-superimposable mirror image isomers of each other. Enantiomers occur if a
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`molecule contains an asymmetric carbon atom. An asymmetric carbon atom (which is also
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`referred to in the literature as a “chiral” carbon atom) has four different atoms or groups of atoms
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`4
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`attached to it. If two of the substituents attached to a carbon are the same (e.g., two hydrogen
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`atoms), the carbon is said to have a plane of symmetry and therefore cannot be asymmetric; and
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`(d) “diastereoisomers” or “diastereomers” are stereoisomers that are not enantiomers.
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`Diastereomers exist in molecules that contain more than one chiral center.
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`16. Following general conventions of stereochemistry, chemists use the symbols “R” (from
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`the latin rectus, meaning right-handed) and “S” (from the latin sinister, meaning left-handed) to
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`identify asymmetric carbon atoms of molecules based on the spatial arrangement of the atoms
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`around them. These designations describe the absolute configuration of the atoms surrounding
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`each asymmetric carbon atom and are assigned by applying a conventional set of rules.1
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`17. The color figure below shows the structural formula of a molecule that has an asymmetric
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`carbon atom (the carbon atom is depicted as the intersection of the four lines). Each of the four
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`groups attached to the center carbon atom is different, which is necessary for this carbon atom to
`
`be “asymmetric”:
`
`1 Chemists also sometimes use the designations “+” and “-” to identify enantiomers. Unlike “R”
`and “S”, the “+” and “-” designations are not assigned by rules, but instead are used to indicate
`the direction in which the molecule in question rotates plane-polarized light (which is an
`empirical result). The “absolute” three-dimensional configuration of an enantiomer is therefore
`most properly described by the “R” or “S” designation.
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`5
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`18. At each asymmetric carbon center, there are two ways of arranging the attached atoms in
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`three-dimensional space, which results in two mirror image structures. These mirror image
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`structures are known as enantiomers. The two mirror image structures of the molecule shown in
`
`the figure above are depicted in the figure below with the vertical line representing a mirror.
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`Atom “A” projects out of the page toward the reader; this orientation is depicted using a solid
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`wedge. Atom “B” is behind the plane of the page, and is shown using a hatched wedge. Atoms
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`“C” and “D” are in the plane of the page.
`
`19. Because the two molecules shown above are non-superimposable mirror images of each
`
`other (in the same way that our two hands are non-superimposable images of each other), they
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`are enantiomers.
`
`C.
`
`Medicinal Chemistry & Drug Discovery and Development
`
`20. The field of medicinal chemistry involves the application of organic chemistry principles
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`to the design, discovery, identification, and preparation of biologically active compounds. The
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`discovery and development of a new drug is a complex, lengthy, and expensive process, with no
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`guarantee of success. As a consequence, very few new pharmaceutical compounds are approved
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`by the FDA annually. Unpredictability and failure are the common and unfortunate realities of
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`medicinal chemistry as applied to new drug design.
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`6
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`21. The first step in a drug discovery project requires identifying a disease or condition to be
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`treated. This decision requires consideration of numerous factors, including an evaluation of the
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`nature of the disease or condition, its prevalence, and the underlying reasons for the
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`shortcomings of existing therapy.
`
`22. Once a disease or condition has been identified, a strategy is developed. The strategy
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`often focuses on a specific biological target and the role it plays (i.e., its mechanism of action) in
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`relation to the disease or condition. Compounds are sought that may activate or inhibit this
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`biological target.
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`23. Drug molecules exert their effects by interacting with specific biological target
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`molecules, which are often proteins or a specific subset of proteins known as enzymes. (In this
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`case, the target enzyme is HMG-CoA reductase.) Target enzymes are typically much larger than
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`the drug molecules themselves. The specific site on the target enzyme where the drug molecule
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`interacts is frequently referred to as the “binding site,” “active site,” or “binding pocket.”
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`24. The binding sites on biological targets have specific three-dimensional shapes and
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`contain functional groups that may react or interact with the drug molecule. A molecule will not
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`bind well at the binding site unless it has a complementary shape, surface charge distribution,
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`binding groups, and the proper configuration that allow it to fit and bind properly. Conversely,
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`very small changes to the target molecule – whether in atomic constituents, or size, or charge, or
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`three-dimensional structure – can have a significant and unpredictable impact on binding. The
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`relationship between the drug molecule and its target is sometimes analogized to the relationship
`
`between a hand and glove.
`
`25. One methodology that is used by medicinal chemists during drug development is known
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`as a structure-activity-relationship (“SAR”) study. Through these SAR studies, medicinal
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`7
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`chemists aim to correlate changes in a compound’s molecular structure with biological effects.
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`The investigator assesses the biological effect of each structural change and makes further
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`changes to incorporate what the investigator hopes will be favorable features and to avoid
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`potentially deleterious ones. In practice, this process involves extensive trial and error
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`experimentation, with little or no confidence of success.
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`26. Attempts to use SAR strategies to maximize the efficiency of structural variations in a
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`search for a new drug are rarely successful. The lack of predictability in an SAR study is well
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`known to chemists attempting to design a new or improved drug. The consequences of even
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`small structural changes on the multiple pharmacokinetic, biological, and chemical properties
`
`needed in a potential drug candidate are unpredictable. Structural changes – both large and small
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`– can drastically alter not only the affinity of a compound for a receptor or biochemical target,
`
`but also other factors such as absorption, distribution, metabolism and excretion. Given the
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`myriad factors that influence drug action, a medicinal chemist cannot with any confidence have a
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`reasonable expectation of success, in advance, as to what effect a given structural change will
`
`have on the overall properties of a compound.
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`27. There are many examples of compounds that have “similar” structures, but significantly
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`different biological actions and activities. For example, methanol (CH3OH) is very toxic,
`
`resulting in blindness and death. In contrast, ethanol (CH3CH2OH), which is also called
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`“alcohol,” is not highly toxic when consumed in moderation, and is used recreationally. Yet
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`methanol and ethanol differ only by a single methylene (–CH2–) group.
`
`28. Similarly, the hormones testosterone and progesterone (shown below) perform extremely
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`different biological functions despite possessing very “similar” chemical structures (the only
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`difference is in the upper right-hand corner of the molecule, where testosterone has a hydroxyl
`
`8
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`Case 1:14-cv-02758-PAC Document 117 Filed 12/19/16 Page 11 of 304
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`group and progesterone an acetyl group). Testosterone plays a key role as a male sex hormone
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`that is involved in promoting increased muscle, bone mass, and body hair growth. In contrast,
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`progesterone plays a key role as a female hormone and is involved in the female menstrual cycle,
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`pregnancy and embryogenesis:
`
`O
`
`O
`
`Testosterone
`
`Progesterone
`
`29. Further, chemical substituents do not act independently. It is often the complex and
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`unpredictable interaction of a molecule’s core and substituents that provides the unique
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`characteristics of similar but still structurally different compounds. The same substituent that
`
`appears beneficial when introduced onto one molecular scaffold may well prove to lack benefit
`
`or be deleterious when introduced onto a different scaffold. A medicinal chemist cannot predict
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`the particular properties of an as-yet untested molecule containing certain structural components
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`based solely on information about each of those structural components in isolation.
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`30. If the structure of an enzyme or protein target is not known (as was the case for HMG-
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`CoA reductase in the late 1980s), the medicinal chemist is essentially operating in the dark.
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`Even when the structure of an enzyme or receptor target is known, it remains a very difficult and
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`complex problem to design and develop a compound to function as a drug using structure-based
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`design principles. The binding of a small molecule to a biological target is a complex process
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`that may involve hydrophobic, polar, and hydrogen bonding interactions on the three-
`
`dimensional binding site. Small changes in the structure of the drug candidate can disrupt
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`9
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`Case 1:14-cv-02758-PAC Document 117 Filed 12/19/16 Page 12 of 304
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`binding by causing the molecule to position differently in the active site. These changes in
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`binding are not easily predicted even with today’s state of the art computational methods, and
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`were far less predictable in the late 1980s.
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`31. The development of a clinical drug candidate involves far more than simply obtaining a
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`compound that has activity against a particular biological target. A drug candidate must satisfy
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`many biological, pharmacological, and physicochemical characteristics before it can reach the
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`clinical trial stage. Each of these characteristics depends on the structure of the molecule, and
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`each can only be determined after extensive evaluation.
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`32. Even when a compound appears to have all of the characteristics desired of a clinical
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`candidate, there is no assurance it will prove to be a safe and effective drug in clinical trials. As
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`a result, only a small fraction of compounds that enter clinical trials ultimately receive FDA
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`approval.
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`IV.
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`NISSAN’S DISCOVERY OF THE NOVEL COMPOUND NOW
`KNOWN AS PITAVASTATIN
`
`33. Nissan began exploratory research on synthetic HMG-CoA reductase inhibitors
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`beginning in late 1986. [PTX-0144, at KN000852821.]
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`10
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`Case 1:14-cv—02758—PAC Document 117 Filed 12/19/16 Page 13 of 304
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`11
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`40. Livalo® is the only FDA-approved statin containing a quinoline core, as well as the only
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`FDA-approved statin containing a cyclopropyl group.
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`41. The unexpected impact of the cyclopropyl group, which provides, among other things
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`enhanced activity against HMG-CoA reductase, was detailed during prosecution of the ‘336
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`patent, including in the June 18, 1992 declaration of Masaki Kitahara, one of the inventors of the
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`‘336 patent. [PTX-0133, at KN001333489-492.].
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`12
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`Case 1:14-cv-02758-PAC Document 117 Filed 12/19/16 Page 15 of 304
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`V.
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`PERSON OF ORDINARY SKILL IN THE ART
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`42. A person of ordinary skill in the art (“POSA”) for purposes of the ‘336 patent would have
`
`had either a Ph.D. degree in organic or medicinal chemistry coupled with several years of
`
`experience in that field, or a lesser degree (e.g., a Master’s degree or a Bachelor’s degree)
`
`coupled with greater experience. Such a POSA would also have had some general knowledge of
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`biochemistry.
`
`43. Plaintiffs’ expert, Dr. Stephen R. Byrn, is personally familiar, through extensive
`
`experience, with the science and practice of organic and medicinal chemistry, the relevant scope
`
`and content of the prior art, and the capabilities of a person of ordinary skill in the art.
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`44. Dr. Byrn received his Ph.D. in chemistry from the University of Illinois in 1970 and was
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`a post-doctoral fellow at UCLA from 1970 to 1972. After his post-doctoral fellowship, Dr. Byrn
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`joined the pharmacy faculty at Purdue University. Since 1994 he has been the head of the
`
`department of Industrial and Physical Pharmacy at Purdue University, and he currently holds the
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`title of Charles B. Jordan Professor of Medicinal Chemistry. From 1988 to 1994 he was the head
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`of Purdue’s department of Medicinal Chemistry and Pharmacognoscy in the School of Pharmacy
`
`and Pharmaceutical Sciences. From 1988 to 1998 he was also the director of the Center for
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`AIDS Research at Purdue. He has extensive knowledge of, and experience in, chemistry,
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`pharmaceutical formulation, and the solid-state properties of pharmaceutical drugs.
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`45. The Court finds that Dr. Byrn is qualified to express an opinion on organic and medicinal
`
`chemistry.
`
`46. Plaintiffs’ expert, William R. Roush, is personally familiar, through extensive
`
`experience, with the science and practice of organic and medicinal chemistry, the relevant scope
`
`and content of the prior art, and the capabilities of a person of ordinary skill in the art.
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`13
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`47. Dr. Roush received his Ph.D. in Chemistry from Harvard University in 1977. After
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`conducting post-doctoral work at Harvard, he joined the faculty at the Massachusetts Institute of
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`Technology, where he served from 1978 to 1987. In 1987 he moved to Indiana University,
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`where he became Distinguished Professor of Chemistry. In 1997 he was appointed the Warner-
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`Lambert/Parke-Davis Professor of Chemistry at the University of Michigan, and subsequently
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`served as the Chairman of the Department of Chemistry at the University of Michigan from
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`2002–2004. In 2004 he was recruited to join the Scripps Research Institute at its new campus in
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`Florida, where he assumed three positions in 2005: Executive Director of Medicinal Chemistry,
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`Professor of Chemistry, and Associate Dean of the Graduate Program.
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`48. Dr. Roush’s research interests at Scripps include organic and medicinal chemistry
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`projects focusing on development of agonists and antagonists of nuclear receptors, development
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`of inhibitors of enzyme targets, and development of inhibitors of transporters responsible for
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`active transport of molecules into and out of cells.
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`49. The Court finds that Dr. Roush is qualified to express an opinion on organic and
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`medicinal chemistry.
`
`VI.
`
`THE CLAIMS OF THE ‘336 PATENT
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`50. The ‘336 patent, entitled “Quinoline Type Mevalonolactones,” is directed to novel HMG-
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`CoA reductase inhibitors (statin compounds) having a quinoline core, along with synthetic
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`methods for making these compounds and methods for using them as pharmaceutical agents.
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`[PTX-0142.]
`
`51. Claim 1 of the ‘336 patent claims a compound is depicted below as Formula [A]:
`
`14
`
`

`

`[Id. at col. 32, ll. 22-36.]
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`52. If one connects the “Z” sidechain depicted in Formula [A] to the rest of the molecule, the
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`chemical structure of claim 1 of the ‘336 patent can be depicted as shown below:
`
`15
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`

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`16
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`Case 1:14-cv-02758-PAC Document 117 Filed 12/19/16 Page 19 of 304
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`condition for allowance. [PTX-0133, at KN001333506.] However, further prosecution was
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`suspended by the Examiner “due to a potential interference.” [Id.]
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`58. An interference relating to quinoline-type mevalonolactones was initially declared
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`between Nissan (first named inventor “Fujikawa”), Sandoz (first named inventor “Wattanasin”),
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`and Warner-Lambert (first named inventor “Picard”). [PTX-0138, at KN000844134.] All three
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`companies had been conducting research on quinoline-core statin molecules as potential HMG-
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`CoA reductase inhibitors.
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`59. Picard subsequently filed a request for adverse judgment (and adverse judgment was
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`entered against it by the Patent Board), after which the interference went forward as to Nissan
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`and Sandoz only. [PTX-0138, at KN000844134.]
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`60. During the interference, Nissan was unsuccessful in its attempts to add “counts” to the
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`interference corresponding to the cyclopropyl-containing quinoline compounds described in the
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`‘336 patent. [PTX-0138 (Board Decision), at KN000844136-141; PTX-0140 (Federal Circuit
`
`Decision), at KN000844237-238.] The Patent Board and the Federal Circuit (on appeal) both
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`recognized Nissan’s cyclopropyl claims as distinct from Sandoz’s claimed invention. [Id.]
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`61. As a direct result of the interference, Sandoz was granted priority with regard to claims
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`directed toward a broad genus of quinoline-core mevalonolactones. [PTX-0138, at
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`KN000844156.] These claims matured into U.S. Patent No. 5,753,675 to Wattanasin, which is
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`listed on the face of the ‘336 patent, and was considered by the Examiner during prosecution of
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`the ‘336 patent. [PTX-0142 (first page); PTX-0133, at KN001333521 (Notice of References
`
`Cited).]
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`62. As an indirect result of the interference, and the Patent Board’s decision not to permit
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`Nissan to add a cyclopropyl count, Nissan was granted priority with regard to claims directed
`
`17
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`Case 1:14-cv-02758-PAC Document 117 Filed 12/19/16 Page 20 of 304
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`toward 2-cyclopropyl quinoline compounds (as in the ‘336 patent). [PTX-0138, at
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`KN000844136-141; PTX-0140, at KN000844237-238.]
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`63. The ‘336 patent issued on January 5, 1999, after resolution of the interference
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`proceedings and after the Examiner again determined that the claims were in a condition for
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`allowance. [PTX-0133, at KN00133513-521.]
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`VIII. PRIORITY DATE
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`64. The ‘336 patent claims the benefit of Japanese Patent Application JP-62-207224 (“JP
`
`‘224”), which was filed on August 20, 1987. [PTX-0345.]
`
`A.
`
`Priority for Claim 1 of the ‘336 Patent
`
`65. JP ‘224 disclosed novel mevalonolactone derivatives and methods for making and using
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`the same. In particular, JP ‘224 disclosed quinoline-type mevalonolactones and derivatives
`
`represented by the following Formula I:
`
`[PTX-0345, at 1, 3.]
`
`66. JP ‘224 also disclosed a related Formula I-2, which is reproduced below:
`
`18
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`Case 1:14-cv-02758-PAC Document 117 Filed 12/19/16 Page 21 of 304
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`[Id. at 7, 11.]
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`67. Formula I-2 depicted five positions – designated R1 through R5 – in which chemical
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`substituents on the molecule could be varied. Table 1 of JP ‘224 further disclosed what some of
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`these R1-R5 substituents could be. The 4th row from the end of Table 1 disclosed the same five
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`substituents found in claim 1 of the ‘336 patent:
`
`19
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`

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`[Id. at 11-12.]
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`68. This highlighted compound can be depicted as follows:
`
`F
`
`N
`
`OH OH
`
`O
`
`OH
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`69. This corresponds to the same compound as that depicted in claim 1 of the ‘336 patent, in
`
`its carboxylic acid form instead of its calcium salt form:
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`20
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`Case 1:14-cv-02758-PAC Document 117 Filed 12/19/16 Page 23 of 304
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`[ . . .]
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`[ . . .]
`
`[Id. at 1-2, 4-5.]
`
`71. Based on this disclosure, R12 could be either hydrogen (yielding the carboxylic acid
`
`compounds of Formula I-2) or a “physiologically hydrolyzable alkyl” (yielding ester derivatives
`
`of Formula I-2) or “M” (yielding salt derivatives of Formula I-2). “M”, in turn, could be an
`
`amine salt or a metal salt, specifically, “a metal capable of forming a salt which is
`
`pharmaceutically acceptable.” Such metal salts could include, “for example, sodium and
`
`potassium.” [Id. at 5 (emphasis added).]
`
`72. Calcium would have been understood by a POSA in 1987 to be a pharmaceutically
`
`acceptable metal salt. [PTX-0332, at 2 and Table I; PTX-0333, at 202 and Table 1.].
`
`21
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`Case 1:14-cv-02758-PAC Document 117 Filed 12/19/16 Page 24 of 304
`
`B. Priority for Claim 2 of the ‘336 Patent
`
`73. Claim 2 of the ‘336 patent recites “a method for reducing hyperlipidemia,
`
`hyperlipoproteinemia or atherosclerosis, which comprises administering an effective amount of
`
`the compound of formula A as defined in claim 1.” [PTX-0142, at col. 32:37-40.]
`
`74. JP ‘224 specifically disclosed the following with respect to the properties of its novel
`
`quinoline compounds:
`
`The compounds of the present invention exhibit high inhibitory activities against
`the cholesterol biosynthesis wherein HMG-CoA reductase acts as a rate limiting
`enzyme, as shown by the test results given hereafter, and thus are capable of
`suppressing or reducing the amount of cholesterol. Thus, the compounds of the
`present invention are useful as curing agents against hyperlipoproteinemia and
`atherosclerosis.
`
`[PTX-0345, at 13.]
`
`IX.
`
`CLAIMS 1 AND 2 OF THE ‘336 PATENT WOULD NOT HAVE
`BEEN OBVIOUS UNDER 35 U.S.C. § 103
`
`A.
`
`Scope and Content of Alleged Prior Art (Quinoline-Core HMG-CoA
`Reductase Inhibitors)
`
`75. U.S. Patent No. 4,761,419 to Picard et al. (“the ‘419 patent” or “Picard”) was filed in the
`
`United States on December 7, 1987, and issued on August 8, 1988. [PTX-0352.] Picard was not
`
`publically available prior to the earliest foreign priority date of the ‘336 patent (August 20,
`
`1987).
`
`76. Picard provided a Table 1 showing the in vitro inhibitory activity of two quinoline-core
`
`compounds with respect to HMG-CoA reductase. [PTX-0352, at col. 11-12.] The inhibitory
`
`activity of these compounds, measured in terms of IC50,2 was found to be 350 nanomolar for the
`
`2 IC50 is the molar concentration of compound at which 50% inhibition of the target enzyme is
`achieved. [PTX-0326, at col. 33:44-47.] The lower the IC50 value, the lower the amount of
`22
`
`

`

`Case 1:14-cv-02758-PAC Document 117 Filed 12/19/16 Page 25 of 304
`
`first compound, and 32 nanomolar for the second. [Id.] These compounds were considerably
`
`different from the compound of claim 1 of the ‘336 patent: both of the Picard Table 1
`
`compounds have a 6-chloro substituent on the quinoline ring (the ‘336 patent does not), whereas
`
`neither of the Picard Table 1 compounds have a cyclopropyl substituent on the quinoline ring
`
`(the ‘336 patent does). [Id.]
`
`77. Example 3 of Picard also showed two compounds that were different from those shown
`
`in Table 1 of Picard. [PTX-0352, at col. 17:48-65.] No IC50 data was provided for the
`
`compounds of Picard Example 3.
`
`78. U.S. Patent No. 4,925,852 to Kesseler et al. (“the ‘852 patent” or “Kesseler”) was filed in
`
`the United States on July 8, 1988, and issued on May 15, 1990. [PTX-0353.] Kesseler was not
`
`publically available prior to the earliest foreign priority date of the ‘336 patent (August 20,
`
`1987), or even the August 3, 1988 priority date advocated by Defendants.
`
`Wattanasin and/or Sandoz Compound 64-
`
`935 appeared in an interference declaration executed by Dr. Sompong Wattanasin of Sandoz
`
`Pharmaceuticals Corporation on November 13, 1992 (“the November 13, 1992 Wattanasin
`
`Declaration”). [PTX-0136, at KN000840502.] That declaration was not publically available
`
`compound required to achieve 50% inhibition, and thus the more potent the activity of the
`compound.
`
`23
`
`

`

`Case 1:14-cv-02758-PAC Document 117 Filed 12/19/16 Page 26 of 304
`
`prior to any filing date associated with the ‘336 patent, let alone the earliest foreign priority date
`
`of August 20, 1987.
`
`81. Wattanasin/Sandoz Compound 64-935 was reported to have an IC50 of 413 nanomolar
`
`with respect to HMG-CoA reductase. [PTX-0138, at KN000844150.]
`
`82.
`
`Wattanasin and/or Sandoz Compound 64-
`
`936 also appeared in the November 13, 1992 Wattanasin Declaration. [PTX-0136, at
`
`KN000840502.]
`
`83. Wattanasin/Sandoz Compound 64-936 was reported to have an IC50 of 530 nanomolar
`
`with respect to HMG-CoA reductase. [PTX-0138, at KN000844150.]
`
`84. The same November 13, 1992 Wattanasin Declaration in which Wattanasin/Sandoz
`
`Compounds 64-935 and 64-936 are identified indicated that Sandoz researchers never planned to
`
`make a quinoline-core HMG-CoA reductase inhibitor with a cyclopropyl group substituted at the
`
`2-position of the quinoline core. [PTX-0136, at KN000840470.]
`
`85. U.S. Patent No. 5,753,675 to Wattanasin (“the ‘675 patent” or “Wattanasin”) was filed in
`
`the United States on March 23, 1990, and issued on May 19, 1998. [PTX-0223.] Wattanasin
`
`was not publically available prior to the earliest foreign priority date of the ‘336 patent (August
`
`20, 1987), or even the August 3, 1988 priority date advocated by Defendants.
`
`86. Wattanasin is cited on the face of the ‘336 Patent. [PTX-0142 (first page).]
`
`87. Wattanasin showed a generic quinoline-core HMG-CoA reductase inhibitor with at least
`
`500 different possibilities for substituents. [PTX-0223, at col.1:7-34;
`
`]
`
`88. Wattanasin provided synthetic examples of various quinoline-core HMG-CoA reductase
`
`inhibitors, none of which contained a cyclopropyl group. [PTX-0223, at cols. 22-34.]
`
`24
`
`

`

`Case 1:14-cv-02758-PAC Document 117 Filed 12/19/16 Page 27 of 304
`
`89. Example 3C in Wattanasin has the same chemical structure as
`
`[Compare PTX-0223, at col. 32:56-65 with PTX-
`
`0136, at KN000840502.]
`
`90. Example 3D in Wattanasin has the same chemical structure as
`
`[Compare PTX-0223, at col. 33:1-11 with PTX-
`
`0136, at KN000840502.]
`
`91. German patent application DE 3905908 (“DE ‘908”) was published on September 6,
`
`1990. [PTX-0320.] DE ‘908 was not publically available prior to the earliest foreign priority
`
`date of the ‘336 patent (August 20, 1987), or even the August 3, 1988 priority date advocated by
`
`Defendants.
`
`92. The compounds labeled “I-51” and “I-520” in the various declarations of Masaki
`
`Kitahara correspond to compounds bearing the same labels in the ‘336 patent. [PTX-0142, at
`
`col. 14:10; 15:5-23; 17:62-18:7; 28:61-64 and Table 11.] Compound I-51
`
`and Compound I-520
`
`were synthesized and tested by
`
`researchers at Nissan. [PTX-0233, at KN001910087.] They are not “prior art” compounds with
`
`respect to the ‘336 patent.
`
`93. The State of Scientific Research on HMG-CoA Red