Case 1:14-cv-02758-PAC Document 108 Filed 12/16/16 Page 1 of 52
`
`UNITED STATES DISTRICT COURT
`SOUTHERN DISTRICT OF NEW YORK
`
`
`Kowa Company, Ltd.,
`Kowa Pharmaceuticals America, Inc., and
`Nissan Chemical Industries, Ltd.,
`
`
`Plaintiffs,
`
`v.
`
`Civil Action No. 14-CV-2758 (PAC)
`
`Amneal Pharmaceuticals, LLC,
`
`
`Defendants.
`
`Kowa Company, Ltd.,
`Kowa Pharmaceuticals America, Inc., and
`Nissan Chemical Industries, Ltd.,
`
`
`Plaintiffs,
`
`v.
`
`Civil Action No. 14-CV-2760 (PAC)
`
`Zydus Pharmaceuticals (USA) Inc., and Cadila
`Healthcare Ltd. (dba Zydus Cadila),
`
`
`Defendants.
`
`
`
`i
`
`

`

`Case 1:14-cv-02758-PAC Document 108 Filed 12/16/16 Page 2 of 52
`
`
`
`Civil Action No. 14-CV-2759 (PAC)
`
`Civil Action No. 14-CV-5575 (PAC)
`
`Kowa Company, Ltd.,
`Kowa Pharmaceuticals America, Inc., and
`Nissan Chemical Industries, Ltd.,
`
`
`Plaintiffs,
`
`v.
`
`Orient Pharma Co., Ltd.,
`
`
`Defendants.
`
`
`Kowa Company, Ltd.,
`Kowa Pharmaceuticals America, Inc., and
`Nissan Chemical Industries, Ltd.,
`
`
`Plaintiffs,
`
`
`v.
`
`Sawai USA, Inc., and
`Sawai Pharmaceutical Co., Ltd.,
`
`
`Defendants.
`
`
`
`ii
`
`
`

`

`Case 1:14-cv-02758-PAC Document 108 Filed 12/16/16 Page 3 of 52
`
`
`
`Kowa Company, Ltd.,
`Kowa Pharmaceuticals America, Inc., and
`Nissan Chemical Industries, Ltd.,
`
`
`Plaintiffs,
`
`
`v.
`
`Apotex, Inc. and Apotex Corp.,
`
`
`Defendants.
`
`
`Kowa Company, Ltd.,
`Kowa Pharmaceuticals America, Inc., and
`Nissan Chemical Industries, Ltd.,
`
`
`Plaintiffs,
`
`
`v.
`
`Lupin Ltd. and Lupin Pharmaceuticals, Inc.,
`
`
`Defendants.
`
`
`
`Civil Action No. 14-CV-7934 (PAC)
`
`Civil Action No. 15-CV-3935 (PAC)
`
`
`
`DEFENDANTS’ PROPOSED FINDINGS AND CONCLUSIONS RE:
`
`ANTICIPATION AND OBVIOUSNESS OF ASSERTED “FORM A” CLAIMS
`
`iii
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`

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`Case 1:14-cv-02758-PAC Document 108 Filed 12/16/16 Page 4 of 52
`Case 1:14-cv—02758—PAC Document 108 Filed 12/16/16 Page 4 of 52
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`
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`PRESENTED BY ALL DEFENDANTS
`PRESENTED BY ALL DEFENDANTS
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`iv
`iV
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`

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`Case 1:14-cv-02758-PAC Document 108 Filed 12/16/16 Page 5 of 52
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`
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`
`
`TABLE OF CONTENTS
`
`DEFENDANTS’ PROPOSED FINDINGS AND CONCLUSIONS RE: ..................................... i 
`
`ANTICIPATION AND OBVIOUSNESS OF ASSERTED “FORM A” CLAIMS .................... iii 
`
`I. 
`
`PROPOSED FINDINGS OF FACT REGARDING ANTICIPATION AND
`OBVIOUSNESS OF THE ’993 PATENT UNDER 35 U.S.C. §§ 102 & 103 ................. 1 
`
`A. 
`
`The ’993 Patent and Its Asserted Claims .............................................................. 1 
`
`1. 
`
`2. 
`
`Specification of the ’993 Patent ................................................................ 2 
`
`Prosecution History of the ’993 Patent ..................................................... 4 
`
`B. 
`
`Technological Background ................................................................................... 7 
`
`1. 
`
`2. 
`
`3. 
`
`4. 
`
`5. 
`
`The Person of Ordinary Skill in the Art of the ’993 Patent ...................... 7 
`
`X-Ray Diffraction (“XRD”) Technology Used in the Patent ................... 8 
`
`Polymorphism in Drug Discovery .......................................................... 11 
`
`Routine Crystallization Screening .......................................................... 12 
`
`Pitavastatin and Other Crystalline Statins Known in the Prior
`Art ........................................................................................................... 14 
`
`C. 
`
`EP ’406 and Nissan’s “Third Party Observation” regarding EP ’406 ................ 15 
`
`1. 
`
`Published European Patent Application No. 0,520,406
`(“EP ’406”) ............................................................................................. 15 
`
`(a) 
`
`Plaintiff Nissan’s Prior Admission and Insistence that
`Example 3 of EP ’406 “Inevitably, Directly and
`Unambiguously” teaches the Claimed Form A ............................ 16 
`
`(b)  Nissan Acquired the ’232.7 Application, and then
`Attempted to Disavow its own Evidence That Example
`3 of EP ’406 Produces Form A ..................................................... 18 
`
`(c)  Nissan’s Original Representations to the EPO in
`December 2006 Accurately Reflected Its Internally
`Documented Results ..................................................................... 21 
`
`(d)  Defendants’ Experts Confirmed Nissan’s Evidence that
`EP ’406 Inevitably Produces Form A ........................................... 23 
`
`i
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`

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`Case 1:14-cv-02758-PAC Document 108 Filed 12/16/16 Page 6 of 52
`
`(i) 
`
`(ii) 
`
`Dr. Roberts Confirmed Nissan’s Conclusion that
`the Product Obtained Was Form A ................................... 24 
`
`Dr. Sessler Confirmed that Nissan Faithfully
`Followed the Procedures of EP ’406 Example 3 .............. 28 
`
`(e) 
`
`Plaintiffs’ Experts Did Not Replicate Example 3 of
`EP ’406.......................................................................................... 30 
`
`2. 
`
`Additional Prior Art Relating to Form A Of Pitavastatin
`Calcium Salt ............................................................................................ 31 
`
`(a)  The WO ’392 Publication ............................................................. 31 
`
`(b)  The WO ’382 Publication ............................................................. 32 
`
`(c) 
`
`Suzuki 1999 .................................................................................. 34 
`
`II. 
`
`PROPOSED CONCLUSIONS OF LAW REGARDING ANTICIPATION
`AND OBVIOUSNESS OF THE ’993 PATENT UNDER 35 U.S.C. §§ 102
`& 103 .............................................................................................................................. 34 
`
`A. 
`
`Claims 1-2, 22-25 of the ’993 Patent Are Anticipated by EP ’406 .................... 34 
`
`1. 
`
`2. 
`
`Anticipation: The Legal Standard .......................................................... 34 
`
`Holding and Analysis .............................................................................. 35 
`
`(a)  EP ’406 Inherently Anticipates the Form A Claims
`(claims 1, 3-25) ............................................................................. 36 
`
`(b)  EP ’406 Inherently Anticipates the Pharmaceutical
`Composition Claim (claim 22)...................................................... 39 
`
`B. 
`
`Even if Not Anticipated by EP ’406, Claims 1, 22-25 of the ’993
`Patent Are Obvious in Light of EP ’406 and the Prior Art ................................. 41 
`
`1. 
`
`2. 
`
`Obviousness: The Legal Standard ......................................................... 41 
`
`Holding and Analysis .............................................................................. 41 
`
`(a)  The Form A Claims (claims 1, 23-25) Are Obvious In
`Light of EP ’406 or WO ’392 and the Prior Art ........................... 41 
`
`(b)  The Pharmaceutical Composition Claim (claim 22) is
`Obvious in Light of EP ’406 and the Prior Art ............................. 44 
`
`
`
`
`
`ii
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`

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`Case 1:14-cv-02758-PAC Document 108 Filed 12/16/16 Page 7 of 52
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`I.
`
`PROPOSED FINDINGS OF FACT REGARDING ANTICIPATION AND
`OBVIOUSNESS OF THE ’993 PATENT UNDER 35 U.S.C. §§ 102 & 103
`
`A.
`
`1.
`
`The ’993 Patent and Its Asserted Claims
`
`The ’993 patent purports to relate to “crystalline forms and the amorphous form
`
`of Pitavastatin calcium, processes for the preparation thereof and pharmaceutical compositions
`
`comprising these forms.” (DTX-1307, the ’993 patent at 1:17-20 (MYLAN(Pitav)009848).) The
`
`’993 patent discloses that “Pitavastatin calcium is known by the chemical name: (3R,5S)-7-[2-
`
`cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptenoic acid hemicalcium
`
`salt.” (Id. at 1:24-26 (MYLAN(Pitav)009848).) Accordingly, it is understood that “pitavastatin
`
`calcium” means the same things as “pitavastatin hemicalcium.”
`
`2.
`
`The ’993 patent issued on October 15, 2013, from U.S. Patent Application No.
`
`13/664,498, which was filed on October 31, 2012. The ’993 patent claims priority to PCT
`
`Application No. PCT/EP2004/050066. (Id. at MYLAN(Pitav)009837), which was assigned
`
`European Patent Application No. 04707232.7 (“EP ’232”) upon entry into the national phase in
`
`Europe. (DTX-1327 at MYLAN(Pitav)059991 (EP ’232 File History).) The earliest priority date
`
`to which the ’993 patent claims entitlement is February 12, 2003. The assignee and owner of the
`
`patent is Plaintiff Nissan Chemical Industries, Ltd. (“Nissan”).
`
`3.
`
`Claims 1 and 22-23 are directed to several different polymorphic forms of
`
`pitavastatin hemicalcium salt – identified as Forms A, B, C, D, E, F or the amorphous form.
`
`With respect to Form A, claim 1 claims:
`
`1. A crystalline polymorph A, B, C, D, E, F, or the amorphous
`form, of [pitavastatin calcium] salt wherein
`A) polymorph A exhibits a characteristic X-ray powder
`diffraction pattern with characteristic peaks expressed in 2θ at
`5.0 (s), 6.8 (s), 9.1 (s), 10.0 (w), 10.5 (m), 11.0 (m), 13.3 (vw),
`13.7 (s), 14.0 (w), 14.7 (w), 15.9 (vw), 16.9 (w), 17.1 (vw), 18.4
`
`
`
`1
`
`

`

`Case 1:14-cv-02758-PAC Document 108 Filed 12/16/16 Page 8 of 52
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`
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`(m), 19.1 (w), 20.8 (vs), 21.1 (m), 21.6 (m), 22.9 (m), 23.7 (m),
`24.2 (s), 25.2 (w), 27.1 (m), 29.6 (vw), 30.2 (w), 34.0 (w)…
`wherein, for each of said polymorphs, (vs) stands for very strong
`intensity; (s) stands for strong intensity; (m) stands for medium
`intensity; (w) stands for weak intensity; (vw) stands for very
`weak intensity.
`(DTX-1307 at 10:50-11:37.)
`
`4.
`
`Claims 22 and 23 each depend from claim 1. Claim 22 claims “[a]
`
`pharmaceutical composition comprising an effective amount of the crystalline polymorph or
`
`amorphous form according to claim 1, and a pharmaceutically acceptable carrier.” (Id. at 13:7-
`
`10.) Claim 23 claims crystalline polymorphs A, B, C, D, E, F or the amorphous form of
`
`[pitavastatin calcium] “wherein polymorph A has an X-ray powder diffraction pattern
`
`substantially as depicted in FIG. 1” of the patent, and “the amorphous form has an X-ray powder
`
`diffraction pattern substantially as depicted in FIGS. 7A and 7B” of the patent. (Id. at 13:11-25.)
`
`5.
`
`Claims 24 and 25 are effectively the same as claims 1 and 23, respectively, only
`
`specifically directed to form A. Claim 24 claims form A pitavastatin calcium exhibiting the
`
`same characteristic x-ray powder diffraction peaks recited in claim 1 for form A. (Id. at 13:26-
`
`37.) Claim 25 claims form A pitavastatin calcium “having an X-ray powder diffraction pattern
`
`substantially as depicted in FIG. 1.” (Id. at 13:38-41.)
`
`In this case, Plaintiffs assert against Amneal, Apotex, Orient, and Sawai only claims 1
`
`and 22-25. Of those claims, Plaintiffs assert only claims 1, 22 and 23 against Lupin and Zydus.
`
`1.
`
`Specification of the ’993 Patent
`
`6.
`
`The ’993 patent discloses that pitavastatin calcium, and processes for its
`
`preparation, were known in the art by 2003. (DTX-1307, the ’993 patent at 1:43-67
`
`(MYLAN(Pitav)009848).) For example, the ’993 patent discloses:
`
`2
`
`
`

`

`Case 1:14-cv-02758-PAC Document 108 Filed 12/16/16 Page 9 of 52
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`
`
`A full synthetic procedure for the preparation of Pitavastatin
`calcium is described in EP-A-0520406. In the process described in
`this patent Pitavastatin calcium is obtained by precipitation from
`an aqueous solution as a white crystalline material with a melting
`point of 190-192 C.
`(Id. at 1:62-67 (MYLAN(Pitav)009848).)
`7.
`The ’993 patent also discloses that “[i]t is known that pharmaceutical substances
`
`can exhibit polymorphism,” which it defines as “the ability of any substance to have two or more
`
`different crystal structures.” (DTX-1307, the ’993 patent at 1:67-2:3 (MYLAN(Pitav)009848).)
`
`8.
`
`The ’993 patent recognizes that “[d]rug substances may also encapsulate solvent
`
`molecules when crystallized,” which may form solvates or hydrates and also refers to the
`
`amorphous form. (DTX-1307, the ’993 patent at 2:3-6 (MYLAN(Pitav)009848).) Additionally,
`
`the ’993 patent recognizes that polymorphs, hydrates, solvates and the amorphous forms may
`
`have different physical properties, such as melting points and solubility. (Id. at 2:6-8
`
`(MYLAN(Pitav)009848).)
`
`9.
`
`The ’993 patent also purports to describe processes for the preparation of the
`
`various alleged polymorphic forms of pitavastatin calcium claimed. For example, the ’993
`
`patent explains that:
`
`Form A can be generally prepared from Pitavastatin sodium
`upon reaction with CaCl2 in an aqueous reaction medium. .
`. . The aqueous reaction medium usually contains at least
`80% b.w. of water; preferably it is water or water
`containing minor amounts of solvents and/or reactants from
`previous steps.
`(DTX-1307, the ’993 patent at 6:4-14 (MYLAN(Pitav)009850).) The ’993 patent provides one
`
`example that allegedly can be used to prepare Form A as claimed by the ’993 patent:
`
`3
`
`
`

`

`Case 1:14-cv-02758-PAC Document 108 Filed 12/16/16 Page 10 of 52
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`
`
`
`
`(Id. at 8:27-53 (Example 1) (MYLAN(Pitav)009851).)
`10.
`All other examples in the ’993 patent are directed to the alleged preparation of
`
`Forms B-F and the amorphous form, as defined by the ’993 patent, and rely upon various
`
`recrystallizations of Form A. (DTX-1307, the ’993 patent at 8:55–10:30 (Examples 2-9)
`
`(MYLAN(Pitav)009851-52).) With respect to recrystallization, the ’993 patent employs several
`
`common solvents to recrystallize pitavastatin calcium, including for example isopropanol,
`
`acetone, ethanol and methanol. (See id. at 8:55–10:30 (MYLAN(Pitav)009851-52).)
`
`2.
`
`Prosecution History of the ’993 Patent
`
`11.
`
`The prosecution history of the ’993 patent reflects that it issued as a result of the
`
`Examiner’s explicit error as to the closest prior art. The history also reflects that Nissan was
`
`aware of the true closest prior art, because that particular reference was a published application
`
`4
`
`
`

`

`Case 1:14-cv-02758-PAC Document 108 Filed 12/16/16 Page 11 of 52
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`
`
`belonging to Nissan. Despite its knowledge of the truth, however, Nissan did nothing to alert the
`
`Examiner or correct the record. Accordingly, the ‘993 patent issued without the Examiner
`
`having even recognized the closest prior art of Nissan’s own published application.
`
`12.
`
`Specifically, the Examiner found that the closest prior art disclosed pitavastatin
`
`sodium – as opposed to the claimed pitavastatin calcium. (DTX-247 at KN001335152.) In her
`
`first and only office action, the Examiner stated:
`
`The closest art [are] US Patents 5011930, 5856336 and 5872130
`which disclose the compound pitavastatin sodium and how it is
`made.
`
`However, the hemicalcium salt or its amorphous or crystalline
`forms are not disclosed.
`(Id. at KN001335152 (emphasis added).)
`
`13.
`
`The Examiner’s conclusion ignored the express statements about the prior art in
`
`the ’993 specification itself. Indeed, the specification discloses that Nissan’s very own European
`
`Publication No. EP 0 520 406 A1 (“EP ’406”) (DTX-1324) discloses “[a] full synthetic
`
`procedure for the preparation of Pitavastatin calcium,” in the form of a “white crystalline
`
`material.” (DTX-1307 at 1:62-67 (MYLAN(Pitav) 009848).) The Examiner evidently
`
`overlooked this statement of the closest prior art.
`
`14.
`
`Nissan facilitated the Examiner’s oversight. Back in 2006, Nissan had submitted
`
`a so-called Third Party Observation in the European Patent Office, against a competitor’s then-
`
`pending claim to the same Forma A pitavastatin calcium salt as in the ‘993 patent. In a formal
`
`submission, Nissan argued that the competitor’s Form A claim was not novel, because
`
`Nissan’s prior art EP ‘406 application disclosed a process that makes Form A Pitavastatin
`
`calcium salt. As set forth below, Nissan’s submission constitutes a party admission of inherent
`
`5
`
`
`

`

`Case 1:14-cv-02758-PAC Document 108 Filed 12/16/16 Page 12 of 52
`
`
`
`anticipation of the ‘993 patent. But to the point here, Nissan plainly knew that EP ‘406 was
`
`closer prior art than any sodium salt – and decided not to tell the Examiner.
`
`15.
`
`Further, Nissan disclosed its Third Party Observation in ways calculated to be
`
`overlooked by the Examiner. First, Nissan buried the Third Party Observation among dozens of
`
`far less relevant references, in so-called Information Disclosure Statements (“IDS’s”). DTX-247
`
`at KN001334697 (IDS form listing Third Party Submission as “Reference AAN”) &
`
`KN001334178-81 (copy of “AAN”).
`
`16.
`
`Second, Nissan did not direct the Examiner to a complete copy of the submission,
`
`which Nissan had denominated “Reference AAN.” That reference, however, is missing the
`
`scientific data (i.e., the proof of its position) Nissan had withheld from the “Refereance AAN”
`
`copy all the scientific data and proof supporting its statements. The copy Nissan identified as
`
`“Referance AAN” amongst the less relevant references was missing the key data found in the
`
`original document by Defendants in this case.1
`
`
`
`17.
`
`Third, Nissan did not tell the Examiner that the Third Party Submission dealt with
`
`EP ‘406, even though Nissan knew it did. On its face, the document submitted as “Reference
`
`AAN” does not refer to EP ‘406 by number or name. Instead, it refers to the prior art reference
`
`as “D1.”
`
`18.
`
`The file history reflects that any alleged consideration by the Examiner of EP
`
`’406 and Nissan’s EP ’406 Observation was either non-existent or highly cursory – as reflected
`
`by her incorrect observation that the closest prior art is pitavastatin sodium. The Examiner
`
`
`1 A copy of the Third Party Submission was also buried in what seems to be prosecution
`history of a Japanese patent applications. Accordingly, it was surrounded by documents in
`Japanese and about a Japanese patent application. For reasons not clear, the two copies of that
`entire Japanese prosecution history are in the ‘993 prosecution history. (Id. at KN001334227-54;
`KN001334362-82.)
` 
`
`6
`
`
`

`

`Case 1:14-cv-02758-PAC Document 108 Filed 12/16/16 Page 13 of 52
`
`
`
`issued her sole office action on May 30, 2013. (Id. at KN001335149-64.) The Examiner
`
`attached to that office action a search report and three IDS forms. These attachments indicate
`
`that all on a single day, May 23, 2013, the Examiner ran her searches and supposedly
`
`“considered” 95 individual references. (Id. at KN001335154 (search notes), KN001335155-59, -
`
`62, -64 (IDS forms).)
`
`B.
`
`19.
`
`Technological Background
`
`Defendants’ expert, Dr. Kevin Roberts, provided a brief background on the
`
`relevant technology. Dr. Roberts is the Brotherton Professor of Chemical Engineering at the
`
`University of Leeds, in England. For forty years, in both in academia and in industry, he has
`
`worked, taught, published and edited extensively in the fields of polymorphism, crystallization,
`
`crystal form characterization and crystallography.
`
`1.
`
`The Person of Ordinary Skill in the Art of the ’993 Patent
`
`20.
`
`According to Dr. Roberts, a person of ordinary skill in the art of the ‘993 patent as
`
`of February 12, 2003, would have either 1) a high level of education with such a person holding
`
`an advanced degree (i.e., Ph.D. or Master’s Degree) or 2) a bachelor’s degree in chemistry,
`
`pharmacy, chemical engineering, or related disciplines and at least several years of experience
`
`related to organic synthesis and/or evaluation of solid state forms in the pharmaceutical industry,
`
`and an appreciation for the various factors that relate to drug development, including an
`
`understanding of solvate chemistry. Such a person would understand that the drug development
`
`process requires a multi-disciplinary approach, and could draw upon not only his or her own
`
`skills, but also the specialized skills of others, to solve any given problem.
`
`21. While definitions of the person of ordinary skill in the art vary slightly among the
`
`experts in this case, there is no evidence that any of those differences would lead any of the
`
`experts to different conclusions.
`
`7
`
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`

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`Case 1:14-cv-02758-PAC Document 108 Filed 12/16/16 Page 14 of 52
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`
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`2.
`
`X-Ray Diffraction (“XRD”) Technology Used in the Patent
`
`22.
`
`The ’993 patent describes and claims particular crystalline forms of Pitavastatin
`
`calcium salt by means of XRD technology, which had been well known to those of ordinary skill
`
`in the art long before 2003. See Trial Testimony of Dr. Kevin Roberts. Pitavastatin calcium salt
`
`is “polymorphic.” This means that when in solid form, it can exist in two or more crystalline
`
`forms that have different three-dimensional arrangements of the molecules in a crystal lattice.
`
`23.
`
`XRD is considered the predominant tool for the study of crystalline materials.
`
`(DTX-1316, Brittain at 235 (MYLAN(Pitav) 062156).) If a sample is crystalline, it will diffract
`
`X-rays at specific angles because of its regular, repeating, organized arrangement. An XRD
`
`pattern is typically displayed as an X-Y plot of intensity (measured in counts) vs. diffraction
`
`angle (measured in units of degrees 2-theta (“2θ”)). A given crystalline form will exhibit a
`
`characteristic pattern of peaks like a fingerprint, generally identified by the positions of these
`
`peaks along the horizontal X-axis and the intensities of these peaks along the vertical Y-axis.
`
`Peak positions are typically identified by their 2θ value or by a “d-spacing” value that
`
`corresponds to this 2θ value. (Id. at 236 (MYLAN(Pitav) 062157).)
`
`24.
`
`For example, Figure 1 of the ’993 patent below is an XRD plot. Along the X-
`
`axis, you can see peaks at various values of “2 Theta Angle” or “2θ.” The height of those peaks
`
`are measured by “Intensity Counts” along the Y-axis. The highest peak appears to be located at
`
`approximately 21º 2θ. It appears to have a height of approximately 1375 intensity counts.
`
`
`
`8
`
`
`

`

`Case 1:14-cv-02758-PAC Document 108 Filed 12/16/16 Page 15 of 52
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`
`
`
`
`(DTX-1307 at MYLAN(Pitav) 009839.)
`
`25.
`
`For a given XRD plot such as this, there is typically a corresponding list of 2θ
`
`peaks. Table 1 of the Patent, for example, is the peak list reported in the ’993 patent
`
`corresponding to Figure 1. Table 1 identifies the location of peaks both by 2θ angle (the middle
`
`column) and by d-spacing (an alternative location statistic commonly used). But rather than
`
`provide numerical intensity count values (e.g. 1375 for the peak at approximately 21º 2θ), Table
`
`1 uses letters to refer to categories of relative intensity for each peak listed.
`
`
`
`9
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`

`

`Case 1:14-cv-02758-PAC Document 108 Filed 12/16/16 Page 16 of 52
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`
`
`
`
`(DTX-1307 at 2:35-60 (MYLAN(Pitav) 009848).)
`
`26.
`
`In comparing XRD data for different samples, it is well-settled that the presence
`
`of peaks at particular 2θ values is of critical importance. It is also well-settled that an error of
`
`margin of plus or minus 0.2º 2θ is applied in determining whether a peak from one sample is
`
`present at a given 2θ position of another sample.
`
`27. With regard to intensity values or counts of each peak in such a comparison, there
`
`can be some variation in the XRD intensity data for two samples even for the same crystalline
`
`form. Small differences in some peak intensity counts may be attributed to different
`
`experimental conditions at the time the XRD testing was done on each sample, and not to
`
`differences in crystalline structure between the two samples. The potential significance of
`
`10
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`
`

`

`Case 1:14-cv-02758-PAC Document 108 Filed 12/16/16 Page 17 of 52
`
`
`
`differences in peak intensities increases with the number and degree of such differences, read in
`
`the context of the entire XRD plot or peak list.
`
`28.
`
`Polymorphs are frequently analyzed by XRD in combination with other means.
`
`The most common other means are differential scanning calorimetry (“DSC”) and measured
`
`water content. DSC analysis measures heat absorption and emission for certain endothermal or
`
`exothermal events, such as melting point, decomposition or recrystallization. Water content
`
`relates primarily to water molecules bound within the crystal lattice of a given structure. In
`
`addition to such bound water within a fixed crystal structure, there often is additional associated
`
`or channel water. In general, the water content in or associated with a crystal form often depends
`
`on the duration and nature of drying to which the crystals were subjected prior to testing.
`
`3.
`
`Polymorphism in Drug Discovery
`
`29.
`
`As of February 2003, it was well-known that solid state forms of drug substances
`
`include crystalline forms (e.g., anhydrous forms and pseudopolymorphs, as well as polymorphs
`
`thereof) and amorphous forms. Persons of ordinary skill in the art relevant to the ’993 patent had
`
`been developing statins, including in solid state forms, such as polymorphic, solvate and
`
`anhydrous form, for years prior to 2003.
`
`30.
`
`Also by 2003, the FDA and other regulatory bodies around the world directed
`
`applicants, in the course of product development, to investigate and confirm whether a chemical
`
`entity existed in different solid-state forms, including polymorphic and amorphous forms, in
`
`preparation for submissions such as a New Drug Application (“NDA”).2 The FDA issued
`
`
`2 DTX-1312, Center for Drug Evaluation and Research, Food and Drug Admin., Dep’t of Health and
` 
`Human Servs., Guideline for Submitting Supporting Documentation in Drug Applications for the Manufacture of
`Drug Substances (1987) at 31-35 (“1987 FDA Guidelines”) (MYLAN(Pitav) 015625-29; DTX-1313, Int’l
`Conference on Harmonisation of Tech. Requirements for Registration of Pharm. for Human Use, ICH Harmonized
`Tripartite Guideline, Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and
`New Drug Products; Chemical Substances, Q6A (1999) at 8 (“ICH Q6A”) (MYLAN(Pitav) 062473).
`11
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`Case 1:14-cv-02758-PAC Document 108 Filed 12/16/16 Page 18 of 52
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`
`
`Guidelines in 1987 to those in drug development advising that, when such properties are
`
`exhibited by a drug substance, appropriate testing should be done to characterize the drug
`
`substance and its physical properties. (DTX-1312, 1987 FDA Guidelines at 31, 33
`
`(MYLAN(Pitav)015625, 015627).) As Byrn 1995 describes:
`
`Interest in the subject of pharmaceutical solids stems in part from
`the Food and Drug Administration’s (FDA’s) drug substance
`guideline that states “appropriate” analytical procedures should be
`used to detect polymorphic, hydrated, or amorphous forms of the
`drug substance. These guidelines suggest the importance of
`controlling the crystal form of the drug substance. The guideline
`also states that it is the applicant’s responsibility to control the
`crystal form of the drug substance and, if bioavailability is affected,
`to demonstrate the suitability of the control methods.
`
`
`(DTX-1318, Byrn 1995 at 945 (MYLAN(Pitav)015333); see also DTX-1319, Threlfall at 2436
`
`(“interest in polymorphism began with the need to satisfy regulatory authorities in various
`
`countries as to the bioavailability of formulations of new chemical entities”)
`
`(MYLAN(Pitav)015545).)
`
`31.
`
`A person of ordinary skill in the art, by 2003, would have understood that
`
`crystalline solid state forms are generally preferred as they offer the advantages of, for example,
`
`chemical and thermodynamic stability. Investigation and consideration of solid state forms of a
`
`particular drug substance was a common part of drug development. (See, e.g., DTX-1314,
`
`Jozwiakowski at 526-27 (MYLAN(Pitav)015493-94).)
`
`4.
`
`Routine Crystallization Screening
`
`32.
`
`Due to the known effects that different solid state forms have with respect to a
`
`given drug substance, as well as the regulatory guidelines and requirements regarding solid state
`
`selection, persons of ordinary skill in the art had long utilized screening techniques to efficiently
`
`identify solid state forms for additional characterization and potential use as a drug substance.
`
`12
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`Case 1:14-cv-02758-PAC Document 108 Filed 12/16/16 Page 19 of 52
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`
`
`The general technique of crystallization had long been taught as part of basic training in a
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`laboratory and was used routinely by chemists in the preparation and purification of organic
`
`compounds. (See generally DTX-1320, James W. Zubrick, Recrystallization, in THE ORGANIC
`
`CHEM LAB SURVIVAL MANUAL 122-38 (4th ed. 1997) (“Zubrick”) (MYLAN(Pitav)015570-90).)
`
`33.
`
`It was well known to a person of ordinary skill in the art that different crystal
`
`forms could be sought by routine recrystallization experiments varying, for example, the solvent
`
`system, temperature, precipitation method, and level of supersaturation. (DTX-1314,
`
`Jozwiakowski at 530 (MYLAN(Pitav)015497); DTX-1318, Byrn 1995 at 946
`
`(MYLAN(Pitav)015334).) In addition to identifying recrystallization experiments generally,
`
`plaintiffs’ expert, Dr. Byrn, in 1999 also identified the use of antisolvents, seeding, freeze-drying
`
`(from mixed-solvents) and the addition of mixtures of different solvents. (DTX-1315, Byrn 1999
`
`at 15-16 (MYLAN(Pitav)015357-58).)
`
`34.
`
`Because solubility was known as a key parameter to many crystallization
`
`methods, the first step in a routine crystallization screen of a compound was to systematically
`
`determine a proper solvent system. (See DTX-1314, Jozwiakowski at 530
`
`(MYLAN(Pitav)015497); DTX-1318.) Plaintiffs’ own scientist acknowledged the routine nature
`
`of such “solubility assessments.” (DTX-1321, 4/6/16 H. Iwasaki Dep. Tr. at 163:10 – 164:20).)
`
`35.
`
`Indeed, as plaintiffs’ own expert, Dr. Byrn, wrote in 1995, the first step in
`
`determining solid state forms is to “crystallize the substance from a number of different solvents”
`
`in order to determine if polymorphs are possible. (DTX-1318, Byrn 1995 at 946
`
`(MYLAN(Pitav) 015334).) Another authority, Dr. Harry Brittain, wrote that persons of ordinary
`
`skill in the art had compiled a litany of information regarding solvents and solid state forms that,
`
`as Brittain stated, “will prove useful in devising a ‘screening’ protocol for the preparation of the
`
`13
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`Case 1:14-cv-02758-PAC Document 108 Filed 12/16/16 Page 20 of 52
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`
`
`various solid state forms of pharmaceuticals.” (DTX-1316, Brittain at 186 (MYLAN(Pitav)
`
`062132).) Commonly known and used solvents included water, methanol, ethanol, propanol,
`
`isopropanol, acetone, acetonitrile, ethyl acetate and mixtures thereof. (DTX-1316, Brittain at
`
`193 (MYLAN(Pitav) 062135); see also id. at 206 (Table 2) (listing 15 most abundant solvents)
`
`(MYLAN(Pitav) 062142); DTX-1318, Byrn 1995 at 946 (MYLAN(Pitav)015334); DTX-1315,
`
`Byrn 1999 at 491 MYLAN(Pitav) 015430).)
`
`36.
`
`After selection of appropriate solvents for use in a solvent screen, a person of
`
`ordinary skill in the art could then recrystallize the known compound in the selected solvents.
`
`Upon isolation of the resulting crystals, a person of ordinary skill in the art would be in possession
`
`of a number of solid state forms of the target compound, which could then be characterized, as
`
`discussed below, using standard methodology in order to select the appropriate solid state form.
`
`5.
`
`Pitavastatin and Other Crystalline Statins Known in the Prior Art
`
`37.
`
`As the ’993 patent itself acknowledges, there was nothing new about Pitavastatin
`
`or even Pitavastatin calcium salt in 2003. Pitavastatin had long been known as a statin. (DTX-
`
`1307, the ’993 patent at 1:21-67 (MYLAN(Pitav)009848).) Statins were known to be a class of
`
`active agents useful to lower lipid levels, including cholesterol, in blood. Accordingly, they were
`
`used for the treatment of hyperlipidemia, among other conditions. (See, e.g., DTX-1323,
`
`International Publication No. WO 03/064392 A1 to Acemoglu et al. at 1 (“WO ’392”)
`
`(MYLAN(Pitav)015084).)
`
`38.
`
`Pitavastatin calcium salt had been specifically known and disclosed in the prior
`
`art. Indeed, as early as June 1992, Plaintiff Nissan in this case filed a European Patent
`
`Application disclosing crystalline forms of Pitavastatin calcium salt as useful statins. That
`
`application published in 1992, and constitutes prior art to the ’993 patent-in-suit. (DTX-1324,
`
`14
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`Case 1:14-cv-02758-PAC Document 108 Filed 12/16/16 Page 21 of 52
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`
`
`European Publication No. EP 0 520 406 A1 to Ohara et al. at 12:22-32 (Example 3) (“EP ’406”)
`
`(MYLAN(Pitav)014994); DTX-1323, WO ’392 at 1-3 (MYLAN(Pitav)015084-86); DTX-1325,
`
`International Publication No. WO 03/064382 A2 to Chen et al. at 25-26 (“WO ’382”)
`
`(MYLAN(Pita