IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________________________
`
`LUPIN LIMITED
`Petitioner
`v.
`JANSSEN SCIENCES IRELAND UC
`Patent Owner, based on Public Filings
`JANSSEN R&D IRELAND
`Patent Owner, based on Electronic Records of PTO
`U.S. Patent No. 8,518,987 B2 to Vermeersch et al.
`Issue Date: August 27, 2013
`Title: Pseudopolymorphic Forms of a HIV Inhibitor
`________________________________
`
`Inter Partes Review Trial No. TBD
`________________________________
`
`Declaration of Frederick J. Northrup, Ph.D. In Support of Lupin Ltd.’s
`Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
`
`
`
`
`
`Lupin Ex. 1069 (Page 1 of 11)
`
`
`________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________________________
`
`LUPIN LIMITED
`Petitioner
`v.
`JANSSEN SCIENCES IRELAND UC
`Patent Owner, based on Public Filings
`JANSSEN R&D IRELAND
`Patent Owner, based on Electronic Records of PTO
`U.S. Patent No. 8,518,987 B2 to Vermeersch et al.
`Issue Date: August 27, 2013
`Title: Pseudopolymorphic Forms of a HIV Inhibitor
`________________________________
`
`Inter Partes Review Trial No. TBD
`________________________________
`
`Declaration of Frederick J. Northrup, Ph.D. In Support of Lupin Ltd.’s
`Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
`
`
`
`
`
`Lupin Ex. 1069 (Page 1 of 11)
`
`
`
`Declaration of Frederick J. Northrup, Ph.D.
`In Support of Lupin Limited’s Petition for Inter Partes Review
`of U.S. Patent No. 8,518,987 B2
`
`I, Frederick J. Northrup, declare as follows:
`
`I.
`
`INTRODUCTION
`
`1.
`
`I have been retained by counsel for Lupin Limited (“Lupin”) in
`
`connection with a petition Lupin intends on filing for inter partes review of U.S.
`
`Patent No. 8,518,987 B2 (“the ‘987 patent”) (Ex. 1001). Specifically, I have been
`
`advised that Lupin intends on requesting that the United States Patent and
`
`Trademark Office (“PTO”) cancel Claims 1-19 of the ‘987 patent as unpatentable
`
`on anticipation and/or obviousness grounds. I understand that this Declaration will
`
`be used to support unpatentability in any trial proceeding initiated in connection
`
`with these grounds.
`
`II. QUALIFICATIONS AND BACKGROUND.
`
`2.
`
`I am currently a Distinguished Senior Lecturer and Director of
`
`Undergraduate Studies in the Department of Chemistry at Northwestern University
`
`in Evanston, Illinois. I have held both positions since September 2008. From
`
`September 1998 to August 2008, I held the position of Senior Lecturer and from
`
`September 1995 to August 2006, I held the position of Director of the Analytical
`
`Services Laboratory. From 1990 through 1998, I was a Lecturer in the Department
`
`of Chemistry at Northwestern University. I have also served as a Research
`
`Associate for the Brookhaven National Laboratory and as a Faculty Research
`
`Participant for Argonne National Laboratory.
`1
`
`
`Lupin Ex. 1069 (Page 2 of 11)
`
`
`
`Declaration of Frederick J. Northrup, Ph.D.
`In Support of Lupin Limited’s Petition for Inter Partes Review
`of U.S. Patent No. 8,518,987 B2
`
`
`3.
`
`My current responsibilities include teaching various undergraduate
`
`laboratory courses in instrumental analysis, spectroscopy and advanced physical
`
`chemistry. I also advise 15-17 freshman students and 15-20 students in the
`
`chemistry major program each year, and I supervise undergraduate students in
`
`independent research projects. As the Director of Undergraduate Studies, I oversee
`
`all aspects of the undergraduate chemistry major program at Northwestern
`
`University. As the former Director of the Analytical Services Laboratory, I was
`
`responsible for management of Analytical Services Laboratory’s instrumentation,
`
`which included optical spectroscopy, NMR spectroscopy, mass spectrometry, and
`
`X-ray diffraction equipment, and supervision of the laboratory staff.
`
`4.
`
`Attached as Exhibit 1070 is my curriculum vitae setting forth my
`
`educational experience, employment history, professional affiliations, and
`
`publications.
`
`5.
`
`I have relied upon my education, background, and experience in
`
`conducting the testing and in forming the opinions set forth herein.
`
`III.
`
`SUMMARY OF ANALYSES.
`
`6.
`
`I have been asked to review the ‘987 patent and the test methods
`
`disclosed therein for the characterization of the purported pseudopolymorphic
`
`forms set forth therein.
`
`2
`
`
`Lupin Ex. 1069 (Page 3 of 11)
`
`
`
`Declaration of Frederick J. Northrup, Ph.D.
`In Support of Lupin Limited’s Petition for Inter Partes Review
`of U.S. Patent No. 8,518,987 B2
`
`
`7.
`
`In accordance with these disclosures, I have also been asked to
`
`conduct testing on three samples sent to me by Dr. Aris G. Kalivretenos from
`
`Aurora Analytics on behalf of counsel for Lupin Limited. The samples were
`
`identified as Darunavir, 0.5 g, Lot No. C13-040215-2; Darunavir, ethanol
`
`recrystallized, 0.5 g; Lot No. C13-040415-E; and Darunavir, isopropanol
`
`recrystallized, 0.4 g, Lot No. C13-040415-I. The sample vials were further labeled
`
`as “Compound 13,” “Compound 13 EtOH recrystallized,” and “Compound 13
`
`iPrOH recrystallized,” respectively.
`
`8.
`
`I specifically conducted Powder X-Ray Diffraction (XRPD) and
`
`Thermogravimetric Analysis coupled with Mass Spectrometry (TGA/MS) on such
`
`samples. Based on my review of the XRPD data, the results showed “Compound
`
`13” is consistent with a predominantly amorphous material and “Compound 13
`
`EtOH recrystallized” and “Compound 13 iPrOH recrystallized” are consistent with
`
`predominantly crystalline materials that I conclude are most likely solvated and
`
`isostructural. Based on my review of the TGA/MS data, all three samples showed
`
`results consistent with the presence of water and other solvents such as alcohols.
`
`IV. BACKGROUND.
`
`A. XRPD.
`
`9.
`
`XRPD is a scientific technique which employs diffraction of X-ray
`
`radiation from powdered, typically crystalline, samples in order to structurally
`3
`
`
`Lupin Ex. 1069 (Page 4 of 11)
`
`
`
`Declaration of Frederick J. Northrup, Ph.D.
`In Support of Lupin Limited’s Petition for Inter Partes Review
`of U.S. Patent No. 8,518,987 B2
`
`characterize such samples. In XRPD (also commonly known as PXRD), an
`
`incident monochromatic beam of X-rays is diffracted from multiple crystals in the
`
`powdered sample. For each crystal in the mixture, the spacing between the planes
`
`in the crystal lattice is comparable to the wavelength of the incident beam. The
`
`diffraction occurs according to Bragg’s Law: n*Ȝ = 2d*sinș. The resulting
`
`diffraction pattern is presented as a plot of diffracted X-ray intensity against the
`
`angle “two-theta” measured in degrees. The term “two-theta” is used because the
`
`diffracted X-rays are detected at twice the angle of the incident irradiating beam.
`
`10.
`
`“Powder X-ray diffraction is the most powerful method for detecting
`
`polymorphs” because it specifically analyzes the packing pattern of atoms. (Ex.
`
`1071, REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 710 (Daniel
`
`Limmer et al. eds., 20th ed. 2000). Since polymorphs have different crystal
`
`structures, the packing patterns will therefore also be different. Id. However,
`
`closely related crystal structures can produce X-ray scattering at similar angles. As
`
`noted above, polymorphs consist of the same molecules stacked in different ways
`
`and consequently several reflections or peaks in the XRPD pattern may appear at
`
`the same or very similar two-theta values. Consequently, one cannot discern a
`
`specific polymorphic form based on a small number of scattering angles; the entire
`
`scattering pattern must be considered.
`
`4
`
`
`Lupin Ex. 1069 (Page 5 of 11)
`
`
`
`Declaration of Frederick J. Northrup, Ph.D.
`In Support of Lupin Limited’s Petition for Inter Partes Review
`of U.S. Patent No. 8,518,987 B2
`
`
`11. Moreover, certain hydrates or solvates, including channel hydrates,
`
`yield similar or nearly identical XRPD patterns irrespective of whether the
`
`channels are filled, part-filled or empty (e.g., desolvated or anhydrous). (Ex. 1038,
`
`Gregory A. Stephenson et al., Formation of Isomorphic Desolvates: Creating a
`
`Molecular Vacuum, 87 J. PHARMACEUTICAL SCI. 536, 536 (1998) (“Stephenson”)).
`
`(discussing the similarity of XRPD patterns among closely related crystals); Ex.
`
`1072, Eric D. Carlson et al., An Integrated High Throughput Workflow for Pre-
`
`Formulations: Polymorph and Salt Selection Studies, DRUG DEVELOPMENT 10, 12
`
`(July/Aug. 2003) (“Iso-structural solvates in particular can have indistinguishable
`
`Raman and XRD patterns.”).
`
`12.
`
`The method of using XRPD as a tool to identify crystalline forms is to
`
`consider a significant number of distinctive peaks for the scattering pattern of a
`
`particular polymorph, perform XRPD analysis on a particular sample, and then to
`
`search for all of these distinctive peaks in the diffraction pattern of the sample.
`
`B.
`
`13.
`
`TGA/MS.
`
`Thermogravimetric analysis (TGA) is a technique to monitor changes
`
`in sample weight as the temperature of the sample is varied in a controlled fashion.
`
`As a sample is heated, it can undergo dehydration, desolvation, or other
`
`decomposition processes resulting in a loss of mass. Measurement of the mass loss
`
`5
`
`
`Lupin Ex. 1069 (Page 6 of 11)
`
`
`
`Declaration of Frederick J. Northrup, Ph.D.
`In Support of Lupin Limited’s Petition for Inter Partes Review
`of U.S. Patent No. 8,518,987 B2
`
`along with knowledge of the material lost can provide information about the
`
`stoichiometric composition of the sample.
`
`14. Mass spectrometry (MS) is an analytical technique for measuring the
`
`mass to charge ratio of ions created from molecules in a sample and ultimately the
`
`molecular weight of the molecules in the sample. Molecular weight can be used to
`
`identify the ion or molecule in question.
`
`15. Combining mass spectrometry detection with TGA creates the
`
`analytical technique TGA/MS to be used in analysis of samples for this
`
`declaration. The use of MS in this technique will provide mass information for use
`
`in identification of ions created from molecules evolving from the sample during
`
`the heating cycle of the TGA. This provides information about the process causing
`
`observed mass loss.
`
`V.
`
`DETAILED ANALYSES.
`
`16.
`
`I was asked by counsel for Lupin to review the ‘987 patent and the
`
`test methods discussed therein for the characterization of compounds.
`
`17.
`
`The ‘987 patent discusses, among other things, polymorphs and
`
`pseudopolymorphs of darunavir. The ‘987 patent purportedly characterizes the
`
`compounds to which the patent relates using XRPD and TGA testing methods.
`
`6
`
`
`Lupin Ex. 1069 (Page 7 of 11)
`
`
`
`Declaration of Frederick J. Northrup, Ph.D.
`In Support of Lupin Limited’s Petition for Inter Partes Review
`of U.S. Patent No. 8,518,987 B2
`
`
`18.
`
`I thus performed XRPD and TGA/MS testing on the samples provided
`
`to me in accordance with the test methods discussed in the ‘987 patent.
`
`19.
`
`The instrumentation used, sample preparation procedures followed,
`
`instrument settings utilized, reagents used, calculations relating to, and results of
`
`this testing are described herein.
`
`A.
`
`Samples Tested.
`
`20. As discussed above, I was sent samples, labelled “Compound 13”,
`
`“Compound 13 EtOH recrystallized”, and “Compound 13 iPrOH recrystallized.” I
`
`received these samples on April 6, 2015.
`
`21. All the samples were stored at 4°C until time of preparation and
`
`returned to such storage between uses.
`
`22.
`
`I prepared the samples for XRPD analysis on April 6, 2015 and for
`
`TGA/MS testing on April 7, 2015.
`
`B.
`
`Description of XRPD and TGA/MS Testing.
`
`1.
`
`XRPD Test Protocol.
`
`23. XRPD analysis was performed on each of the samples received using
`
`a Rigaku Ultima IV XRPD diffractometer. Samples were sufficiently fine powders
`
`as received that no further grinding of them was necessary before analysis.
`
`24.
`
`Samples were mounted on glass slides for XRPD analysis with this
`
`instrument. A small amount of sample was poured onto a glass slide and a second
`7
`
`
`Lupin Ex. 1069 (Page 8 of 11)
`
`
`
`Declaration of Frederick J. Northrup, Ph.D.
`In Support of Lupin Limited’s Petition for Inter Partes Review
`of U.S. Patent No. 8,518,987 B2
`
`glass slide was used to flatten the powder to ensure equal powder height across the
`
`entire sample to be analyzed.
`
`25.
`
`The sample was placed in the path of the X-ray beam of the
`
`instrument and X-ray scattering data were acquired. The X-ray source was a
`
`copper radiation source with a wavelength of 1.54059 Å. The source was operated
`
`at a voltage of 40 kV and a current of 20 mA to provide an X-ray beam of
`
`sufficient intensity for the analysis. Data were collected over the two-theta
`
`scattering angle range 4 – 50 °C degrees with a scan speed of 1.5 degree/minute
`
`and a step size of 0.05 degrees. The software Jade was used to perform peak-
`
`picking to process the data into a table of two-theta scattering angles and
`
`corresponding X-ray scattering intensity.
`
`2.
`
`TGA/MS Test Protocol.
`
`26.
`
`TGA/MS analysis was performed on these samples using a Mettler-
`
`Toledo TGA Q500 instrument equipped with a Pfeiffer-Vacuum quadrupole mass
`
`spectrometer with electron impact ionization. Roughly 20 mg of sample was
`
`weighed precisely and placed into an alumina pan.
`
`27.
`
`TGA/MS analysis was performed under N2 atmosphere. The sample
`
`was held at a fixed 10 °C for five minutes to equilibrate in the instrument and then
`
`the temperature was ramped from 10 °C to 250.0 °C at a 10.0 °C/minute rate
`
`8
`
`
`Lupin Ex. 1069 (Page 9 of 11)
`
`
`
`Declaration of Frederick J. Northrup, Ph.D.
`In Support of Lupin Limited’s Petition for Inter Partes Review
`of U.S. Patent No. 8,518,987 B2
`
`followed by a further five minute isothermal time before turning off the heat. The
`
`mass spectrometer detector monitored ion current at mass to charge ratios 14, 17,
`
`18, 32 and 44.
`
`C.
`
`Test Results.
`
`1.
`
`XRPD
`
`28. XRPD data, plotted as intensity vs. two-theta scattering angle are
`
`shown in exhibits 1073-1075. Data for the sample “Compound 13”, shown in
`
`exhibit 1073, showed only very broad features, indicative of a primarily
`
`amorphous sample. Data for the sample “Compound 13 EtOH recrystallized”,
`
`shown in exhibit 1074, showed a pattern of narrow features indicative of a
`
`primarily crystalline material. Data for the sample “Compound 13 iPrOH
`
`recrystallized”, shown in exhibit 1075, also showed narrow features indicative of a
`
`primarily crystalline material. The scattering patterns for the latter two samples are
`
`qualitatively similar, but quantitatively slightly different indicating the possibility
`
`of solvated crystalline materials which are isostructural.
`
`2.
`
`TGA/MS.
`
`29.
`
`TGA sample mass data are shown in exhibits 1076-1078 and
`
`TGA/MS data are shown in exhibits 1079-1081 for ion current signals at mass to
`
`charge ratio 17, 18 and 44. The TGA sample mass data for “Compound 13” (Ex.
`
`1076) showed a more gradual sample mass loss beginning at 50 °C and continuing
`9
`
`
`Lupin Ex. 1069 (Page 10 of 11)
`
`
`
`Declaration of Frederick J. Northrup, Ph.D.
`In Support of Lupin Limited’s Petition for Inter Partes Review
`of US. Patent No. 8,518,987 B2
`
`to 150 °C. TGA sample mass data for “Compound 13 EtOH recrystallized” (Ex.
`
`1077) and “Compound 13 iPrOH recrystallized” (Ex. 1078) showed sharp mass
`
`losses in the range 70 — 90 °C followed by more gradual samples mass losses to
`
`150 °C. The TGA/MS data (Exs. 1079-1081 respectively for the three samples)
`
`showed increasing signals at mass to charge ratios 17, 18 and 44 during the sample
`
`mass loss periods. These mass to charge signals are consistent with the presence of
`
`water and other solvents such as alcohols in all three samples.
`
`VI. ADDITIONAL INFORMATION.
`
`30.
`
`I am being compensated at my customary hourly fee at the time of my
`
`engagement of $400. My compensation is in no way dependent on the outcome of
`
`Lupin’s petition.
`
`31.
`
`If asked, I anticipate testifying about the analyses discussed in this
`
`Declaration.
`
`32.
`
`I reserve the right to modify and/or supplement
`
`the information
`
`contained herein as necessary or appropriate.
`
`I swear under penalty of perjury that the foregoing is true and correct.
`
`1
`
`/\
`
`
`Frederick J. Northrup
`
`(Wig/20w”
`
`Date
`
`10
`
`Lupin Ex. 1069 (Page 11 of 11)
`Lupin Ex. 1069 (Page 11 of 11)
`
`
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