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 Terence L. Threlfall, Ph.D. In Support of Lupin Ltd.’s
`Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
`
`Lupin Ex. 1025 (Page 1 of 159)
`
`

`

`Declaration of Terence L. Threlfall, Ph.D.,
`In Support of Lupin Ltd.’s Petition for Inter Partes Review
`of U.S. Patent No. 8,518,987 B2
`
`Table of Contents
`
`I.
`
`II.
`
`INTRODUCTION ........................................................................................... 1
`
`QUALIFICATIONS AND BACKGROUND. ................................................ 1
`
`III.
`
`SUMMARY OF OPINIONS ........................................................................... 5
`
`A.
`
`B.
`
`The Claims and Disclosures of the ‘987 Patent. ................................... 6
`
`State of the Knowledge in the Art as of May 2003. .............................. 6
`
`IV. SCIENTIFIC BACKGROUND. ................................................................... 11
`
`A.
`
`B.
`
`C.
`
`D.
`
`Polymorphism and Crystal Forms. ...................................................... 11
`
`Crystallinity and Hydrogen Bonding. ................................................. 13
`
`Hydrates and Solvates. ........................................................................ 15
`
`Solid-State Forms in Pharmaceutical Compositions. .......................... 19
`
`V.
`
`PERSON OF ORDINARY SKILL IN THE ART. ....................................... 23
`
`VI. OVERVIEW OF THE ‘987 PATENT. ......................................................... 26
`
`A. General Information. ........................................................................... 26
`
`B.
`
`Prosecution History of the ‘987 Patent. .............................................. 42
`
`1.
`
`2.
`
`3.
`
`Prosecution History of the ‘352 Application. ........................... 43
`
`Prosecution History of the ‘807 Application. ........................... 45
`
`Van Gyseghem. ......................................................................... 56
`
`C.
`
`D.
`
`Claims of the ‘987 Patent. ................................................................... 59
`
`File History of EP 1567529. ................................................................ 62
`
`VII. DETAILED BASIS FOR OPINIONS. .......................................................... 65
`
`A.
`
`Comparison of Claims of ‘987 Patent with EP ‘929. .......................... 65
`
`
`
`i
`
`Lupin Ex. 1025 (Page 2 of 159)
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`

`

`Declaration of Terence L. Threlfall, Ph.D.,
`In Support of Lupin Limited’s Petition for Inter Partes Review
`of U.S. Patent No. 8,518,987 B2
`
`
`B.
`
`C.
`
`Claim Construction. ............................................................................ 69
`
`The Claimed Subject Matter of the ‘987 Patent Would Have
`Been Anticipated to a Person of Ordinary Skill in the Art. ................ 74
`
`1.
`
`2.
`
`3.
`
`4.
`
`The Presence of Water in Pharmaceutical Processes. .............. 74
`
`Disclosures of Ghosh 1998. ...................................................... 75
`
`Disclosures of the ‘775 patent................................................... 83
`
`Comparison of the Prior Art to the Claims. .............................. 90
`
`a.
`
`b.
`
`The Process of Preparing Darunavir and Its
`Composition As Described and Tested in Ghosh
`1998 Would Produce Darunavir Hydrates and
`Compositions Thereof with All of the Claimed
`Features of Claims 1-19. ................................................. 94
`
`The Process of Preparing Darunavir and Its
`Compositions Described in the ‘775 Patent Would
`Produce Darunavir Hydrates and Compositions
`Thereof with All of the Claimed Features of
`Claims 1-19. ..................................................................107
`
`D.
`
`The Claimed Subject Matter of the ‘987 Patent Would Have
`Been Obvious to a Person of Ordinary Skill in the Art. ...................114
`
`1.
`
`State of the Knowledge as of May 16, 2003. ..........................114
`
`a.
`
`b.
`
`c.
`
`Darunavir, the Molecule, Was Well-known as of
`May 2003. .....................................................................114
`
`A Skilled Artisan Would Have Been Motivated to
`Study the Crystallisation of Darunavir. ........................116
`
`A Person of Ordinary Skill in the Art Would Have
`Understood That Such Crystallisation Screening
`Was Routine. .................................................................118
`
`
`
`
`ii
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`Lupin Ex. 1025 (Page 3 of 159)
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`

`

`Declaration of Terence L. Threlfall, Ph.D.,
`In Support of Lupin Limited’s Petition for Inter Partes Review
`of U.S. Patent No. 8,518,987 B2
`
`
`d.
`
`e.
`
`A Person of Ordinary Skill in the Art Would Have
`Reasonably Expected Darunavir Hydrate to Form. ......124
`
`Darunavir Would Have Been Reasonably
`Expected to Form Hydrates in a Ratio of 0.5 to 3. .......127
`
`2.
`
`Comparison of the Claims to the Art. .....................................129
`
`a.
`
`b.
`
`c.
`
`d.
`
`e.
`
`f.
`
`g.
`
`Claim 1. .........................................................................129
`
`Claim 2. .........................................................................132
`
`Claims 3-5. ....................................................................134
`
`Claims 6-8. ....................................................................138
`
`Claims 9-13. ..................................................................140
`
`Claims 14-18. ................................................................141
`
`Claim 19. .......................................................................142
`
`E.
`
`Secondary Considerations. ................................................................145
`
`VIII. STATEMENT. .............................................................................................155
`
`
`
`
`
`iii
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`Lupin Ex. 1025 (Page 4 of 159)
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`

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`Declaration of Terence L. Threlfall, Ph.D. (Ex. 1025),
`In Support of Lupin Ltd.’s Petition for Inter Partes Review
`of U.S. Patent No. 8,518,987 B2
`
`I, Terence L. Threlfall, 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 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 Senior Research Fellow in the Crystallography Group
`
`within the School of Chemistry at the University of Southampton. I have more
`
`than 50 years of experience in my principal fields of interest of crystallisation,
`
`crystallography, polymorphism, other aspects of solid state structure and
`
`behaviour, and in understanding crystallisation and transformation processes.
`
`3.
`
`Specifically, I received a Bachelor of Science degree in chemistry
`
`from London University in 1956 and a Ph.D. in organic chemistry from London
`
`University in 1971. In 1984, I received the degree of Ll.B. from London
`
`University.
`
`
`
`1
`
`Lupin Ex. 1025 (Page 5 of 159)
`
`

`

`Declaration of Terence L. Threlfall, Ph.D.,
`In Support of Lupin Limited’s Petition for Inter Partes Review
`of U.S. Patent No. 8,518,987 B2
`
`
`4.
`
`In 1962, I was appointed Section Head of Spectroscopy at May &
`
`Baker Ltd., which later became known as Rhone Poulenc Rorer Ltd., and has since
`
`become part of Sanofi-Aventis S.A. Over the years at May & Baker, I introduced
`
`NMR spectroscopy, mass spectroscopy, preparative HPLC and chemical
`
`microscopy to the company. As the Section Head, I was specifically responsible
`
`for the Pearling agent research program which presented substantial crystallisation
`
`challenges. In 1976, I was appointed as the Department Head of Physical
`
`Chemistry. In this capacity, I was responsible for overseeing a substantial group of
`
`scientists, technical officers, and technicians in relation to the origin of samples,
`
`identity of samples, purity of samples, hydration, solvation, polymorphism, salt
`
`formation, crystal habit and amorphicity. In 1983, I was appointed as Process
`
`Research Manager and was responsible for scaling up synthetic routes, which
`
`involved consideration of the purity, purification, crystallisation, stability and
`
`filterability of samples. In 1987, I became a Principal Scientist, in which capacity
`
`my main activity was patent maintenance, but I also organized liaisons with
`
`schools and universities and acted as an internal scientific consultant. Over my
`
`twenty-nine years at May & Baker, I gained considerable experience of a wide
`
`variety of situations and of problems associated with
`
`the
`
`identification,
`
`purification, crystallisation and separation of compounds of all kinds, but
`
` 2
`
`
`
`
`
`Lupin Ex. 1025 (Page 6 of 159)
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`

`

`Declaration of Terence L. Threlfall, Ph.D.,
`In Support of Lupin Limited’s Petition for Inter Partes Review
`of U.S. Patent No. 8,518,987 B2
`
`particularly with organic pharmaceuticals. One of these was the antibiotic
`
`chlorobiocin. In 1972, I was a co-author of an article on this antibiotic.
`
`5.
`
`Prior to taking a position at the University of Southampton, I was the
`
`Industrial Liaison Executive in the Department of Chemistry at the University of
`
`York. Specifically, I joined the University of York faculty in 1991 and was later
`
`appointed a Research Fellow. At the University of York, as well as while liaising
`
`with industry, I organized short courses for industry, participated in skills-based
`
`workshops for undergraduates, ran the external analytical service and conducted
`
`research on polymorphs, instrumentation and molecular templates.
`
`6.
`
`Besides supervising research students in the crystallography group at
`
`the University of Southampton, I am currently investigating crystallisation
`
`processes, including processes designed to promote the growth of crystals that are
`
`better and more perfect (i.e., fewer crystal defects) and that are large enough for
`
`single crystal diffraction work and for other studies.
`
`7.
`
`From the mid-1990s, I have personally carried out at least 500
`
`crystallisations per year, particularly for the preparation of polymorphs, hydrates,
`
`solvates and co-crystals. Over the past 15 years, several of my studies relating to
`
`polymorphs and their crystallisation have been published.
`
`Lupin Ex. 1025 (Page 7 of 159)
`
` 3
`
`
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`
`
`

`

`Declaration of Terence L. Threlfall, Ph.D.,
`In Support of Lupin Limited’s Petition for Inter Partes Review
`of U.S. Patent No. 8,518,987 B2
`
`
`8.
`
`In April 2006, I gave a lecture on crystallisation at the British
`
`Crystallographic Association Annual Meeting. In August 2007, I gave a lecture on
`
`crystallisation to the European Crystallography Association Meeting. I regularly
`
`lecture at such conferences. For example, I gave invited lectures at the British
`
`Crystallographic Association Autumn Meeting in Edinburgh in November 2010
`
`and at the CPOSS (Computer Prediction of the Organic Solid State) annual
`
`meeting in March 2011. My most recent appearances where I lectured by
`
`invitation were at the Pharmaceutical and Thermal Analysis Conference in Graz,
`
`Austria in May 2012; the Polymorphism and Crystallization conference in Prague,
`
`Czech Republic in November 2013; and before the Hungarian Academy of
`
`Sciences in Budapest, Hungary in April 2013.
`
` I presented lectures on
`
`crystallisation and polymorphism at the Crystal Growth of Organic Materials
`
`meeting in Limerick, Ireland in July 2013; at the British Association for Crystal
`
`Growth meeting in Leeds in July 2014; and at the University of Rouen, France in
`
`November 2014. In addition I regularly present lectures on crystallisation and
`
`polymorphism for industry.
`
`9.
`
`Exhibit 1026 is my curriculum vitae setting forth my educational
`
`experience, employment history, professional affiliations, and publications.
`
`Lupin Ex. 1025 (Page 8 of 159)
`
` 4
`
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`
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`

`

`Declaration of Terence L. Threlfall, Ph.D.,
`In Support of Lupin Limited’s Petition for Inter Partes Review
`of U.S. Patent No. 8,518,987 B2
`
`
`10.
`
`Prior to preparing this Declaration, I reviewed numerous documents,
`
`including but not limited to, the ‘987 patent and its file history; references in
`
`existence long before the ‘987 patent issued (described in greater detail below);
`
`other references and articles relevant to the case; and parts of the trial transcript in
`
`Janssen Products, L.P. et al. v. Lupin Ltd. et al., Consolidated Case No. 10-cv-
`
`5954 (D.N.J.), a prior litigation concerning related U.S. Patent No. 7,700,645 B2
`
`(“the related ‘645 patent”), which purportedly claims an ethanolate solvate form of
`
`darunavir. A list of the documents that I have considered and relied in connection
`
`with forming my opinions is included in Exhibit 1027. I also relied upon my
`
`education, background, and experience in reaching the conclusions and in forming
`
`the opinions set forth herein.
`
`11.
`
`I am being compensated at my customary hourly fee at the time of my
`
`engagement of $450 (or the equivalent in British Pound Sterling). My
`
`compensation is in no way dependent on the outcome of Lupin’s petition.
`
`III.
`
`SUMMARY OF OPINIONS
`
`12.
`
`I have been asked to opine on the subject matter set forth in the ‘987
`
`patent and its file history, including its discussion of purported hydrates of the
`
`compound
`
`(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl
`
`(1S,2R)-3-[[(4-
`
`Lupin Ex. 1025 (Page 9 of 159)
`
` 5
`
`
`
`
`
`

`

`Declaration of Terence L. Threlfall, Ph.D.,
`In Support of Lupin Limited’s Petition for Inter Partes Review
`of U.S. Patent No. 8,518,987 B2
`
`aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-hydroxypropylcarbamate,
`
`which is now known as darunavir.
`
`A.
`
`13.
`
`The Claims and Disclosures of the ‘987 Patent.
`
`The ‘987 patent, amongst other things, purports to claim hydrates of
`
`the compound darunavir, within a range of compound to water ratios, and
`
`compositions containing the same. Although the claims are directed to “hydrates,”
`
`the specification fails to characterise how they are prepared and isolated. In fact,
`
`the specification spends far more time describing other solvated forms, including
`
`the ethanolate solvate; fails to disclose any purported benefit associated with the
`
`preparation of hydrates; and arguably shows the existence of, at most, solvate-
`
`hydrates. For this reason, I am not convinced that the purported inventors of the
`
`‘987 patent were even in possession of all of the specific hydrated forms that they
`
`have claimed. Rather, they appear to claim a large range of possible hydrates of
`
`darunavir, whether stoichiometric or non-stoichiometric, and compositions
`
`containing the same, without having characterised the same in the specification.
`
`B.
`
`14.
`
`State of the Knowledge in the Art as of May 2003.
`
`I have also been asked to discuss the state of knowledge for a person
`
`of ordinary skill in the art as of May 16, 2003, regarding the compound darunavir
`
`Lupin Ex. 1025 (Page 10 of 159)
`
` 6
`
`
`
`
`
`

`

`Declaration of Terence L. Threlfall, Ph.D.,
`In Support of Lupin Limited’s Petition for Inter Partes Review
`of U.S. Patent No. 8,518,987 B2
`
`as well as the development and design of solid-state forms of pharmaceutical
`
`products, including those comprising the compound darunavir.
`
`15. By the May 2003 timeframe, a person of ordinary skill in the art
`
`would have known of the existence of darunavir as a potent HIV Protease
`
`Inhibitor. In fact, Arun K. Ghosh et al., Potent HIV Protease Inhibitors
`
`Incorporating High-Affinity P2-Ligands and (R)-(Hydroxyethylamino)Sulfonamide
`
`Isostere, 8 BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 687 (1998) (“Ghosh
`
`1998”) (Ex. 1002) discloses how to prepare the compound darunavir, teaches that
`
`the compound was in fact synthesized, and further discloses its potent HIV
`
`protease activity. U.S. Patent No. 6,248,775 B1 (“the ‘775 patent”) (Ex. 1003)
`
`claims darunavir as an HIV protease inhibitor and similarly discloses how to
`
`prepare the compound well before the May 2003 timeframe.
`
`16.
`
`It is my opinion that at least Ghosh 1998 and the ‘775 patent provide
`
`sufficient teachings to enable one of ordinary skill in the art how to make hydrates
`
`of darunavir (in accordance with the broad definitions of “hydrates” and
`
`“hydration” set forth in the ‘987 patent), including within the ratios of compound
`
`to water claimed. It is thus my opinion that in the May 2003 timeframe, a person
`
`of ordinary skill in the art would have been enabled to synthesize darunavir hydrate
`
`that meets the requirements of the ‘987 patent claims based on at least either one of
`
` 7
`
`
`
`
`
`Lupin Ex. 1025 (Page 11 of 159)
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`

`

`Declaration of Terence L. Threlfall, Ph.D.,
`In Support of Lupin Limited’s Petition for Inter Partes Review
`of U.S. Patent No. 8,518,987 B2
`
`these two references. My opinion is confirmed by the Applicants’ arguments
`
`during prosecution of the ‘987 patent that their own specification enabled the
`
`synthesis of the claimed hydrates (and compositions comprising the same) based
`
`on Examples which purportedly disclose the claimed compound and water. (See,
`
`e.g., Ex. 1012, ‘807 application PH, 7/20/2012 Reply at 8). Specifically,
`
`Applicants pointed to an Example which discusses water being added to a solution
`
`comprising some darunavir substance as well other Examples that discuss the
`
`conversion of various forms of darunavir upon exposure to various relative
`
`humidities. (Id. at 8-9). If these are sufficient to enable the ‘987 patent, Ghosh
`
`1998 or the ‘775 patent, by virtue of their similar disclosures, enable the claimed
`
`hydrates as well. My opinion is also confirmed by review of the Patent Owner’s
`
`own reference, Elke Van Gyseghem et al., Solid State Characterization of the Anti-
`
`HIV Drug TMC114: Interconversion of Amorphous TMC114 Ethanolate and
`
`Hydrate, 38 EUR. J. PHARMACEUTICAL SCI. 489 (2009) (“Van Gyseghem”) (Ex.
`
`1006). This reference explains that darunavir hydrates will likely form in the
`
`presence of water upon spontaneous conversion of some darunavir substance
`
`(including a solvate or amorphous form) at ambient conditions. (Id. at 497). This
`
`further demonstrates that the enabling processes of Ghosh 1998 and the ‘775 patent
`
`necessarily prepare the claimed hydrates. Moreover, as discussed below, repetition
`
` 8
`
`
`
`
`
`Lupin Ex. 1025 (Page 12 of 159)
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`

`

`Declaration of Terence L. Threlfall, Ph.D.,
`In Support of Lupin Limited’s Petition for Inter Partes Review
`of U.S. Patent No. 8,518,987 B2
`
`of the Ghosh 1998 art confirms the inherent presence of the claimed hydrates based
`
`on the ‘987 patent’s definition of the same.
`
`17.
`
`Furthermore, it is my opinion that by May 2003 timeframe, there was
`
`a sufficient body of scientific knowledge in the possession of the person of
`
`ordinary skill in the art teaching that crystalline forms of pharmaceutical drugs,
`
`including hydrates, were known in the art and were preferred over amorphous
`
`forms, thus creating motivation for the skilled chemist to attempt crystallisation of
`
`darunavir with an expectation that he or she would succeed. For example, by the
`
`relevant timeframe, the Food and Drug Administration (“FDA”) had explained
`
`why performing such crystallisation screens were critical in identifying the best
`
`solid-state form of a candidate for use in a pharmaceutical drug product and further
`
`noted that such crystallisation screens often produced hydrates. (See Ex. 1028,
`
`Guideline for Submitting Supporting Documentation in Drug Applications for the
`
`Manufacture of Drug Substances, FOOD & DRUG ADMINISTRATION (1987) (“FDA
`
`Guidelines”)).
`
`18. Regulatory guidelines required any drug compound being considered
`
`for further development to undergo certain routine evaluations, and usually before
`
`clinical trials meaningfully began. It was known that drug molecules frequently
`
`existed in more than one solid state form (whether polymorphic, hydrated,
`
` 9
`
`
`
`
`
`Lupin Ex. 1025 (Page 13 of 159)
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`

`

`Declaration of Terence L. Threlfall, Ph.D.,
`In Support of Lupin Limited’s Petition for Inter Partes Review
`of U.S. Patent No. 8,518,987 B2
`
`amorphous, etc.), and
`
`thus, such guidelines encouraged comprehensively
`
`identifying and characterising such forms during the early stages of drug
`
`development. (Ex. 1004, Stephen Byrn et al., Pharmaceutical Solids: A Strategic
`
`Approach to Regulatory Considerations, 12 PHARMACEUTICAL RES. 945, 945
`
`(1995) (“Byrn 1995”)). The prior art had further disclosed how such routine
`
`crystallisation screens should be performed. (Id. at 945-46).
`
`19.
`
`Furthermore, by May 2003, Gautam Desiraju, a well-known expert in
`
`the field of crystallisation, taught that compounds like darunavir, in which there is
`
`an imbalance in the ratio of hydrogen bond donors to hydrogen bond acceptors, are
`
`more likely to form hydrates. (Ex. 1005, Gautam R. Desiraju, Hydration in
`
`Organic Crystals: Prediction from Molecular Structure, 6 J. CHEMICAL SOC’Y
`
`CHEMICAL COMM. 426, 427 (1991) (“Desiraju 1991”)). With this knowledge in
`
`hand, in my opinion, a person of ordinary skill in the art would have reasonably
`
`expected that performing a routine crystallisation screen could form hydrates of
`
`darunavir.
`
`20. As to the ratio of compound to water elements of the claims of the
`
`‘987 patent, all this demonstrates is that the purported inventors attempted to claim
`
`a majority of the likely ranges of ratios of water to compound, namely between a
`
`hemi- and tri-hydrate. Particularly in view of the fact that no specific hydrate is
`
`
`
`
`10
`
`Lupin Ex. 1025 (Page 14 of 159)
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`

`

`Declaration of Terence L. Threlfall, Ph.D.,
`In Support of Lupin Limited’s Petition for Inter Partes Review
`of U.S. Patent No. 8,518,987 B2
`
`actually properly characterised in the specification of the ‘987 patent, I find the
`
`ranges claimed to be apparent and utterly obvious.
`
`21. As to the formulation elements of the claims of the ‘987 patent, the
`
`idea of formulating compounds, including darunavir, with a carrier was well-
`
`known in the art. Such compositions were in fact specifically disclosed in Ghosh
`
`1998 and claimed in the ‘775 patent. Furthermore, the use of hydrates, in
`
`particular, in formulating compositions by May 2003, was simply ubiquitous in the
`
`art. In sum, the claims of the ‘987 patent attempt to claim what was known and
`
`obvious in the art.
`
`22.
`
`I have also seen no evidence in the specification or otherwise, that the
`
`claimed “hydrates,” or compositions containing thereof, had any unexpected
`
`benefits over any prior art darunavir. Indeed, neither the specification nor the
`
`prosecution history of the ‘987 patent offers any comparison of the hydrated forms
`
`claimed to what was disclosed in Ghosh 1998 and the ‘775 patent.
`
`IV.
`
`SCIENTIFIC BACKGROUND.
`
`A.
`
`Polymorphism and Crystal Forms.
`
`23. A vast majority of organic molecules, including large, complex
`
`pharmaceutical compounds with torsional flexibility, are capable of existence in
`
`the solid state in a variety of crystalline and non-crystalline forms. (See Ex. 1029,
`
`
`
`
`11
`
`Lupin Ex. 1025 (Page 15 of 159)
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`

`

`Declaration of Terence L. Threlfall, Ph.D.,
`In Support of Lupin Limited’s Petition for Inter Partes Review
`of U.S. Patent No. 8,518,987 B2
`
`Preface, in POLYMORPHISM IN PHARMACEUTICAL SOLIDS iii, iii-v (Harry G. Brittain
`
`ed., 1999) (“Brittain”); Ex. 1030, David J.W. Grant, Theory and Origin of
`
`Polymorphism, in POLYMORPHISM IN PHARMACEUTICAL SOLIDS 1, 8 (Harry G.
`
`Brittain ed. 1999) (“Grant”)). This variety can be due to different modes of
`
`packing of the molecules in the crystal, called polymorphism. (Ex. 1031, John
`
`Haleblian & Walter McCrone, Pharmaceutical Applications of Polymorphism, 58
`
`J. PHARMACEUTICAL SCI. 911 (1969) (“McCrone”)). These different modes of
`
`packing are often accompanied by changes in the shape (conformation) of the
`
`molecule, or based on the lack of long-range periodic order, resulting in
`
`amorphous forms. (Id.; Ex. 1029, Brittain at iii; Ex. 1030, Grant at 8).
`
`24.
`
`Sometimes three or more components, such as an organic molecule,
`
`plus water plus a solvent such as ethanol find it ideal to pack together into a crystal
`
`lattice. (Ex. 1032, J. Keith Guillory, Generation of Polymorphs, Hydrates,
`
`Solvates, and Amorphous Solids, in POLYMORPHISM IN PHARMACEUTICAL SOLIDS
`
`183, 206-07 (Harry G. Brittain ed., 1999) (“Guillory”)). At other times, a molecule
`
`can pack together with a second large molecule to form a crystal lattice. (Id. at
`
`215). For many decades, these were called molecular adducts, or molecular
`
`compounds or molecular complexes, but in more recent times they have come to
`
`be called “co-crystals” in pharmaceutical parlance. (See Ex. 1033, Örn Almarsson
`
`
`
`
`12
`
`Lupin Ex. 1025 (Page 16 of 159)
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`

`

`Declaration of Terence L. Threlfall, Ph.D.,
`In Support of Lupin Limited’s Petition for Inter Partes Review
`of U.S. Patent No. 8,518,987 B2
`
`& Michael J. Zaworotko, Crystal Engineering of
`
`the Composition of
`
`Pharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a New Path to
`
`Improved Medicines?, CHEMICAL COMM. 1889, 1893 (2004) (“Almarsson”)).
`
`25.
`
`If the molecule in question has acidic or basic centres, then it can
`
`attract basic or acidic groups respectively, to form a salt. In salts, exchange of
`
`hydrogen from the acidic to the basic centre in the form of hydrogen ions (protons)
`
`has taken place and a strong ionic bond is formed. (Ex. 1035, Steven S. Zumdahl,
`
`CHEMISTRY 44, 297, 592 (1986) (“Zumdahl”)). Alternatively, a neutral molecule
`
`may be the second component of a crystal. So, there are a number of ways in
`
`which two or more components can come together to form a crystalline, or non-
`
`crystalline, solid.
`
`B.
`
`26.
`
`Crystallinity and Hydrogen Bonding.
`
`The existence and stability of a crystalline form can be either due to
`
`favourable shape fitting, as when a second molecule, often a small one, occupies a
`
`hole in the crystal lattice created by the difficulty encountered by awkwardly
`
`shaped molecules to pack together compactly; or the favourable circumstance is
`
`more often due to specific attraction between the two (or more) components. (Ex.
`
`1034, Stephen R. Byrn et al., Hydrates and Solvates, in SOLID-STATE CHEMISTRY
`
`
`
`
`13
`
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`

`

`Declaration of Terence L. Threlfall, Ph.D.,
`In Support of Lupin Limited’s Petition for Inter Partes Review
`of U.S. Patent No. 8,518,987 B2
`
`OF DRUGS 233, 234 (2d ed. 1999) (“Byrn 1999”)). These attractions are most
`
`commonly due to hydrogen bonding. (Id. at 234, 236).
`
`27. Virtually every organic molecule, especially one with biological
`
`activity, contains hydrogen atoms commonly attached to carbon, oxygen, nitrogen
`
`or sulfur, although equally the hydrogen atoms they can be attached to other, less
`
`common, elements. The hydrogen atoms on oxygen or nitrogen are less strongly
`
`bound than those on carbon, so that an electron rich area of a second molecule can
`
`attract such a hydrogen atom to form a hydrogen bond. (Ex. 1035, Zumdahl at
`
`299-301, 385-386).
`
`28.
`
`Equally it could be regarded as the electron deficient hydrogen
`
`attracting the electrons of the high electron density region. Such hydrogen bonds
`
`are relatively strong, directional, attractions whose force falls off slowly with
`
`distance, so they form strong bonds between molecules. Hence, they can be crystal
`
`structure determining. The prediction of structures of crystals by consideration of
`
`the formation of hydrogen bond networks has become a fundamental basis of the
`
`area of organic (and organometallic) solid-state science known as crystal
`
`engineering. (Ex. 1005, Desiraju 1991 at 426; Ex. 1036, R. Docherty, The
`
`Application of Computational Chemistry to the Study of Molecular Materials, in
`
`
`
`
`14
`
`Lupin Ex. 1025 (Page 18 of 159)
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`

`

`Declaration of Terence L. Threlfall, Ph.D.,
`In Support of Lupin Limited’s Petition for Inter Partes Review
`of U.S. Patent No. 8,518,987 B2
`
`CRYSTAL GROWTH OF ORGANIC MATERIALS 2, 2-3 (Allan S. Myerson et al. eds.,
`
`1996) (“Docherty”)).
`
`29. Hydrogen bonds form an essential component of many solids
`
`consisting of only one component because they can form between electron rich
`
`regions and electron poor hydrogen atoms of a single molecular species. Weaker
`
`but significant hydrogen bonds also form from hydrogen atoms on carbon. (Ex.
`
`1036, Docherty at 2). Similarly, halogens (iodine, bromine, chlorine and possibly
`
`fluorine) can form weaker hydrogen and halogen bonds. The resulting crystal
`
`structure is determined by the interplay of the various attractions and repulsions
`
`between the molecule in such a way so as to minimize the overall energy. (Id. at 2-
`
`4).
`
`C.
`
`Hydrates and Solvates.
`
`30. Because it is a very small entity, water, H—O—H, with two hydrogen
`
`atoms capable of forming strong hydrogen bonds and oxygen, the electron pairs of
`
`which can act as hydrogen bond acceptors, is particularly prone to enter into the
`
`crystal lattice of organic compounds. (Ex. 1005, Desiraju 1991 at 426; Ex. 1034,
`
`Byrn 1999 at 233, 236). These resulting species are ordinarily known as hydrates.
`
`(Ex. 1034, Byrn 1999 at 236).
`
`
`
`
`15
`
`Lupin Ex. 1025 (Page 19 of 159)
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`

`

`Declaration of Terence L. Threlfall, Ph.D.,
`In Support of Lupin Limited’s Petition for Inter Partes Review
`of U.S. Patent No. 8,518,987 B2
`
`
`31. Desiraju 1991 in fact teaches that “[b]ecause of its small size and
`
`excellent hydrogen bonding ability, water is almost never an innocuous bystander
`
`in an organic crystal structure.” (Ex. 1005, Desiraju 1991 at 426). Desiraju 1991
`
`further teaches that “[w]ater is incorporated into organic crystals far more
`
`frequently than other common solvents.” (Id. at 427). Desiraju 1991 further
`
`states:
`
`Of the 69 691 entries in the 1988 (3.1) version of the CSD, 33 886 do
`not contain any metal atom and of these, 3696 are solvates. It is
`appropriate to consider only those entries without metal atoms since
`water enters the coordination sphere of transition metal ions so
`readily. Even when these ‘pure’ organics are surveyed, the number of
`entries having water of crystallisation is far in excess of the number
`having other solvents. The following figures were obtained: water
`(2566); methanol (306); diethyl ether (175); benzene (173); ethanol
`(168); acetone (108); chloroform (102); other (98).
`
`(Id.).
`
`
`32. Hydrates are thus very common and can be very easily formed, at
`
`times inadvertently, due to the prevalence of trace water in solvents, in the
`
`atmosphere, and on surfaces, or directly through the use of water as a
`
`crystallisation solvent. (Ex. 1034, Byrn 1999 at 239-43; Ex. 1004, Byrn 1995 at
`
`945, 949). This is precisely why such forms are generally the subject of
`
`
`
`
`16
`
`Lupin Ex. 1025 (Page 20 of 159)
`
`

`

`Declaration of Terence L. Threlfall, Ph.D.,
`In Support of Lupin Limited’s Petition for Inter Partes Review
`of U.S. Patent No. 8,518,987 B2
`
`conversion studies requiring changing the relative humidity and monitoring to
`
`demonstrate whether or not conversion occurs. (Ex. 1004, Byrn 1995 at 949, 952).
`
`33. As noted in the art in regards to stoichiometric ratios, there is an
`
`expectation that, should a hydrate form (and, as discussed above, it is quite
`
`common), it will be a monohydrate. (See, e.g., Ex. 1037, Terence L. Threlfall,
`
`Analysis of Organic Polymorphs: A Review, 120 ANALYST 2435, 2450 (1995)
`
`(“Threlfall”)). However, it is noteworthy that the space in a unit cell for a small
`
`molecule can result in multiple, fractional, irrational, or variable molar ratios.
`
`(Id.). Thus, when looking at pharmaceutical compounds, one expects to obtain
`
`hydrates of various rat