Case 1:19-cv-01489-RGA Document 94-1 Filed 07/17/20 Page 2 of 501 PageID #: 2189
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`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
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`IN RE: SITAGLIPTIN PHOSPHATE
`(’708 & ’921) PATENT LITIGATION
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`MDL No. 19-2902-RGA
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`C.A. Nos. 19-310-RGA,
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`19-311-RGA,
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`19-312-RGA,
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`19-313-RGA,
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`19-314-RGA,
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` 19-317-RGA,
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`19-318-RGA,
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`19-319-RGA,
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` 19-321-RGA,
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`19-347-RGA,
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` 19-1489-RGA
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`DECLARATION OF GRAHAM BUCKTON, Ph.D., D.Sc.
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`I, Graham Buckton, declare and state as follows:
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`I.
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`INTRODUCTION
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`1.
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`I have been retained as an expert witness by Teva Pharmaceuticals USA and
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`Watson Laboratories, Inc.; Sandoz Inc.; Lupin Limited and Lupin Pharmaceuticals, Inc.; Anchen
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`Pharmaceuticals, Inc. and Par Pharmaceutical, Inc.; and Wockhardt Bio AG and Wockhardt USA
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`LLC; Sun Pharmaceutical Industries Ltd; Apotex Inc. and Apotex Corp.; and Zydus
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`Pharmaceuticals (USA) Inc. and Cadila Healthcare Limited (collectively, “Defendants”). I have
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`been asked by counsel for Defendants to provide my opinion about the meaning, to a person of
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`ordinary skill in the art, of the following terms in the claims of U.S. Patent No. 7,326,708 (“the
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`’708 patent”):
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` “crystalline monohydrate [of the dihydrogen phosphate salt of sitagliptin]”
`(claims 4 and 24)
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`1
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` “characteristic absorption bands obtained from the X-ray powder diffraction
`pattern at spectral d-spacings of” (claims 5-7)
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` “crystallizing the dihydrogenphosphate salt of [sitagliptin] at 25 °C” (claim
`24)
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`2.
`
`I have personal knowledge of the facts stated herein and am competent to testify
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`to the same.
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`II.
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`SUMMARY OF OPINIONS
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`3.
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`In my opinion, a person of ordinary skill in the art:
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` would understand the phrase “crystalline monohydrate [of the dihydrogen
`phosphate salt of sitagliptin]” to mean “a repeating unit cell incorporating a
`fixed 1:1 ratio of water to a dihydrogenphosphate salt of sitagliptin”
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` would not understand the literal meaning of the term “characteristic
`absorption bands obtained from the X-ray powder diffraction pattern at
`spectral d-spacings of” as written; and
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` would understand the phrase “crystallizing the dihydrogenphosphate salt of
`[sitagliptin] at 25 °C” to mean “performing the crystallization of the
`monohydrate of sitagliptin dihydrogenphosphate wherein the formation of
`crystalline solids begin at 25 °C.”
`
`III. QUALIFICATIONS AND CREDENTIALS
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`4.
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`I am currently working as a pharmaceutical consultant and am an Emeritus
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`Professor of Pharmaceutics at UCL School of Pharmacy, University of London.
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`5.
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`I received my Bachelor of Pharmacy from Chelsea College, University of London
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`in 1981, a Ph.D. from King’s College, University of London in 1985, and a Doctor of Science
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`from University of London in 1997 for my research work in pharmaceutical materials science.
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`6.
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`From 1988 to 2015, I was on the faculty of the School of Pharmacy at University
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`of London. I became a Professor of Pharmaceutics in 1998, and served as the Head of the
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`Department of Pharmaceutics from 2001 to 2007. My research interests during my academic
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`career related to investigating the behaviour of pharmaceutical materials, in relation to
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`2
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`pharmaceutical processing and formulation. This work included modifying the physical
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`properties of powders by crystallisation and physical manipulation as well as preparation and
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`analytical characterisation of powders for pharmaceuticals.
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`7.
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`Prior to joining the faculty at the School of Pharmacy at University of London, I
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`was a Lecturer in Pharmacy at Chelsea Department of Pharmacy at King’s College at the
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`University of London from 1984 to 1988. I also worked as a pre-registration pharmacist at the
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`Charing Cross Hospital from 1981 to 1982, as well as a locum tenens pharmacist from 1982 to
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`1988. In 1987, I was seconded at Ciba-Geigy Pharmaceuticals in their Advanced Drug Delivery
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`Research unit for about 6 months.
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`8.
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`Additionally, in 2000, I founded, and was Chief Executive Officer of,
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`Pharmaterials Ltd, a company that provided salt selection, polymorph screening, pre-
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`formulation, formulation development, analytical development, stability testing and GMP
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`clinical trial manufacturing. I sold my final stake in the company in 2012.
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`9.
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`I am currently a member of the Chemistry, Pharmacy and Standards
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`Subcommittee of the Commission on Human Medicines1, and I am on the steering committee of
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`The Handbook of Pharmaceutical Excipients. I was Editor of the International Journal of
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`Pharmaceutics for a 10-year period and served on the editorial boards of several journals,
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`including Pharmaceutical Research, the American Association of Pharmaceutical Scientists
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`(AAPS) Journal and AAPS Pharm Sci Tech. I have received a number of awards and have been
`
`
`1 The Commission on Human Medicines (CHM) is the body which grants and revokes marketing
`authorisations for drug products in the UK, equivalent to the FDA in the US. Decisions are
`made through expert groups, following assessments by staff at the Medicines and Healthcare
`products Regulatory Agency (MHRA). Prior to CHM, UK medicines regulation was through the
`Committee on Safety of Medicines (CSM). I was a member of CSM and chaired its Chemistry,
`Pharmacy and Standards committee.
`
`3
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`made a fellow of the Royal Pharmaceutical Society, the Royal Society of Chemistry, AAPS and
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`the Academy of Pharmaceutical Sciences of Great Britain.
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`10.
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`I have authored over 180 peer-reviewed journal publications as well as a book,
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`and I have given over 130 invited and external lectures since 2001. I have also been named as an
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`inventor on a number of patents and patent applications.
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`11.
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`A copy of my curriculum vitae is attached as J.A. 26.
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`IV. MATERIALS CONSIDERED
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`12.
`
`In forming my opinions and preparing this declaration, I have relied upon my
`
`years of training, knowledge and experience in the relevant field, and have reviewed, among
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`other things, the ’708 patent, the Declaration of Professor Allan S. Myerson, Ph.D. Regarding
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`Claim Construction (J.A. 3) and the materials cited therein, and the materials cited in this
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`declaration.
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`V.
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`LEGAL STANDARDS
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`13.
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`In formulating my opinions, counsel in this case has informed me of certain
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`principles of U.S. patent law that govern claim construction and indefiniteness of claim terms.
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`The discussion of legal principles set forth below is not intended to be exhaustive and is merely
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`intended to provide some context for the opinions that I provide.
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`14.
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`I understand that terms in a patent claim are given the meaning they would have
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`to a person of ordinary skill in the art at the time of the invention in view of the patent’s claims,
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`the specification, and prosecution history. I understand that when construing claim terms, the
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`words of the claims provide the starting point for claim construction and must be given their
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`ordinary and customary meaning in the field of the invention. I understand, however, that the
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`inventors may assign their own meaning to the words of a claim by acting as their own
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`lexicographers. I understand that any special definition given to words or terms must be clearly
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`4
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`defined in the specification or prosecution history to alter the plain and ordinary meaning of
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`those terms. Furthermore, I understand that narrower definitions of claim terms may be
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`appropriate if a patentee clearly and unambiguously surrendered subject matter during
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`prosecution. I further understand that “extrinsic evidence,” such as dictionaries or treatises,
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`though not given as much weight as the claim language, may sometimes also demonstrate the
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`ordinary and customary meaning of a term to a person of ordinary skill in the art.
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`15.
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`I further understand that a claim is indefinite if it fails to inform those skilled in
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`the art about the scope of the invention with reasonable certainty. I understand that if it would be
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`apparent to one of skill in the art, based on the specification, that the invention set forth in a
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`claim is not what the patentee regarded as his invention, then that claim is indefinite. I also
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`understand that even when a POSA would understand that a disputed term may mean something
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`other than what the words of a claim literally say, if the specification provides no alternative
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`meaning for literal words of the claim, and the claim, as literally written, is nonsensical or
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`incomprehensible, then that claim is indefinite. I understand that it is the role of neither a POSA
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`nor the Court to redraft claims to make them operable or sustain their validity.
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`VI.
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`THE PATENT-IN-SUIT AND THE DISPUTED CLAIM TERMS
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`16.
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`The ’708 patent is titled “Phosphoric Acid Salt of a Dipeptidyl Peptidase-IV
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`Inhibitor.” I understand that the ’708 patent was filed on June 23, 2004, and issued on February
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`5, 2008.
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`17.
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`I understand that the following claims are representative of the claims implicated
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`by the terms at issue for claim construction:
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`1. A dihydrogenphosphate salt of 4-oxo-4-[3-(trifluoromethyl)-5,6-
`dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-
`trifluorophenyl)butan-2-amine of structural formula I:
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`5
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`or a hydrate thereof.
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`4. The salt of claim 2 characterized in being a crystalline
`monohydrate.
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`5. The salt of claim 4 characterized by characteristic absorption
`bands obtained from the X-ray powder diffraction pattern at
`spectral d-spacings of 7.42, 5.48, and 3.96 angstroms.
`
`24. A process for preparing the crystalline monohydrate of claim 4
`comprising the steps of:
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`(a) crystallizing the dihydrogenphosphate salt of structural formula
`(II):
`
`
`
` at 25° C. from a mixture of isopropanol and water, such that the
`water concentration is above 6.8 weight percent;
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`(b) recovering the resultant solid phase; and
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`(c) removing the solvent therefrom.
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`6
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`18. With respect to claim 4, the patent specification states that the crystalline
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`monohydrate form of sitagliptin dihydrogenphosphate “was shown to be monohydrate by X-ray
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`powder diffraction and thermogravimetric analysis.” J.A. 1 (’708 patent) at 13:19-21. The
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`patent specification further provides data from these X-ray powder diffraction (“XRPD”) and
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`thermogravimetric (“TGA”) analyses. J.A. 1 (’708 patent) at 13:29-36, 14:12-28. In addition,
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`the patent specification further characterises the claimed crystalline monohydrate using nuclear
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`magnetic resonance and differential scanning calorimetry (“DSC”). J.A. 1 (’708 patent) at
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`13:37-14:11, 14:29-46.
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`19.
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`Relevant to my opinions herein, the patent specification discloses that, when the
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`monohydrate is subjected to TGA, the monohydrate does not begin to lose water until heated to
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`over approximately 100 °C. J.A. 1 (’708 patent) at Figure 42. The specification also discloses
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`that, when the monohydrate is subjected to DSC, the monohydrate has two thermal events: one
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`with an onset at 138.1 °C (and peak at 140.7 °C) and a second with an onset at 209.6 °C (and
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`peak at 213.2 °C). J.A. 1 (’708 patent) at Figure 53.
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`20. With respect to claim 24, the ’708 patent provides a single specific detailed
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`example of crystallising sitagliptin dihydrogenphosphate through solution cooling:
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`A 250 mL round bottom flask equipped with an overhead stirrer,
`heating mantle and thermocouple, was charged with 31.5 mL of
`isopropanol (IPA), 13.5 mL water, 15.0 g (36.9 mmol) of (2R)-4-
`oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-
`a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)
`butan-2-amine
`freebase and 4.25 g (36.9 mmol) of 85% aqueous phosphoric acid.
`The mixture was heated to 75° C. A thick white precipitate formed
`at lower temperatures but dissolved upon reaching 75° C. The
`solution was cooled to 68° C. and then held at that temperature for
`2 h. A slurry bed of solids formed during this age time [the solution
`can be seeded with 0.5 to 5 wt % of small particle size (alpine
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`2 The TGA method is described at J.A. 1 (’708 patent) at 14:12-28.
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`3 The DSC method is described at J.A. 1 (’708 patent) at 14:29-46.
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`7
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`milled) monohydrate]. The slurry was then cooled at a rate of 4° C./h
`to 21° C. and then held overnight. 105 mL of EPA was then added
`to the slurry. After 1 h the slurry was filtered and washed with 45
`mL IPA (solids can also be washed with a water/IPA solution to
`avoid turnover to other crystal forms). The solids were dried on the
`frit with open to air. 18.6 g of solids were recovered.
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`J.A. 1 (’708 patent) at 12:64-13:15.
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`21. With respect to the claim terms that I was asked to address, I understand that the
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`parties dispute the meanings of those terms and propose the following respective constructions
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`and/or arguments:
`
`Claim Term
`
`Defendants’ Proposed
`Construction
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`Merck’s Proposed
`Construction
`
`“crystalline monohydrate [of
`the dihydrogen phosphate salt
`of sitagliptin]” (claims 4 and
`24)
`
`“a repeating unit cell
`incorporating a fixed 1:1 ratio
`of water to a
`dihydrogenphosphate salt of
`sitagliptin”
`
`Plain and ordinary meaning.
`
`To the extent the Court deems
`a construction to be
`necessary, then:
`
`Indefinite.
`
`“a repeating unit cell
`incorporating a 1:1 ratio of
`water to a
`dihydrogenphosphate salt of
`sitagliptin”
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`Not indefinite: “characteristic
`diffraction peaks
`corresponding to d-spacings
`of”
`
`“performing the
`crystallization of the
`monohydrate of sitagliptin
`dihydrogenphosphate wherein
`the formation of crystalline
`solids begins at 25 °C”
`
`“performing the
`crystallization of the
`dihydrogenphosphate salt of
`sitagliptin wherein some or
`all of the crystallization
`occurs at 25 °C”
`
`“characteristic absorption
`bands obtained from the X-
`ray powder diffraction pattern
`at spectral d-spacings of”
`(claims 5-7)
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`“crystallizing the
`dihydrogenphosphate salt of
`[sitagliptin] at 25 °C” (claim
`24)
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`8
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`VII. THE PERSON OF ORDINARY SKILL IN THE ART (“POSA”)
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`22.
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`I understand that the person of ordinary skill in the art (“POSA”) is a hypothetical
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`person who is presumed to have known all of the relevant art at the time of the invention. I
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`understand factors that may be considered in determining the level of ordinary skill in the art
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`may include: (A) type of problems encountered in the art; (B) prior art solutions to those
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`problems; (C) rapidity with which innovations are made; (D) sophistication of the technology;
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`and (E) educational level of active workers in the field.
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`23.
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`I understand that Plaintiff contends that certain claims of the ’708 patent are
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`entitled to a date of invention as early as December 13, 2001, and that Defendants contend all
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`claims of the ’708 patent are entitled to a date of invention no earlier than June 24, 2003. My
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`opinions regarding the qualifications and knowledge of a POSA expressed herein would not
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`change regardless of which date of invention applies.
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`24.
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`In my opinion, a POSA for the ’708 patent would include a person having a
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`doctoral degree in pharmaceutical sciences, a field of chemistry relating to physical form of
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`crystals or drug delivery, or a related field with at least two years’ experience working with solid
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`state materials for pharmaceuticals, including characterisation thereof, in relation to the
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`development of pharmaceutical formulations. A POSA may have an education level lower than
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`a doctoral degree in pharmaceutical sciences, chemistry, or a related field if they have
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`commensurately more relevant work experience. A POSA may have also worked as part of a
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`multi-disciplinary team and drawn upon not only his or her own skills, but also consulted with
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`others on the team having specialised skills, to solve a given problem. I would have been a
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`person of skill in the art at 2001-2004.
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`25.
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`I understand that Dr. Myerson provides a slightly different definition of a POSA;
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`however, my opinions would not change if I were to use Dr. Myerson’s definition.
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`9
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`VIII. DETAILED OPINIONS
`A.
`
`“crystalline monohydrate [of the dihydrogen phosphate salt of sitagliptin]”
`(claims 4 and 24)
`1.
`
`Background on Crystalline Solids and Hydrates
`
`26.
`
`The majority of drug substances exist as crystalline solids. J.A. 8 (Vippagunta
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`2001)4 at 4. These crystalline solids are made up of drug molecules packed in repeating three-
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`dimensional structures called unit cells. J.A. 8 (Vippagunta 2001) at 4; J.A. 27 (Brittain & Byrn
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`1999)5 at 75-76.
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`27.
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`Some crystal forms include molecules from the solvent used in the crystallisation
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`process; these are called solvates. J.A. 8 (Vippagunta 2001) at 4; J.A. 9 (Newman 2002)6 at 31.
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`The presence of solvent molecules in the crystal lattice imparts different physicochemical
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`properties compared to crystal lattices composed of unit cells containing the drug molecule
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`alone. J.A. 8 (Vippagunta 2001) at 4; J.A. 9 (Newman 2002) at 31; J.A. 28 (Khankari 1995)7 at
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`61-62.
`
`28.
`
`In the case where the solvent molecules in a crystal lattice are water, the crystals
`
`are called hydrates. Some crystalline hydrates have water molecules present at regular positions
`
`in the unit cells making up the crystal lattice (J.A. 28 (Khankari 1995) at 62; J.A. 9 (Newman
`
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`4 Sudha R. Vippagunta et al., “Crystalline solids,” Advanced Drug Delivery Reviews, 48:3–26
`(2001).
`
`5 Harry G. Brittain and Stephen R. Byrn, “Structural Aspects of Polymorphism,” in
`POLYMORPHISM IN PHARMACEUTICAL SOLIDS (Harry G. Brittain ed., 1st ed. 1999).
`
`6 A.W. Newman and G.P. Stahly, “Form Selection of Pharmaceutical Compounds,” in
`HANDBOOK OF PHARMACEUTICAL ANALYSIS (2002).
`
`7 Rajendra K. Khankari and David J.W. Grant, “Pharmaceutical hydrates,” Thermochimica Acta,
`248:61-79 (1995).
`
`10
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`2002) at 31; J.A. 20 (Guillory 1999)8 at 203), whilst other hydrates have water molecules in
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`voids in the crystal lattice that can form during the crystallisation process (J.A. 8 (Vippagunta
`
`2001) at 4; J.A. 20 (Guillory 1999) at 203, 205; J.A. 29 (Florence)9 at 18).
`
`29. When a crystal incorporates water molecules at regular fixed positions, the
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`resulting hydrate is called a stoichiometric hydrate. J.A. 28 at 62 (Khankari 1995) (“In
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`[stoichiometric] hydrates, water occupies definite positions in the crystal lattice, usually by
`
`forming hydrogen bond(s) . . . with the anhydrate drug molecules.”); see also J.A. 20 (Guillory
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`1999) at 202-03; J.A. 29 (Florence) at 18. In stoichiometric hydrates, the water molecules are
`
`held in fixed positions and contribute to the dimensions and strength of the unit cell in the crystal
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`lattice. J.A. 28 (Khankari 1995) at 63.
`
`30.
`
`In contrast, non-stoichiometric hydrates (sometimes called channel hydrates)
`
`occur when water molecules “merely occup[y] voids,” i.e., empty spaces, “in the crystal”
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`structure. J.A. 29 (Florence) at 18. Consequently, the water molecules “[are] not part of the
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`crystal bonding” and “not in well-defined positions and therefore [] present in variable amounts.”
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`J.A. 29 (Florence) at 18; J.A. 30 (Byrn 1999)10 at 512.
`
`31.
`
`Stoichiometric and non-stoichiometric hydrates can also be differentiated by how
`
`easily their associated water molecules can be removed or added. Stoichiometric hydrates will
`
`have water bonded into the lattice and generally will lose their water molecules less readily (and
`
`will usually do so in stoichiometric amounts, i.e., in a stoichiometric monohydrate, one molecule
`
`
`8 J. Keith Guillory, “Generation of Polymorphs, Hydrates, Solvates, and Amorphous Solids,” in
`POLYMORPHISM IN PHARMACEUTICAL SOLIDS (Harry G. Brittain ed., 1st ed. 1999).
`
`9 A.T. Florence and D. Attwood, “Properties of the Solid State” in PHYSICOCHEMICAL
`PRINCIPLES OF PHARMACY (3d ed. 1998).
`
`10 Stephen R. Byrn et al., SOLID-STATE CHEMISTRY OF DRUGS (2d ed. 1999).
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`11
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`of water per molecule of drug compound will be removed at, essentially, a discrete temperature),
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`than non-stoichiometric hydrates. Water molecules in non-stoichiometric hydrates tend to be
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`lost and added readily with changes in the environment (such as relative humidity and
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`temperature). J.A. 29 (Florence) at 18; J.A. 8 (Vippagunta 2001) at 15-16; J.A. 30 (Byrn 1999)
`
`at 512.
`
`32.
`
`Stoichiometric hydrates can be classified based on the ratio of water to drug
`
`molecules. Monohydrates have a ratio of drug to water molecules of 1:1, other types of hydrates,
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`such a dihydrates (1 drug molecule to 2 water molecules), trihydrates (1:3), and hemihydrates
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`(2:1) are further examples of stoichiometric hydrates. J.A. 9 (Newman 2002) at 32. Given that
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`non-stoichiometric hydrates vary in the content of water in the crystal as a function of
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`environmental conditions, it is clear that as they are heated (for example) they will progress from
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`a high to low water content in the crystal. For a non-stoichiometric hydrate, even though, at
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`certain environmental conditions, the ratio of water molecules to drug substance in the crystal
`
`may happen to be an integer, a POSA would not consider it to be a stoichiometric hydrate at that
`
`moment in time.
`
`33.
`
`Different crystal forms (e.g. anhydrate or different hydrates) of the same drug
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`substance will be expected to have different physicochemical properties. J.A. 8 (Vippagunta
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`2001) at 4 (“Because different crystalline polymorphs and solvates differ in crystal packing,
`
`and/or molecular conformation as well as in lattice energy and entropy, there are usually
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`significant differences in their physical properties, such as density, hardness, tabletability,
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`refractive index, melting point, enthalpy of fusion, vapor pressure, solubility, dissolution rate,
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`other thermodynamic and kinetic properties and even color.”) A POSA will typically pick a
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`certain crystalline hydrate or polymorph to formulate into a drug product based on its stability
`
`12
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`over normal processing and storage conditions, and its other physicochemical properties. In fact,
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`the ’708 patent states that the claimed crystalline monohydrate has “advantageous properties in
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`the preparation of solid pharmaceutical dosage forms” in view of its “enhanced chemical and
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`physical stability.” J.A. 1 (’708 patent) at 4:21-28.
`
`2.
`
`Defendants’ Proposed Construction Is Consistent with How a POSA
`Would Understand the Term “Crystalline Monohydrate” in View of
`the Specification
`
`34.
`
`The ’708 patent repeatedly refers to “the crystalline monohydrate.” J.A. 1 (’708
`
`patent) 2:23-39, 4:3-16, 4:39-5:10, 13:37-40, 13:64-14:47. A POSA would understand that “the
`
`crystalline monohydrate” described in the ’708 patent is a stoichiometric monohydrate with
`
`water held in a fixed defined position in the unit cell. In other words, a crystalline monohydrate
`
`that incorporates water molecules into a unit cell at a fixed 1:1 ratio of water to sitagliptin
`
`dihydrogenphosphate. This is the standard use of the term in the art, it is what is described in the
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`specification, and it is supported by the TGA and DSC analysis of the claimed crystalline
`
`monohydrate.
`
`35.
`
`TGA and DSC analyses are each techniques that can be used to measure the loss
`
`of water from hydrates. J.A. 31 (Byrn 1995)11 at 949 (“TGA is another powerful method for the
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`analysis of [hydrates]. . . . DSC is also a good method for detecting solvates since there is
`
`usually heat change involved in desolvation, especially for hydrates.) TGA shows loss of water
`
`by recording a loss in mass of the crystalline solid upon heating, while DSC shows a loss of
`
`water in the form of a thermal event during heating.
`
`36.
`
`A POSA reading the ‘708 patent would understand the crystalline monohydrate
`
`that is described and claimed to be a stoichiometric hydrate, and this view would be supported by
`
`
`11 Stephen Byrn et al., “Pharmaceutical Solids: A Strategic Approach to Regulatory
`Considerations,” Pharmaceutical Research 12:945-954 (1995).
`
`13
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`the TGA data in the ’708 patent specification, which demonstrate that water in the crystalline
`
`monohydrate is not lost readily until heated to over 100 °C, and the crystal then loses
`
`approximately 3.4% mass12. J.A. 1 (’708 patent) at Figure 4. This would support the POSA’s
`
`understanding and reading that the crystalline monohydrate is stoichiometric. In contrast, if the
`
`water was not part of a stoichiometric crystalline monohydrate, but instead only loosely
`
`associated with the crystal, and in variable amounts, i.e., non-stoichiometric, the crystal would
`
`lose mass from the loss of water over a range of temperatures and with such mass loss (at least
`
`starting) well before being heated to 100 °C.
`
`37.
`
`Likewise, the DSC trace of the crystalline monohydrate would support the
`
`POSA’s reading of the specification that the crystalline monohydrate is stoichiometric. It shows
`
`a first endotherm with an onset at 138.1 °C. J.A. 1 (’708 patent) at Figure 5. This indicates a
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`stoichiometric monohydrate because the water loss, which contributes to this first endotherm,
`
`occurs as a single event, and at above 100 °C. In contrast, DSC of a non-stoichiometric hydrate,
`
`i.e., a hydrate containing loosely associated water in variable amounts, would not show a single
`
`endotherm associated with water loss over such a small temperature range; instead, the loosely
`
`held water would have been lost over a wider range of temperatures and with onset well before
`
`100 °C.
`
`38.
`
`In view of the above, a POSA reading the patent specification would understand
`
`the claimed crystalline monohydrate to be stoichiometric, and thus, incorporating a fixed 1:1
`
`ratio of water to a dihydrogenphosphate salt of sitagliptin, which comports with Defendants’
`
`proposed construction.
`
`
`12 The molecular weight of sitagliptin phosphate monohydrate is 523 g/mol
`(https://pubchem.ncbi.nlm.nih.gov/compound/Sitagliptin-phosphate-monohydrate) and the
`monohydrate amounts to 3.4% of this.
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`14
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`39.
`
`In his declaration submitted in this litigation, Merck’s expert, Dr. Myerson states
`
`that “[a] hydrate is a type of solvate where water is the incorporated solvent” and “[i]n hydrates,
`
`the amount of water incorporation can vary, often at stoichiometric amounts.” J.A. 3 (Myerson
`
`Decl.) ¶ 34. By stating, in the context of the monohydrate claim term, that hydrates
`
`“incorporate” water molecules at “stoichiometric amounts”, Dr. Myerson appears to be stating
`
`that the claimed crystalline monohydrate is a stoichiometric monohydrate. Nevertheless, Dr.
`
`Myerson does not accept that the word “fixed” is required in the claim construction. I agree that
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`the specification and relevant claims are addressing a stoichiometric monohydrate. In my
`
`opinion, however, the word “fixed” in Defendants’ proposed construction is appropriate because
`
`it ensures that the claim is not incorrectly construed as encompassing a non-stoichiometric
`
`hydrate (at some environmental condition). The reality is that the fixed 1:1 ratio is what a POSA
`
`would understand the ’708 patent to describe; the transient existence of a 1:1 ratio in a non-
`
`stoichiometric hydrate is not. Including the word “fixed” in the construction makes this clear.
`
`B.
`
`“characteristic absorption bands obtained from the X-ray powder diffraction
`pattern at spectral d-spacings of” (claims 5-7)
`1.
`
`Background on X-Ray Powder Diffraction
`
`40.
`
`X-rays can be used to characterise the packing of molecules in a crystal. Using a
`
`technique called x-ray diffraction, an x-ray beam is directed onto a single crystal or a powder and
`
`the x-rays are diffracted by the molecules of the crystals and detected by a detector to create
`
`diffraction peaks at different angles around the sample. The angles at which the x-rays are
`
`diffracted depend on the structure of the crystal lattice as well as the wavelength of the incident
`
`x-rays. This relationship is described by Bragg’s law:
`
`where
`
`n λ=2 d sinθ
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`15
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`Merck Exhibit 2279, Page 15
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`n = the order of the diffraction pattern
`λ = the wavelength of the incident beam
`d = the distance between the planes of the crystal
`θ = the angle of the diffracted beam
`
`
`
`
`
`
`J.A. 24 (Brittain 1999)13 at 231. By using X-rays of known wavelength and measuring the angle
`
`of the diffraction peaks, it is possible to use Bragg’s law to calculate the distance between the
`
`planes of the crystal lattice (i.e., “d-spacings”). J.A. 24 (Brittain 1999) at 235-36.
`
`2.
`
`A POSA Would Not Understand the Literal Meaning of the Claim
`Term “characteristic absorption bands obtained from the X-ray
`powder diffraction pattern at spectral d-spacings of”
`
`41.
`
`I understand that Defendants’ position is that the term “characteristic absorption
`
`bands obtained from the X-ray powder diffraction pattern at spectral d-spacings of” is indefinite,
`
`while Merck’s proposed construction for this term is: “characteristic diffraction peaks
`
`corresponding to d-spacings of.”
`
`42.
`
`Absorption and diffraction are different physical processes. Absorption relates to
`
`something being taken into something else, whereas diffraction is a process whereby a beam (in
`
`this case, x-rays) is spread out by passing through a narrow gap. The data generated from an
`
`XRPD experiment are diffraction intensities as a function of the angle 2θ, which show as
`
`different diffraction peaks at characteristic diffraction angles. The data generated from X