Case 1:19-cv-01489-RGA Document 94-1 Filed 07/17/20 Page 236 of 501 PageID #: 2423
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`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`
`
`IN RE: SITAGLIPTIN PHOSPHATE (’708
`& ’921) PATENT LITIGATION
`
`
`
`
`MDL No. 19-2902-RGA
`
`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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`19-347-RGA,
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`19-1489-RGA,
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`
`
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`
`
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`REPLY DECLARATION OF PROFESSOR ALLAN S. MYERSON, Ph.D.
`REGARDING CLAIM CONSTRUCTION
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`
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`Merck Exhibit 2280, Page 1
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`TABLE OF CONTENTS
`
`I.
`II.
`III.
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`
`
`
`
`
`
`
`BACKGROUND .................................................................................................................1
`THE PERSON OF ORDINARY SKILL IN THE ART ......................................................1
`CLAIM CONSTRUCTION .................................................................................................1
`A.
`“the salt of claim 1 [or 2] . . .” (claims 2, 3, and 21 of the ’708 patent) ..................1
`B.
`“crystalline monohydrate [of the dihydrogenphosphate salt of sitagliptin]”
`(claims 4 and 24 of the ’708 patent) ........................................................................5
`“characteristic absorption bands obtained from the X-ray powder
`diffraction pattern at spectral d-spacings of” (claims 5–7 of the ’708
`patent) ......................................................................................................................6
`crystallizing the dihydrogenphosphate salt of [sitagliptin] at 25ºC” (claim
`24 of the ’708 patent) ...............................................................................................7
`
`D.
`
`C.
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`
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`Merck Exhibit 2280, Page 2
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`I, Allan S. Myerson, declare as follows:
`
`I.
`
`BACKGROUND
`
`1.
`
`I have reviewed the Declaration of Dr. Graham Buckton, dated May 4, 2020,
`
`(“Buckton Dec.”) and the attached exhibits, submitted on behalf of Teva Pharmaceuticals USA
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`and Watson Laboratories, Inc.; Sandoz Inc.; Lupin Limited and Lupin Pharmaceuticals, Inc.;
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`Anchen Pharmaceuticals, Inc. and Par Pharmaceutical, Inc.; and Wockhardt Bio AG and
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`Wockhardt USA LLC; Sun Pharmaceutical Industries Ltd; Apotex Inc. and Apotex Corp.; and
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`Zydus Pharmaceuticals (USA) Inc. and Cadila Healthcare Limited (collectively, “Defendants”).
`
`In this declaration, I will respond to the opinions set forth in Dr. Buckton’s declaration.
`
`2.
`
`In reaching the opinions I express herein, I have considered the ’708 patent and its
`
`prosecution history, the materials cited in this declaration, my previous Declaration Regarding
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`Claim Construction dated March 20, 2020 (“Opening Dec.”) and the materials cited therein, as
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`well as my training, general knowledge, basic principles, and experience in the relevant scientific
`
`disciplines.
`
`II.
`
`THE PERSON OF ORDINARY SKILL IN THE ART
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`3.
`
`I understand that Dr. Buckton provided a slightly different definition of the person
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`of ordinary skill in the art (“POSA”). See Buckton Dec. ¶24. My opinions would not change
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`under his definition of the POSA.
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`III. CLAIM CONSTRUCTION
`
`A.
`4.
`
`“the salt of claim 1 [or 2] . . .” (claims 2, 3, and 21 of the ’708 patent)
`
`Dr. Buckton did not provide an opinion on this term. Particularly, he did not
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`rebut my opinion that a hydrate is a type of salt, and that the POSA would understand the
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`reference to the “salt of claim 1” in the ’708 patent claims 2, 3 and 21 to include all forms of
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`salts, including hydrates. See Opening Dec. ¶61.
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`1
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`5.
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`As discussed in my previous declaration, salts are electrically neutral compounds
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`that consist of atoms or molecules held together via bonds that include some degree of ionic
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`transfer between the acid and the base. See Opening Dec. ¶29.
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`6.
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`Pharmaceutical salts can sometimes exist as crystalline solids, which in turn can
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`potentially take different crystalline forms. Different crystalline forms have different
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`arrangements in their three dimensional crystalline lattice. One type of crystalline form is known
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`as a hydrate. A hydrate is a crystalline form of a given compound in which water is part of the
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`crystalline lattice. The POSA would understand that hydrates are a type of pharmaceutical salt.
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`J.A. 37 (Giron),1 73 (using tetracaine hydrochloride to describe a monohydrate, tetrahydrate, and
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`hemihydrate); J.A. 38 (Bastin),2 432 (“The methanesulfonate salt, however, was a stable
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`monohydrate form . . . .”).
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`7.
`
`Consistent with this general understanding, the ’708 patent repeatedly refers to
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`hydrates as being a type of salt. J.A. 1 (’708 Patent), 4:13–18 (“the dihydrogenphosphate salt
`
`drug substance is substantially phase pure monohydrate”); 4:24–26 (“In particular, the enhanced
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`chemical and physical stability of the crystalline dihydrogenphosphate salt monohydrate
`
`constitutes advantageous properties . . . “); 5:12–13 (“crystalline dihydrogenphosphate salt
`
`monohydrate”); 5:15–16 (same); 6:27 (same); 6:52–53 (same); 14:64–65 (same); 14:66–67
`
`(same); 15:5–6 (same); 15:16 (same); 15: 31 (same); Example 8; 13:30–31 (“crystalline
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`monohydrate form of the dihydrogenphosphate salt”); 13:37–38 (same); 13: 65–66 (same);
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`14:14–15 (same); 14:30–31 (same); 14:48–49 (same); 15:47–48 (same).
`
`
`1 D. Giron and D.J.W. Grant, “Evaluation of Solid-State Properties of Salts,” in HANDBOOK OF
`PHARMACEUTICAL SALTS, P.H. Stahl, C.G. Wermuth (Eds.) (2002).
`2 R.J. Bastin, M.J. Bowker, B.J. Slater, “Salt Selection and Optimisation Procedures for
`Pharmaceutical New Chemical Entities,” Organic Process Research & Development 4:427-35
`(2000).
`
`2
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`Merck Exhibit 2280, Page 4
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`8.
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`Claim 1 of the ’708 patent covers “a dihydrogenphosphate salt [of sitagliptin] of
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`structural formula I or a hydrate thereof.” The “dihydrogenphosphate salt … ” limitation recites
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`a compound “of structural formula I” that is and must be present in any polymorphic form,
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`without specifying which form. For example, the “dihydrogenphosphate salt … of structural
`
`formula I” is present in the hydrate form. Id. at 2:63–65 (“In particular, the instant invention
`
`provides a crystalline monohydrate of the dihydrogenphosphate salt of formula I”); 3:53–55 (“In
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`a further embodiment of the present invention, the dihydrogenphosphate salt of structural
`
`formulae I-III is a crystalline hydrate.”); 3:57–60 (“A further embodiment of the present
`
`invention provides the dihydrogenphosphate salt drug substance of structural formulae I-III that
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`comprises the crystalline monohydrate present in a detectable amount.”); 6:26–29 (“The
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`solubility of the crystalline dihydrogenphosphate salt monohydrate of formula I in water has
`
`been found to be about 72 mg/mL.”); 6:56–60 (“General Methods for Crystallizing the
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`Monohydrate of the Dihydrogenphospahte Salt of Structural Formula I.”); 15:47-50 (“An
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`intravenous (i.v.) aqueous formulation is defined as the monohydrate of dihydrogenphosphate
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`salt of formula I in 10mM sodium acetate/0.8% saline solution at pH 4.5±0.2.”). I do not
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`understand these points to be in dispute. Further, the image of the compound in structural
`
`formula I indicates that there are no restrictions on the chirality of the compound; claim 1 does
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`not speak at that level of specificity with respect to chirality.
`
`9.
`
`As discussed in my previous declaration (Opening Dec. ¶62), claims 2 and 3 of
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`the ’708 patent limit the compound in structural formula I by imposing a chirality requirement,
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`effectuated by replacing structural formula I with structural formulas II and III, respectively.
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`This is illustrated using the wedge-dash notation to recite the (R)- and (S)- configurations,
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`respectively, of the salt of claim 1. As with structural formula I, the written description of the
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`3
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`Merck Exhibit 2280, Page 5
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`’708 patent explains that the dihydrogenphosphate salt of 4-oxo-4-[3-(trifluoromethyl)-5,6-
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`dihydro[1,2,4]triazolo[4,3-a]pyrazin-7 (8H)-yl]-l-(2,4,5-trifluorophenyl)butan-2-amine of
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`structural formulas II and III can be a hydrate. J.A. 1 (’708 Patent), 3:53–55 (“In a further
`
`embodiment of the present invention, the dihydrogenphosphate salt of structural formulae I-III is
`
`a crystalline hydrate.”); Figs. 2–5; 13:29–14:47 (description of figures 2–5). As a result, the
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`replacement of formula I with formulas II and III, respectively, does not exclude hydrates. This
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`understanding of claims 2, 3, and 21 is further supported by the other claims in the ’708 patent,
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`the specification, as well as the prosecution history, which I discussed in my previous declaration
`
`(Opening Dec. ¶¶63–65) and which Dr. Buckton does not dispute.
`
`10.
`
`I understand that Defendants have argued that the relationship between salts and
`
`hydrates is analogous to the relationship between acids and salts, citing U.S. Patent No.
`
`5,273,995 (the “’995 patent”). J.A. 39. I disagree. The genus-species relation of salts to
`
`hydrates is not the same as the relationship of acids and salts. With respect to the ’995 patent,
`
`claim 1 of that patent covered atorvastatin acid, atorvastatin lactone, or pharmaceutically
`
`acceptable salts thereof. As described above, a salt is formed via a chemical reaction between an
`
`acid and a base. The POSA would understand that, in order to form a pharmaceutically
`
`acceptable salt, atorvastatin acid would need to undergo a chemical reaction whereby a proton
`
`from the atorvastatin acid is donated to a base. The POSA would not consider the resulting salt
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`to be an “acid,” since the salt does not have an available proton to donate (which is the
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`characteristic feature of an acid). The POSA would therefore not consider a reference to
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`“atorvastatin acid” to generically include salts in the same way salts include hydrates. Put
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`another way, a salt is not a subset of an acid.
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`4
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`Merck Exhibit 2280, Page 6
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`B.
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`“crystalline monohydrate [of the dihydrogenphosphate salt of sitagliptin]”
`(claims 4 and 24 of the ’708 patent)
`
`11.
`
`I understand that Defendants have modified their proposed construction of
`
`“crystalline monohydrate” to be similar to the one Merck proposes but adds the word “fixed.”
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`However, as I explained in my previous declaration, the term “crystalline monohydrate” has a
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`clear plain and ordinary meaning in the pharmaceutical sciences, and “fixed” would not be part
`
`of the POSA’s understanding of the term. Opening Dec. ¶¶66–68. The POSA understands that a
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`monohydrate is a type of hydrate where the drug compound is in a 1:1 ratio with water in a
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`repeating unit cell. Id. It is unclear what function, if any, the term “fixed” contributes to the
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`meaning of “crystalline monohydrate.”
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`12.
`
`Dr. Buckton appears to opine that the term “fixed” is necessary in order to
`
`distinguish stoichiometric hydrates from non-stoichiometric hydrates. See Buckton Dec. ¶¶29–
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`39. But this is not so. Non-stoichiometric hydrates, as Dr. Buckton himself admits, have a
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`structure where “water molecules ‘merely occup[y] voids,’ i.e., empty spaces, ‘in the crystal’
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`structure.” Id. ¶30. Merck’s construction of the term “crystalline monohydrate”—“a repeating
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`unit cell incorporating a 1:1 ratio of water to a dihydrogenphosphate salt of sitagliptin”—
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`indicates that the water is not just in voids or empty spaces, but rather in the unit cell. Thus the
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`additional term “fixed” is not necessary to the definition of “crystalline monohydrate.”
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`13.
`
`Based on Dr. Buckton’s declaration, particularly his discussion of
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`thermogravimetric (“TGA”) analyses and differential scanning calorimetry (“DSC”), see
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`Buckton Dec. ¶¶18–19, 35–37, I can only posit that Defendants are attempting to use the claim
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`construction process to argue that Merck must use TGA and DSC to prove that Defendants
`
`infringe claim 4 of the ’708 patent. But claim 4 does not require any particular analytical
`
`techniques to prove infringement. And a variety of analytical techniques can be utilized to
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`5
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`identify the crystalline monohydrate of the dihydrogenphosphate salt of sitagliptin. I observe,
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`for example, that claims 5–16 of the ’708 patent—which depend on claim 4 and therefore are
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`narrower—recite specific characterizations of the crystalline monohydrate from a handful of
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`techniques, including X-ray powder diffraction (claims 5–8), solid state nuclear magnetic
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`resonance (claims 9–14), TGA (claim 15), and DSC (claim 16). Any one of these techniques, or
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`a combination of these techniques, can be used to identify the crystalline monohydrate of claim
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`4. Additionally, the POSA would understand that other analytical techniques can also be used to
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`establish the presence of crystalline monohydrate.
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`C.
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`“characteristic absorption bands obtained from the X-ray powder diffraction
`pattern at spectral d-spacings of” (claims 5–7 of the ’708 patent)
`
`14.
`
`Dr. Buckton opines that the 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” because the term “characteristic absorption bands” is not
`
`typically associated with X-ray powder diffraction (“XRPD”). See Buckton Dec. ¶¶41–46.
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`15.
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`Dr. Buckton does not opine, however, that the POSA would fail to understand the
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`scope of claims 5–7 as a whole. In my opinion, the POSA would have no doubt about the scope
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`of the claims: the POSA would understand them to require diffraction peaks corresponding to
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`particular d-spacings, as measured by X-ray powder diffraction. Dr. Buckton does not offer a
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`contrary opinion or any alternative interpretation that the POSA might have for these claims.
`
`16.
`
`The specification of the ’708 patent discloses:
`
`FIG. 1 shows the X-ray diffraction pattern for the crystalline
`monohydrate form of the dihydrogenphosphate salt of structural
`formula II. The monohydrate exhibited characteristic diffraction
`peaks corresponding to d-spacings 7.42, 5.48, and 3.96 angstroms.
`The monohydrate was further characterized by the d-spacings of
`6.30, 4.75, and 4.48 angstroms. The monohydrate was even further
`characterized by the d-spacings of 5.85, 5.21, and 3.52 angstroms.
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`6
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`J.A. 1 (’708 Patent), 13:29–36 (emphasis added). The POSA reading this disclosure would
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`recognize that the three sets of d-spacings identified in the specification correspond exactly to
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`those in claims 5–7. This understanding is further supported by claim 8, which recites “the salt
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`of claim 7 further characterized by the X-ray powder diffraction pattern of FIG. 1.” Id., claim 8.
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`This would confirm for the POSA that the claims recite characteristic diffraction peaks
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`corresponding to the identified d-spacings. Dr. Buckton does not address this disclosure in the
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`specification.
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`17.
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`In fact, Dr. Buckton opines that the POSA “might assume that claims 5-7 of the
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`’708 patent contain a mistake or a typographical error and would have made more sense if they
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`had used the words ‘characteristic diffraction peaks corresponding to d-spacings . . . . ’”
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`Buckton Dec. ¶46. I agree with Dr. Buckton that the POSA would view the recital of
`
`“characteristic absorption bands” in claims 5–7 to be an obvious error. In view of the claims as a
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`whole and the specification, the POSA would not be confused by that error, and there would be
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`no doubt in the POSA’s mind what the claims encompassed. The POSA would understand that
`
`the claims required diffraction peaks corresponding to the identified d-spacings, as measured via
`
`XRPD.
`
`D.
`
`crystallizing the dihydrogenphosphate salt of [sitagliptin] at 25ºC” (claim 24
`of the ’708 patent)
`
`18.
`
`As an initial matter, I observe that Dr. Buckton’s declaration does not address the
`
`language of claim 24. Claim 24 recites:
`
`24. A process for preparing the crystalline monohydrate of claim 4
`comprising the steps of:
`
`(a) crystallizing the dihydrogenphosphate salt of structural formula
`(II):
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`7
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`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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`J.A. 1 (’708 Patent), claim 24. As I noted in my previous declaration, there is nothing in the
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`claim language itself that suggests to the POSA that the formation of crystalline solids must
`
`begin at 25°C. The use of “comprising” in the claim language would suggest to the POSA that
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`the crystallization process in claim 24 could include additional steps that are not explicitly
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`recited in the claim language. These additional steps could include crystallization or seeding at
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`higher temperatures so long as some crystallization occurs at 25°C.
`
`19.
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`Dr. Buckton opines that the POSA would understand the term “crystallizing . . . at
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`25°C” as referring to the temperature at which crystals begin forming. See Buckton Dec. ¶55. In
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`his declaration, however, Dr. Buckton acknowledges that “crystallization involves nucleation
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`and crystal growth.” Id. at ¶49. I agree with this latter opinion from Dr. Buckton, which is
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`inconsistent with his purported understanding of the claim term at issue. As I explained in my
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`opening declaration, the first step of crystallization (that is, when crystallization begins) is
`
`known as nucleation. Opening Dec. ¶38. The second step of crystallization is crystal growth.
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`Id. at ¶39. Dr. Buckton’s acknowledgment that crystallization encompasses both nucleation and
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`crystal growth is inconsistent with his opinion that the “crystallizing” term in claim 24 refers
`
`only to nucleation.
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`8
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`Merck Exhibit 2280, Page 10
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`20.
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`To support his interpretation of the “crystallizing” term in claim 24, Dr. Buckton
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`cites U.S. Patent No. 4,810,789 (Behme). Buckton Dec. ¶¶55–60. I disagree that the Behme
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`reference supports Dr. Buckton’s position.
`
`21.
`
`Behme discusses a compound, buspirone hydrochloride, that exhibits two
`
`polymorphic forms: P203 and P188. J.A. 32 (Behme), 3:13–23. As the Behme patent explains,
`
`the crystallization of the P203 polymorph is favored at temperatures above 95°C, while
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`crystallization of the P188 polymorph is favored at temperatures below 95°C. Id. The Behme
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`patent discloses various procedures to preferentially crystallize either P203 or P188. For
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`example, Examples 1 through 6 of the patent disclose methods for selectively crystallizing P203.
`
`See id. at 6:64–9:14. In order to favor formation of the P203 polymorph, these examples
`
`maintain a high temperature—above 95°C—while the compound crystallizes. Id.
`
`22.
`
`The Behme patent also discusses how the solid, crystalline product is isolated
`
`after the crystallization is complete. For the P203 polymorph (which crystallizes above 95°C)
`
`the Behme patent discloses that one option is to isolate the crystalline material while the
`
`temperature is maintained above 95°C. See id. at 4:56–63 (noting that “filtration of the P203
`
`polymorph is often carried out at temperatures above 95°C”). This approach would avoid any
`
`formation of P188 polymorph, which crystallizes below 95°C.
`
`23.
`
`However, the Behme patent discloses that it was possible to isolate the P203
`
`crystalline material at room temperature, without substantial contamination from the P188
`
`polymorph, because of the very low solubility of buspirone hydrochloride in the solvents used.
`
`See id. at 4:56–63; 5:27–33 (“In actual practice, a solvent or solvent mixture is selected in which
`
`buspirone hydrochloride has only slight solubility below about 100° C. In these instances, the
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`solid product is compose of P203 with only negligible amounts of P188 present. This permits
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`9
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`isolation of solid product more conveniently at room temperature.”). In other words, the Behme
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`inventors found that—after crystallizing out the P203 polymorph above 95°C—they could
`
`decrease the temperature below 95°C to room temperature with only negligible formation of the
`
`P188 crystalline material. All of the examples in the Behme patent that crystallize the P203
`
`polymorph use this isolation technique. See id. at 7:10–15.
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`24.
`
`The Behme patent is consistent with my interpretation of the “crystallizing” term
`
`in claim 24 of the ’708 patent. Of particular note is the description of the crystallization
`
`procedure in Example 6. In that example, the composition was heated to around 137°C to fully
`
`dissolve the buspirone hydrochloride. See id. at 8:46–51; 9:6–7. The patent then states the
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`following: “The heat was removed and the contents of the flask allowed to cool spontaneously.
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`After 20 minutes, the contents of the flask cooled to 114°[C] and crystals began to form. At
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`110°C, crystallization was very rapid and the mixture became thick.” Id. at 8:51–55. As that
`
`description indicates, the crystallization in Example 6 began at 114°C. Nevertheless, the patent
`
`states that “crystallization was very rapid” at a lower temperature of 110°C. Id. This
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`statement—that crystallization occurred at a temperature that was lower than the temperature
`
`when crystals began to form—is consistent with my interpretation of the disputed claim term and
`
`is inconsistent with Dr. Buckton’s.
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`25.
`
`Example 3 of the Behme patent further supports my interpretation. In that
`
`example, the solution was first heated to 155°C and allowed to “cool slowly” from that
`
`temperature. Id. at 7:52–55. The patent reports that “crystallization occurred as the temperature
`
`dropped to 100°[C].” Id. The POSA would understand that statement to mean that crystals
`
`formed and grew across that temperature range. The Behme patent’s use of the term
`
`“crystallization” as referring to a process that occurs over a range of temperatures is consistent
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`10
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`with my interpretation of the disputed claim term and is inconsistent with Dr. Buckton’s.
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`26.
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`Dr. Buckton’s principal argument with respect to the Behme patent appears to be
`
`that—because that patent refers to crystallization occurring “above 95°C,” and yet included
`
`examples where the solution was lowered to room temperature before the crystals were
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`isolated—“crystallization” in that patent must “refer to the temperatures at which crystals begin
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`to form.” Buckton Dec. ¶¶56–57.
`
`27.
`
`I disagree with Dr. Buckton’s interpretation of the Behme patent. First, as I
`
`described above, the Behme patent includes several examples where it describes “crystallization”
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`as occurring at temperatures other when crystallization began. Example 6 explicitly identifies a
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`crystallization temperature (110°C) different from the temperature at which crystals began to
`
`form (114°C). See J.A. 32 (Behme), 8:51–55.
`
`28.
`
`Second, Dr. Buckton’s argument ignores the Behme inventors’ observation that—
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`in all of the Examples Dr. Buckton cites where the P203 polymorph is isolated—the “very
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`limited solubility of buspirone hydrochloride in the selected solvent system result[ed] in
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`crystallization of essentially all the product isolable from the liquid media at temperatures above
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`the 95°[C] transition temperature,” which permitted isolation of the P203 polymorph “with only
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`negligible contamination by the P188 polymorph.” See id. at 7:10–15. In other words, as
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`described above, the Behme patent inventors found that practically all of the desired P203
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`polymorph would crystallize above 95°C, even when the temperature was subsequently dropped
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`to room temperature. To the extent crystallization below 95°C did occur as the temperature
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`dropped to room temperature, it resulted in “contamination” with a different polymorph, P188.
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`Id. Thus, when the Behme patent says that the P203 polymorph was “crystallized . . . at
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`temperatures above about 95° C,” id. at 2:60–62, it is referring to the temperature at which the
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`crystallization of the P203 polymorph occurred, not just when the crystallization began. Again,
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`this is consistent with my interpretation of the disputed claim term.
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`29.
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`Dr. Buckton contends that, under my interpretation, the Behme crystallization of
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`the P203 polymorph “would be encompassed by ‘crystallizing . . . at 25°C.’” Buckton Dec. ¶59.
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`That is incorrect. As discussed above, the Behme patent makes clear that practically all of the
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`P203 polymorph crystallizes above 95°C in the patents’ examples, and the “negligible” amount
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`of crystallization that occurs below that temperature is of a different polymorph, P188. As such,
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`the procedure described in Behme would not constitute a crystallization of the P203 polymorph
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`at 25°C, since that polymorph did not crystallize at that temperature.
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`30.
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`Dr. Buckton also cites Guillory 1999 to support his interpretation. See Buckton
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`Dec. ¶¶56, 58 (citing J.A. 20). However, the disclosure of Guillory 1999 is entirely cumulative
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`of Behme, simply stating that—in Behme—“when buspirone hydrochloride is crystallized above
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`95°C the higher melting form is obtained.” J.A. 20 (Guillory 1999) at 189. As noted above, this
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`statement is consistent with my interpretation because effectively all of the high-melting
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`polymorph in Behme (P203) crystallized out of solution above 95°C. The statements from
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`Guillory 1999 and Behme are referring to when crystallization occurred, not just when it began.
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`31.
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`Dr. Buckton cites one of my publications (Lee)3 and opines that it provides
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`support for interpreting the crystallization temperature as the temperature at which crystals begin
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`forming. Buckton Dec. ¶66. I disagree. First, in its introduction, Lee states that “crystallization
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`occurs by nucleation and growth mechanisms.” J.A. 33 (Lee), 4002 (emphasis added).
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`Likewise, the introduction discusses “crystallization rate” and notes that “crystallization can be
`
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`3 H.K. Lee, A.S. Myerson, and K. Levon, “Nonequilibrium Liquid-Liquid Phase Separation in
`Crystallizable Polymer Solutions,” Macromolecules 25:4002–4010 (1992).
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`characterized as the linear growth of spherulite size with time.” Id. Those statements are all
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`consistent with my present interpretation, which is that “crystallization” is the occurrence, not
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`just the onset, of crystal formation. Similarly, in the sentence that bridges pages 4005 to 4006,
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`Lee states, “the liquid-liquid phase separation is due to similar local concentration fluctuations
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`but occurs at the early stage of crystallization.” J.A. 33 at 4005–06 (emphasis added). This
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`statement is inconsistent with Dr. Buckton’s interpretation, under which “crystallization” would
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`only refer to the onset of crystallization.
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`32.
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`Dr. Buckton opines that the measurements that were taken in the Lee paper
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`support his interpretation. Buckton Dec. ¶66. But he fails to quote the actual language from the
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`paper, which states that the “melting points (extrapolated) and the crystallization temperature
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`(onset) were measured by DSC.” J.A. 33 (Lee), 4003 (emphasis added). The “onset”
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`parenthetical in that quote makes clear that the phrase “crystallization temperature,” standing
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`alone, would encompass the temperatures at which crystals formed and grew. In the Lee paper,
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`we were specifically interested in studying nucleation—that is, the onset of crystallization—
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`under different conditions. Thus, the particular crystallization temperature that we measured was
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`the onset of crystallization. Contrary to Dr. Buckton’s assertions, the terminology in the Lee
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`paper is consistent with, and supports, my interpretation of the “crystallizing” term in claim 24 of
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`the ’708 patent.
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`33.
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`Dr. Buckton opines that the Example in the ’708 patent is not a crystallization at
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`25°C. See Buckton Dec. ¶62. For the reasons stated in my Opening Declaration, see Opening
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`Dec. ¶75, I disagree with Dr. Buckton. The POSA would understand that at least some
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`crystallization in that Example occurred at 25°C. Indeed, Dr. Buckton appears to agree with the
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`scientific premise of my opinion, stating that it is “likely” that there was “growth of existing
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`monohydrate crystals” at 25°C in the Example in the ’708 patent. See Buckton Dec. ¶63. As
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`explained above, Dr. Buckton has acknowledged that “crystal growth” is part of crystallization.
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`Id. at ¶49. As such, Dr. Buckton should agree that crystallization occurred in the Example in the
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`’708 patent at 25°C. His opinion that crystallization in the Example did not occur at 25°C
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`appears to be premised on his assumption that “crystallization” only occurs when crystals begin
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`forming. See id at ¶62 (“It is meaningless and misleading to describe this as crystallization at
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`any temperature other than . . . 68 °C.”). As I have explained throughout this declaration and my
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`opening declaration, however, the POSA would understand that “crystallization” involves both
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`the nucleation and growth of crystals.
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`34.
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`I also disagree with Dr. Buckton’s opinion that it is “meaningless” to describe
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`crystallization as occurring at 25°C if crystals begin forming at a higher temperature than that.
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`See id. at ¶62; see also id. at ¶64 (“[I]nterpreting the term . . . to require only that some
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`crystallisation, even a small amount, occurs at 25 °C conveys no meaningful information to a
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`POSA.”). The temperature at which crystals form as part of a crystallization procedure can be
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`important information, including because different polymorphs can form at different
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`temperatures. This is precisely the case in the Behme patent, on which Dr. Buckton relies, where
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`different polymorphs crystallized above and below 95°C. For similar reasons, I disagree with
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`Dr. Buckton’s assertion that Merck’s proposed construction “renders the temperature limitation
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`essen