IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`___________________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________________
`MYLAN PHARMACEUTICALS INC., TEVA PHARMACEUTICALS USA,
`INC., WATSON LABORATORIES, INC., DR. REDDY’S LABORATORIES,
`INC., DR. REDDY’S LABORATORIES, LTD., and SUN
`PHARMACEUTICALS INDUSTRIES LTD.1
`Petitioners,
`v.
`MERCK SHARP & DOHME CORP.
`Patent Owner.
`U.S. Patent No. 7,326,708 to Cypes et al.
`Issue Date: February 5, 2008
`Title: Phosphoric acid salt of a dipeptidyl peptidase-IV inhibitor
`Inter Partes Review No.: IPR2020-00040
`
`Reply Declaration of Dr. Mukund Chorghade, Ph.D.
`
`1 Teva Pharmaceuticals USA, Inc. and Watson Laboratories, Inc. were joined as a
`party to this proceeding via Motion for Joinder in IPR2020-01045; Dr. Reddy’s
`Laboratories, Inc. and Dr. Reddy’s Laboratories, Ltd. were joined as a party to this
`proceeding via a Motion for Joinder in IPR2020-01060; and Sun Pharmaceuticals
`Industries Ltd. was joined as a party to this proceeding via Motion for Joinder in
`IPR2020-01072.
`
`Mylan (IPR2020-00040) Ex. 1035 p. 001
`
`
`___________________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________________
`MYLAN PHARMACEUTICALS INC., TEVA PHARMACEUTICALS USA,
`INC., WATSON LABORATORIES, INC., DR. REDDY’S LABORATORIES,
`INC., DR. REDDY’S LABORATORIES, LTD., and SUN
`PHARMACEUTICALS INDUSTRIES LTD.1
`Petitioners,
`v.
`MERCK SHARP & DOHME CORP.
`Patent Owner.
`U.S. Patent No. 7,326,708 to Cypes et al.
`Issue Date: February 5, 2008
`Title: Phosphoric acid salt of a dipeptidyl peptidase-IV inhibitor
`Inter Partes Review No.: IPR2020-00040
`
`Reply Declaration of Dr. Mukund Chorghade, Ph.D.
`
`1 Teva Pharmaceuticals USA, Inc. and Watson Laboratories, Inc. were joined as a
`party to this proceeding via Motion for Joinder in IPR2020-01045; Dr. Reddy’s
`Laboratories, Inc. and Dr. Reddy’s Laboratories, Ltd. were joined as a party to this
`proceeding via a Motion for Joinder in IPR2020-01060; and Sun Pharmaceuticals
`Industries Ltd. was joined as a party to this proceeding via Motion for Joinder in
`IPR2020-01072.
`
`Mylan (IPR2020-00040) Ex. 1035 p. 001
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`
`
`Table of Contents
`LIST OF MATERIALS CONSIDERED ........................................................ 1
`I.
`PERSON OF ORDINARY SKILL IN THE ART (“POSA”) ......................... 1
`II.
`LEGAL STANDARD ..................................................................................... 2
`III.
`IV. REPLY OPINIONS ......................................................................................... 2
`A.
`The Reproduction of the Salt-Forming Step of WO498 Produces
`1:1 Sitagliptin DHP Every Time ........................................................... 6
`Dr. Matzger’s Reproduction of WO420 Does Not in Any Way
`Resemble WO498................................................................................29
`a.
`Use of Isopropanol Instead of Methanol ...................................30
`b.
`Use of 70°C Instead of Ambient Temperatures ........................32
`c.
`The Additional Water ...............................................................33
`The Solubility Study
`that Seems
`to Be
`the Focus of
`Dr. Matzger’s Declaration Does Not Resemble the Process of
`WO498 ................................................................................................33
`D. My Independent Review of EX2225, ¶¶23-52 ....................................35
`
`C.
`
`B.
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`Reply Declaration of Dr. Mukund Chorghade, Ph.D.
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`I, Mukund Chorghade, Ph.D., do hereby declare and state as follows:
`
`1.
`
`I am the same Mukund Chorghade that provided the Declaration of
`
`Mukund Chorghade in connection with this matter. EX1002. I provide this
`
`testimony below:
`
`2.
`
`My experience and qualifications are provided in EX1002. In addition
`
`to my prior qualifications, I have recently been elected Fellow of the Indian
`
`Chemical Society and the International Union of Pure and Applied Chemistry.
`
`3.
`
`I have been retained on behalf of the Petitioner Mylan Pharmaceuticals
`
`Inc. for the above-captioned inter partes review (“IPR”). I am being compensated
`
`for my time as stated in EX1002. My compensation does not depend in any way on
`
`the outcome of this IPR.
`
`I.
`4.
`
`LIST OF MATERIALS CONSIDERED
`In formulating my opinions, I have considered the materials referenced
`
`in this Declaration.2
`
`II.
`
`PERSON OF ORDINARY SKILL IN THE ART (“POSA”)
`
`2 My review includes EX2101, EX2103, EX1001, EX1004, EX2192, EX2221,
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`EX2222, EX2223, EX2224, EX2225, EX2226, EX2227, and EX2051 and any other
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`document referenced in this Declaration.
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`1
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`Reply Declaration of Dr. Mukund Chorghade, Ph.D.
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`5.
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`The opinions in this Declaration are from the perspective of a POSA as
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`previously defined (and applying the same relevant priority date). EX1002.
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`6.
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`I have reviewed the POSA definitions of Dr. Matzger (EX2103, ¶¶63-
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`64) and Dr. Myerson (EX2101, ¶¶39-40). My opinions in this Declaration and my
`
`Opening Declaration (EX1002) would not change if I applied the definition of a
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`POSA proposed by Dr. Matzger or Dr. Myerson instead of my own.
`
`III. LEGAL STANDARD
`7.
`My understanding of the applicable legal standards is provided in
`
`EX1002.
`
`IV. REPLY OPINIONS
`8.
`After reviewing the Matzger and Myerson Declarations, I remain of the
`
`opinion that under the prior art process of WO498 (Example 7), the sitagliptin base
`
`can only be monopronated at the primary amine, which results in formation of the
`
`dihydrogen phosphate salt every time. Put simply, all experimental evidence
`
`indicates “there is only one possible molecular ratio, a 1:1 ratio, that will be present
`
`as a pharmaceutically suitable salt of sitagliptin and phosphoric acid, namely
`
`sitagliptin dihydrogen phosphate.” EX2225, ¶¶52, ¶24 (4063-19-01 (using 1:5.01));
`
`EX1004, Example 7. As I have explained, as of the priority date, if the excess of
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`highly saturated HCl solution of Example 7 of WO498 only created a 1:1 sitagliptin
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`HCl salt, then phosphoric acid (which is a slightly weaker acid when compared to
`
`2
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`HCl) would fare no different. EX2051, 55:3-8, 53:14-18, 145:22-147:5; EX1025,
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`155:16-20, 150:7-13.
`
`9.
`
`The only sitagliptin salt exemplified in WO498 is a 1:1 HCl salt
`
`(Example 7):
`
`EX1025, 96:22-97:4. Example 7 was done in methanol and at ambient conditions.
`
`EX1025, 93:2-94:2; EX1004, 46:23 (cross-referencing Example 1). WO498
`
`includes a list of only eight particularly preferred acids for forming such salts,
`
`including explicitly phosphoric acid, to use with basic drug substances like
`
`sitagliptin. I agree with Dr. Matzger that looking at Example 7, when replacing
`
`phosphoric acid for HCl, a POSA “can imagine that the [1:1 phosphoric acid salt]
`
`would exist.” EX1025, 146:21-147:5.
`
`10.
`
`In connection with this Declaration, I have been asked to comment on
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`certain uncontested and unrebutted experiments described in EX2225, ¶¶24-52 and
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`evaluate whether a POSA would consider any of them reproductions of Example 7
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`3
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`Reply Declaration of Dr. Mukund Chorghade, Ph.D.
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`of WO498 if phosphoric acid were used in the place of HCl.3 Based on my review,
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`I conclude that Dr. Chyall’s work at EX2225, ¶¶24-52, particularly Experiment
`
`3 I have always understood that the starting reactants of Example 7 involve the use
`
`of protected sitagliptin. However, a POSA would know that the protecting group is
`
`immediately removed by an acid to generate the sitagliptin free amine. The
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`sitagliptin free amine molecule then forms the final salt (i.e., 1:1 sitagliptin DHP
`
`salt) upon contacting another phosphoric acid molecule. No POSA would contend
`
`that phosphoric acid would not remove the blocking group. Phosphoric acid,
`
`although a weaker acid when compared to HCl, would immediately remove any
`
`acid-labile protecting group. Indeed, even Dr. Matzger (despite having worked with
`
`the BOC protecting group (EX1025, 43:16-44:6)) did not take a position that acids
`
`(including phosphoric acid) do not remove protecting groups. When asked what
`
`would happen if the HCl in Example 7, which uses the BOC-protected sitagliptin,
`
`was replaced with phosphoric acid, Dr. Matzger automatically removed the BOC-
`
`protecting group and explained you would get a “phosphoric acid solution of
`
`sitagliptin.” EX1025, 219:18-220:5. In other words, without even thinking,
`
`Dr. Matzger removed the BOC-protecting group from the sitagliptin amine upon
`
`exposure to phosphoric acid as any POSA would do. Again, any POSA would know
`
`that phosphoric acid would remove a BOC-protecting group from an amine.
`
`4
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`Reply Declaration of Dr. Mukund Chorghade, Ph.D.
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`4063-19-01 (1.00:5.01 sitagliptin to phosphoric acid), represents a reproduction of
`
`WO498 using phosphoric acid in the place of HCl.4
`
`11.
`
`I have also been asked to review Dr. Matzger’s reproduction of WO420
`
`and compare it Example 7 of WO498. At the outset, I do not understand how a
`
`protocol (WO420) that came into being a decade after any relevant priority date has
`
`any bearing on what the POSA would have known as of the relevant priority date.
`
`In any event, Dr. Matzger’s protocol does not resemble the Example 7 of WO498.
`
`It includes material and unnecessary changes including using isopropanol instead of
`
`methanol.5 As such, I believe that Dr. Matzger’s work has no relevance in evaluating
`
`the prior art process, i.e., Example 7 of WO498.
`
`12.
`
`In paragraph 131 of Dr. Matzger’s Declaration, Dr. Matzger discusses
`
`Dr. Chyall’s experiment 4031-25-01. EX2103, ¶131 (citing EX2226 at 25-26). I
`
`4 I note that the molar ratio of API to phosphoric acid Dr. Chyall used was far more
`
`than Dr. Matzger’s experiments. EX1025, 175:10-176:2.
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`5 More specifically, the experiments of WO420/Dr. Matzger that Merck alleges
`
`makes non-1:1 salts (EX2103, ¶¶120-122) was conducted using IPA/water and
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`involved very different conditions than the methanol system at ambient temperatures
`
`used in Example 7 of WO498.
`
`5
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`have also been asked to determine if Dr. Chyall’s experiment 4031-25-01 in anyway
`
`resembles the process of WO498.
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`13.
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`Finally, I have been asked to review the methanol experiments EX2225
`
`in ¶¶23-52, and the data provided in EX2225 directed to that work, and provide my
`
`opinion as to whether I agree that Dr. Chyall made the 1:1 sitagliptin DHP salt in all
`
`12 experiments.6
`
`The Reproduction of the Salt-Forming Step of WO498
`A.
`Produces 1:1 Sitagliptin DHP Every Time
`14. At the outset, I understand that neither Merck, Dr. Matzger nor
`
`Dr. Myerson contested or rebutted the experiments contained in EX2225, ¶24.
`
`Indeed, they did not contest or rebut anything in EX2225, ¶¶23-52. I note, however,
`
`that Dr. Matzger’s Declaration referenced the very paragraph where Dr. Chyall
`
`provided a summary of his methanol experiments. EX2103 at ¶126 (“See EX2225
`
`(Chyall First Decl., August 3, 2010) at ¶¶23–25”).7 I understand that Dr. Matzger
`
`said that he had the opportunity to review each of the exhibits in his Declaration and
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`6 In this regard, I also have been provided with Dr. Chyall’s lab notebook #4063
`
`(EX1030) that was not part of EX2225 as a source of further corroboration.
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`7 Dr. Matzger seems to have reviewed more than just this section in EX2225.
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`EX2103, ¶131 (“See EX2225 (Chyall First Decl., August 3, 2010) at ¶ 69”).
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`6
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`Reply Declaration of Dr. Mukund Chorghade, Ph.D.
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`that any distinctions or comments he wanted to make to any exhibit were included
`
`in his Declaration. EX1025, 29:3-5. I also understand Dr. Matzger was satisfied
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`with the thoroughness of his review and explained that if he did not discuss
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`something in his Declaration, he was not providing any distinction or comments.
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`EX1025, 14:20-15:15. Separately, I have reviewed Dr. Matzger’s Declaration and
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`he never provided any substantive discussion about the experiments detailed in
`
`EX2225, ¶¶23-52.8
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`15. Although I did not conduct the experiments described in EX2225,
`
`¶¶23-52, I have spent decades reviewing other people’s experimental data and
`
`manuscripts. In this regard, I served, and continue to serve, on the editorial boards
`
`of Journal of Organic Chemistry, Organic Process Research and Development, and
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`other journals of the American Chemical Society (“ACS”); Journals of the Indian
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`8 I understand that Merck submitted a Declaration, which has been labelled by Mylan
`
`as EX1028, where an attorney for Merck in the Israeli Proceedings reviewed
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`EX2225 and other related documents (EX1028, ¶2) and, after reviewing the
`
`document, the attorney for Merck confirmed that the documents were “true and
`
`correct.” See, e.g., EX1028, ¶9. I have been informed that the Israeli Proceedings
`
`pertain to Patent Registration Application 172563, an Israeli counterpart of the ’708
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`patent. EX1028, ¶1.
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`7
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`Chemical Society, Bentham Publishers and Elsevier. I continue to review and
`
`referee papers submitted to several other professional journals such as Tetrahedron
`
`Letters, Tetrahedron, Catalyst, Current Pharmaceutical Design, Chimica Oggi,
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`Industrial and Engineering Chemistry and many others. Put simply, in connection
`
`with my professional career, I reviewed experimental data throughout my career,
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`and I continue to do so today.
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`16. Below I have reproduced Table 1 in EX2225, ¶24. Table 1 provides a
`
`summary of Dr. Chyall’s methanol experiments.
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`As Table 1 shows, each of the experiments was run in methanol while various other
`
`parameters were changed (e.g., temperature, ratio of API:phosphoric acid, and the
`
`8
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`inclusion of water). EX2225 states that even though conditions were changed, all
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`12 experiments resulted in only the 1:1 sitagliptin DHP salt. EX2225, ¶48, ¶72.9
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`17. While Dr. Chyall’s intention may have been a “deliberate attempt to
`
`obtain a phosphate salt other than a 1:1 adduct of sitagliptin and phosphoric acid”
`
`EX2225, ¶23, as Dr. Matzger explained, the POSA focuses on what actually
`
`happens. EX1025, 36:5-13. Here, that was the repeated formation of the 1:1
`
`sitagliptin DHP salt.
`
`18.
`
`EX2225 provides the experimental protocols for each of the
`
`12 experiments provided in the Table 1. EX2225, ¶¶33-44.
`
`19.
`
`For each of the 12 salt formation experiments described above, EX2225
`
`includes experimental data:
`
` XRPD patterns (Exhibit I) EX2225, pp. 195-207.
`
` NMR spectra (Exhibit J) EX2225, pp. 208-265.
`
` DSC plots (Exhibit K) EX2225, pp. 266-279.
`
`9 As Dr. Chyall explained, these 12 experiments would be “representative.”
`
`EX2192, ¶56. I agree. Even if the API:phosphoric acid was increased beyond
`
`1:5.01, based on these “representative” experiments, no different result would be
`
`achieved, i.e., based on the representative experiments, a 1:1 sitagliptin DHP salt
`
`would be formed every time. See also EX2192, ¶77.
`
`9
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`Reply Declaration of Dr. Mukund Chorghade, Ph.D.
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` Elemental analyses (Exhibit L), pp. 280-295.10
`I understand the results of this data are uncontested and unrebutted.
`
`Table 2 of EX2225, ¶48 is reproduced below:
`
`20.
`
`21.
`
`10 I note that the elemental analysis was run at Galbraith Labs which is the same lab
`
`used by Dr. Matzger when conducting his work. As Dr. Matzger explained,
`
`“[s]cientists routinely use commercial analytical services such as Galbraith
`
`Laboratories for techniques that they do not conduct in their own labs and rely upon
`
`the data generated from these services…Galbraith Laboratories is a reputable
`
`third-party lab that specializes in a number of analytical techniques such as elemental
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`analysis.” EX1029, ¶ 11. I am familiar with Galbraith Laboratories and agree that
`
`it is a reputable lab; I have used them previously and reviewed data from them.
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`10
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`22.
`
`EX2225 provides an analysis of elemental analysis in ¶¶49-51. I also
`
`understand that Dr. Matzger also relies on elemental analysis. EX2103, ¶143. As
`
`Dr. Chyall explained, which Dr. Matzger or Dr. Myerson did not contest, the
`
`elemental analysis confirms that “all twelve salt formation experiment samples are
`
`conclusive for the generation of sitagliptin dihydrogen phosphate in these samples.”
`
`EX2225, ¶48.
`
`23. Dr. Chyall repeatedly noted that all 12 experiments generated the 1:1
`
`sitagliptin DHP salt:
`
`46. Based on the analytical data obtained in the salt
`formation experiments (XRPD, proton NMR, DSC, and
`elemental analysis), it is my conclusion that all twelve salt
`formation experiments resulted in sitagliptin dihydrogen
`phosphate. I note that elemental analysis and proton NMR
`provide information about the chemical content and
`structure of the compound. Furthermore, XRPD and DSC
`data provide information about the physical properties of
`the compound (crystalline form and melting temperature,
`respectively). Based on all the analytical data I conclude
`that the samples are sitagliptin dihydrogen phosphate. The
`above conclusion is supported by the comparison of the
`observed physical properties to the characteristic physical
`properties of sitagliptin dihydrogen phosphate published
`in the literature.
`
`11
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`47. Upon analysis of the XRPD patterns obtained on the
`twelve experimental samples, it is my conclusion that all
`salt formation experiments resulted in known crystalline
`forms or mixtures of known crystalline forms of sitagliptin
`dihydrogen phosphate disclosed in US 2010/0041885 Al
`and WO 2005/020920. Additional support for the
`identification of these samples as crystalline solids was
`obtained from the DSC analyses of the materials, which
`display a melt endotherm for the materials. The chemical
`shift positions of the resonances and their corresponding
`integrated
`intensities
`in
`the proton NMR spectra
`demonstrate that the salt formation experiment samples
`prepared at Aptuit are sitagliptin dihydrogen phosphate.
`In addition, the NMR spectra for these twelve samples
`match the spectrum obtained for the sitagliptin dihydrogen
`phosphate sample obtained from Teva.
`
`48. The elemental analyses of all twelve salt formation
`experiment samples are conclusive for the generation of
`sitagliptin dihydrogen phosphate in these samples. It is
`not possible for any of the samples to contain other than a
`1:1 adduct of sitagliptin and phosphoric acid, which is
`sitagliptin dihydrogen phosphate. This is because the
`relative amounts of nitrogen and phosphorus in the ratio of
`13.86/6.13 would be substantially different for other
`stoichiometries of sitagliptin and phosphoric acid. Table
`2, below, provides theoretical values, the elemental
`
`12
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`analysis results, and the deviation between measured and
`theoretical values.
`
`represent
`52. The experiments described above
`common and reasonable attempts to deliberately obtain
`different possible molecular combinations of a basic API,
`such as sitagliptin, and phosphoric acid. Even when either
`sitagliptin or phosphoric acid was used in great excess,
`only
`sitagliptin
`dihydrogen
`phosphate
`resulted.
`Furthermore, experiments conducted at sub-ambient and
`elevated temperature, and experiments conducted in the
`presence of water, also only resulted in sitagliptin
`dihydrogen phosphate. These experiments indicate that
`there is only one possible molecular ratio, a 1:1 ratio, that
`will be present as a pharmaceutically suitable salt of
`sitagliptin and phosphoric acid, namely sitagliptin
`dihydrogen phosphate.
`
`72. The salt formation experiments performed on
`sitagliptin phosphate encompassed a wide range of
`experimental conditions in deliberate attempts to prepare
`a phosphate salt other than a 1:1 adduct of sitagliptin and
`phosphoric acid. None of these experiments were
`successful in this regard, providing only crystalline
`sitagliptin dihydrogen phosphate (1:1 adduct) as an
`isolable product. From these experiments alone, I believe
`it is not possible to prepare any pharmaceutically suitable
`salt of sitagliptin with phosphoric acid other than
`
`13
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`sitagliptin dihydrogen phosphate using common and
`standard laboratory procedures.
`
`24.
`
`In my opinion, experiment 4063-19-01 (using 1:5.01) is a reproduction
`
`of the salt forming step of Example 7 with phosphoric acid used in the place of HCl.11
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`Only the 1:1 sitagliptin DHP salt was produced in experiment 4063-19-01. The
`
`uncontested experimental data was “conclusive for the generation” of 1:1 sitagliptin
`
`DHP salt. EX2225, ¶48, ¶24, ¶46, ¶52, ¶47, ¶72, ¶75.12
`
`25.
`
`Indeed, I note that Dr. Atwood (Merck’s expert in the Israeli
`
`Proceedings) did not dispute that Dr. Chyall made the 1:1 sitagliptin DHP salt when
`
`using excess phosphoric acid. EX2221, ¶72 (“In the remaining five experiments
`
`11 Again, while I understand that Example 7 uses sitagliptin with a blocking group
`
`on it, as any POSA would know, phosphoric acid would immediately remove the
`
`protecting group and the reaction would proceed to the final salt forming step of
`
`contacting sitagliptin free amine with phosphoric acid. Dr. Chyall’s work focuses
`
`on the salt forming step, as did Dr. Matzger’s experimental work.
`
`12 Dr. Chyall actually did a series of experiments increasing the amount of
`
`phosphoric acid. EX2225, ¶52, ¶24 (4063-03-01 (using 1:2.10); 4063-19-01 (using
`
`1:5.01)). As the levels of phosphoric acid were increased from equimolar to a five
`
`times molar excess, no other salt other than 1:1 DHP salt formed.
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`14
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`(4063-03-01, 4063-19-01, 4063-32-01, 4063-50-01, 4063-56-01), Dr. Chyall used a
`
`molar excess of phosphoric acid” (emphasis added));13 see also EX2192, ¶55
`
`(“Despite varying conditions, solvents and molar ratios of starting materials, every
`
`salt that I obtained was determined to be sitagliptin dihydrogenphosphate salt (a 1:1
`
`salt). Indeed, Prof. Atwood does not dispute the results of these experiments”
`
`(emphasis added)).
`
`13 Dr. Atwood complained about the dropwise addition of phosphoric acid. Putting
`
`aside the fact that Dr. Matzger used the same procedure, I address this below.
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`26.
`
`Experiment 4063-19-01 uses 1:5.01 molar ratio of sitagliptin to
`
`phosphoric acid. The reaction was done in methanol (like Example 7) and at ambient
`
`temperatures. Other experimental details are provided in EX2225, ¶37:14
`
`37. Sitagliptin base: phosphoric acid (1.00:5.01) in
`methanol
`(Sample 4063-19-01):
` Sitagliptin base
`(499.9 mg) was weighed into a 100 mL round bottom
`flask. Methanol (5 mL) was added resulting in a clear,
`colorless solution. The flask was placed in a water bath
`(T=22.0 °C). Phosphoric acid stock solution (1.230 mL of
`5.0M phosphoric acid in methanol) was added dropwise
`with stirring. Slight turbidity was noted after 3 hours
`40 minutes. The solids were allowed to slurry for
`approximately one day. The solids were collected by
`vacuum filtration and allowed to air-dry. The solids were
`analyzed by XRPD (file 401062), DSC (file 401063),
`proton NMR (file 401064), and elemental analysis (LIMS
`234584).
`
`14 I understand that Dr. Chyall set his ambient temperature at 22°C. As I stated in
`
`my Opening Declaration, to a POSA “ambient” also means “about 25°C.” EX1002,
`
`p.43, n.14. Dr. Matzger did not dispute this opinion. As the 12 experiments show,
`
`if methanol is used, temperature changes have no impact on the reaction. EX2225,
`
`¶24 (temperatures from 0°C to 65°C only resulting in the 1:1 sitagliptin DHP).
`
`16
`
`Mylan (IPR2020-00040) Ex. 1035 p. 018
`
`
`
`Reply Declaration of Dr. Mukund Chorghade, Ph.D.
`
`27.
`
`Since Example 7 uses HCl (gas) (EX1025, 99:22, EX2051, 138:16-18),
`
`the POSA would have to make changes to use phosphoric acid which is supplied as
`
`an aqueous solution. Dr. Matzger made a similar observation. EX1025, 220:6-21.
`
`Specifically, Example 7 of WO498 uses ~1,000-fold excess of HCl15 but as a POSA
`
`would know, it would not be feasible to use ~1,000-fold excess of phosphoric acid.
`
`EX1025, 220:6-21.16 Rather a lower amount would have to be used. While
`
`Dr. Matzger provided his reasons for why a 1,000-fold excess of phosphoric acid
`
`was not feasible (id.), I will also add that because phosphoric acid is a liquid (unlike
`
`gaseous HCl), a 1,000-fold excess would result in reactivity issues due to solution
`
`dilution. In addition, given that phosphoric acid always contains water, the addition
`
`15 When HCl gas is bubbled through methanol, it creates a saturated solution since
`
`HCl is soluble in methanol.
`
`16 Indeed, when asked what change he would have to make, Dr. Matzger only pointed
`
`to a different amount of excess phosphoric acid because it would not be feasible to
`
`use a 1,000-fold excess of phosphoric acid (unlike HCl in Example 7). EX1025,
`
`220:6-21. He did not point to any change in the solvent or temperature of Example 7.
`
`Dr. Matzger’s proposed change, i.e., a different amount of phosphoric acid, was what
`
`Dr. Chyall did.
`
`17
`
`Mylan (IPR2020-00040) Ex. 1035 p. 019
`
`
`
`Reply Declaration of Dr. Mukund Chorghade, Ph.D.
`
`of a 1,000-fold excess would mean the solution would effectively be a water solution
`
`instead of the methanol solution used in Example 7.
`
`28. As Dr. Matzger explained (with which I agree), the POSA would have
`
`used some other amount of phosphoric acid. As I explain below, 5-fold excess of
`
`phosphoric acid is an appropriate modification of Example 7 if phosphoric acid were
`
`used instead of HCl. It provides for a significant excess of phosphoric acid in the
`
`reaction (in the place of HCl) while at the same time allowing the solvent system of
`
`Example 7 to remain methanol-based by limiting the addition of water that comes
`
`along with the use of phosphoric acid.17
`
`29. Moreover, Dr. Chyall let the reaction stir for 24 hours even though
`
`Example 7 reports 1 hour. EX1004, Example 7. The increased time in Experiment
`
`4063-19-01 actually biases the reaction to form a non-1:1 DHP salt with a higher
`
`17 Moreover, as Dr. Chyall explained, “Prof. Atwood argues that my dropwise
`
`addition of phosphoric acid in experiments intended to have excess phosphoric acid
`
`actually created a starting condition with a great excess of sitagliptin. Id. at ¶¶ 73,
`
`74. Applying Prof. Atwood’s reasoning, at the start of my experiments with excess
`
`sitagliptin, dropwise addition of phosphoric acid to sitagliptin created a starting
`
`condition with a great excess of sitagliptin, which would strongly favor formation of
`
`a 2:1 salt, if it could ever form.” EX2192, ¶77.
`
`18
`
`Mylan (IPR2020-00040) Ex. 1035 p. 020
`
`
`
`Reply Declaration of Dr. Mukund Chorghade, Ph.D.
`
`stoichiometry if such a salt is at all possible. But the experimental data
`
`unambiguously indicates only the presence of 1:1 sitagliptin DHP salt even after 24
`
`hours. Given no other sitagliptin salt formed even after 24 hours, there is no driving
`
`force for the formation of a salt other than 1:1 DHP salt. Again, the conclusions of
`
`Dr. Chyall that all 12 experiments made only the 1:1 sitagliptin DHP salt were not
`
`contested by Dr. Matzger, Dr. Atwood or Merck.
`
`30. While I agree an impact of time could be higher yields of the 1:1 salt,
`
`there are no yield parameters in any of the challenged claims. In any event, if the
`
`reaction product were analyzed after one hour, the salt formed would not change.
`
`The POSA would only find a 1:1 sitagliptin DHP salt, albeit at a slightly lower yield.
`
`31. Along this same line, Dr. Chyall observed that “[s]light turbidity was
`
`noted after 3 hours 40 minutes” in Experiment 4063-19-01. EX2225, ¶37. This does
`
`not mean that the 1:1 sitagliptin DHP salt did not form in the first hour. It would
`
`start forming sometime within the first hour. Rather, the turbidity afterward is
`
`indicative that the amount of 1:1 sitagliptin DHP salt was approaching the saturation
`
`point in the system as it continued to build up and was starting to come out of
`
`solution, not whether the salt had formed. EX2051, 120:2-8. If the POSA would
`
`have analyzed the reaction after an hour and examined the salt, they would only have
`
`found 1:1 sitagliptin DHP salt, albeit in a lesser amount.
`
`19
`
`Mylan (IPR2020-00040) Ex. 1035 p. 021
`
`
`
`Reply Declaration of Dr. Mukund Chorghade, Ph.D.
`
`32. As to the use of methanol, the POSA would have no reason to change
`
`methanol in Example 7 to some other solvent if phosphoric acid was used in the
`
`place of HCl. Well before the relevant priority date, the POSA would know that
`
`phosphoric acid is soluble in methanol. EX2221, pp. 103-105; EX2051, 164:12-
`
`165:8. Given there were no incompatibility issues, there would be no reason to
`
`change the solvent. Id. Again, when Dr. Matzger was asked what changes he would
`
`make to Example 7 if phosphoric acid was used in the place of HCl, he did not
`
`suggest using a different solvent. EX1025, 220:6-21.
`
`33.
`
`There would also be no reason to change the temperature of the reaction
`
`of Example 7 beyond ambient. Experiment 4063-19-01 was done at ambient
`
`temperatures. Phosphoric acid can be and is typically used at ambient temperatures.
`
`The POSA cannot exclude the possibility that applying heat could result in a
`
`different salt. As Dr. Atwood (Merck’s expert) explained in the Israeli Proceedings,
`
`“higher temperatures affect the kinetics of the reaction and may ‘favor’ a reaction
`
`which is otherwise not energetically favored.” EX2221, ¶¶57, 59; see also EX1025,
`
`92:15-21. Simply put, there is no reason to change this parameter in Example 7 of
`
`WO498. Again, when Dr. Matzger was asked what changes he would make to
`
`Example 7 if phosphoric acid was used in the place of HCl, he did not suggest using
`
`a different temperature. EX1025, 220:6-21.
`
`20
`
`Mylan (IPR2020-00040) Ex. 1035 p. 022
`
`
`
`Reply Declaration of Dr. Mukund Chorghade, Ph.D.
`
`34.
`
`Example 7 step B uses 22 mg (4.3x10-5 mol)18 of BOC-protected
`
`sitagliptin but teaches to use an “analogous” procedure to Example 1. An
`
`“analogous” reaction in methanol19 from Example 1 to Example 7 would mean that
`
`0.38 mL of methanol would be used. Therefore, the molar concentration would be
`
`0.11M.20 Dr. Chyall’s experiment 4063-19-01 used 499.9 mg of sitagliptin base in
`
`18 BOC-protected sitagliptin has a molecular weight of 507 g/mol. 22 mg of BOC-
`
`protected sitagliptin would therefore be equivalent to 4.3x10-5 mol. I note that
`
`Example 7 states “22 mg, 0.039 mmol” BOC-protected sitagliptin was used. Based
`
`on the molecular weight of BOC-protected sitagliptin, “0.039 mmol” appears to be
`
`an error in the text. I have therefore used the 22 mg to carry out my calculations, as
`
`a POSA would have physically weighed out 22 mg of compound to carry out the
`
`experiment (the POSA does not weight out moles, it is a calculated value).
`
`19 Example 1, which is not sitagliptin, reports 0.226 mmol in 2 mL of methanol.
`
`Example 7 uses 4.3x10-5 mol of BOC-protected sitagliptin. What this means is that
`
`if an analogous procedure is used, the amount of methanol used in Example 7 must
`
`maintain the same molar concentration ((4.3x10-2 mmol * 2 mL)/0.226 mmol = 0.38
`
`mL).
`
`20 4.3x10-5 mol/3.8x10-4 L = 0.11 M.
`
`21
`
`Mylan (IPR2020-00040) Ex. 1035 p. 023
`
`
`
`Reply Declaration of Dr. Mukund Chorghade, Ph.D.
`
`6.23 mL of solvent,21 or a molar concentration of 0.2M.22 Dr. Matzger’s experiments
`
`involve 1.503 mg of sitagliptin base in 4.6 mL of solvent, or a molar concentration
`
`of 0.8M.23 In all of the experiments, the sitagliptin was dissolved. EX2225, ¶37
`
`21 Experiment 4063-19-01 used 1.230 mL of 5.0M phosphoric acid in methanol. A
`
`POSA would know that the most commonly used phosphoric acid solution is
`
`phosphoric acid 85 wt% in water. For example, to create a 500 mL stock solution
`
`of 5.0M phosphoric acid in methanol, 171 mL of 85 wt% phosphoric acid would be
`
`added to enough methanol to make a total of 500 mL. (0.5 L x 5M x 98g/mol H3PO4)
`
`x (100 g/85 g H3PO4) x (1 mL/1.685g density of 85 % phosphoric acid) = 171 mL
`
`concentrated acid. 171 mL x 15% water = 25.6 mL water in 0.5 L. Accordingly,
`
`there would be only 0.06 mL of water in the total 0.2M solution.
`
`22 Sitagliptin base has a molecular weight of 407 g/mol. 499.9 mg of sitagliptin base
`
`is therefore equivalent to 1.2x10-3 mol. 1.2x10-3 mol/ (5 mL methanol + 1.230 mL
`
`of 5.0M phosphoric acid in methanol) = 0.2M.
`
`23 1.503 mg of sitagliptin base is equivalent to 3.7x10-3 mol. 3.7x10-3 mol/ (3.2 mL
`
`isopropanol + 1.4 mL distilled water) = 0.8M.
`
`22
`
`Mylan (IPR2020-00040) Ex. 1035 p. 024
`
`
`
`Reply Declaration of Dr. Mukund Chorghade, Ph.D.
`
`(“clear, colorless solution”); EX2
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