`
`IN THE UNITED STATES DISTRICT COURT
`
`FOR THE DISTRICT OF DELAWARE
`
`IN RE OZEMPIC (SEMAGLUTIDE) PATENT
`LITIGATION
`
`C.A. No. 22-md-3038-CFC
`
`CONFIDENTIAL
`
`NOVO NORDISK INC. AND NOVO
`NORDISK A/S,
`
`
`
`
`
`
`Plaintiffs/Counterclaim Defendants,
`
`v.
`
`
`RIO BIOPHARMACEUTICALS INC., et al.,
`
`
`
`Defendants/Counterclaim Plaintiffs.
`
`
`
`
`
`NOVO NORDISK INC. AND NOVO
`NORDISK A/S,
`
`Plaintiffs/Counterclaim Defendants,
`v.
`
`
`MYLAN PHARMACEUTICALS INC.,
`
`Defendants/Counterclaim Plaintiffs.
`
`C.A. No. 22-294-CFC
`
`C.A. No. 22-cv-1040-CFC
`
`
`
`Opening Expert Report of Dr. Paul Dalby
`Regarding Invalidity of U.S. Patent No. 10,335,462
`
`
`
`Novo Nordisk Exhibit 2538
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00001
`
`

`

`TABLE OF CONTENTS
`
`
`Page
`
`
`I.
`
`Qualifications and Background ...................................................................... 1
`A.
`Education and Experience; Prior Testimony........................................ 1
`B.
`Basis for Opinions and Materials Considered ...................................... 5
`C.
`Retention and Compensation ............................................................... 6
`Summary of Opinions ..................................................................................... 6
`II.
`III. Legal Standards .............................................................................................. 8
`IV. Person of Ordinary Skill in the Art ............................................................... 10
`V.
`The ’462 Patent And Asserted Claims 4, 5, 7 .............................................. 13
`A.
`The Formulation Claims of the ’462 Patent ....................................... 13
`B.
`The Prosecution History of the ’462 Patent ....................................... 14
`VI. Claim Construction ....................................................................................... 17
`VII. Background on GLP-1 Compound Formulations Used to Treat
`Diabetes ........................................................................................................ 19
`A.
`Parenteral formulations and components thereof were well-
`known ................................................................................................. 19
`GLP-1 compounds were well-known ................................................. 20
`GLP-1 agonists and related formulations were well-known .............. 23
`Parenteral dosage forms for peptide-based drugs .............................. 23
`1.
`Tonicity and osmolarity of the parenteral formulation ............ 25
`2.
`pH and buffering capacity of the parenteral formulation ........ 26
`3.
`Avoiding particulates in the parenteral formulation ................ 27
`4.
`Vehicles and diluents of the parenteral formulation ................ 27
`5.
`Excipients of the parenteral formulation ................................. 28
`VIII. Scope and Content of the Prior Art .............................................................. 29
`A. WO 2011/138421 (“WO ’421”) ......................................................... 30
`B.
`Clinical Trial No. NCT00696657 (NCT657) ..................................... 31
`C. WO 2006/097537 (“WO ’537”) ......................................................... 33
`
`B.
`C.
`D.
`
`i
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`CONFIDENTIAL
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`Novo Nordisk Exhibit 2538
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00002
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`
`
`IX.
`
`X.
`
`TABLE OF CONTENTS
`(continued)
`
`Page
`
`Lovshin ............................................................................................... 37
`D.
`U.S. Patent No. 8,114,833 (“’833 patent”) ........................................ 38
`E.
`F. Madsbad 2011 .................................................................................... 39
`G. Other Art That Informs the POSA’s Knowledge ............................... 40
`1.
`U.S. Patent No. 6,268,343 (the “Knudsen patent”) ................. 40
`2.
`Victoza label ............................................................................ 42
`3. WO 03/002136 (“WO ’136”)................................................... 42
`4.
`Additional prior art and references .......................................... 44
`5.
`The inventor’s knowledge of the formulation art .................... 45
`Invalidity of the Claims of the ’462 Patent .................................................. 45
`A.
`The State of the Art and a POSA’s Background Knowledge ............ 46
`B.
`Claims 4, 5, and 7 of the ’462 patent would have been obvious
`over WO ’421, NCT657, WO ’537, and/or Lovshin, optionally
`in view of one or more of the ’833 Patent and Madsbad, in view
`of the knowledge of a POSA .............................................................. 53
`1.
`The dependent limitations of claim 4 would have been
`obvious ..................................................................................... 54
`The dependent limitations of claim 5 would have been
`obvious ..................................................................................... 59
`The dependent limitations of claim 7 would have been
`obvious ..................................................................................... 62
`Conclusion ............................................................................... 64
`4.
`Claims 4, 5, and 7 of the ’462 patent would have been obvious
`over WO ’421 alone or in view of the ’833 patent ............................ 65
`Claims 4, 5, and 7 of the ’462 patent would have been obvious
`over WO ’537 considering Lovshin ................................................... 68
`Reservation of Rights ................................................................................... 69
`
`C.
`
`D.
`
`2.
`
`3.
`
`ii
`
`CONFIDENTIAL
`
`Novo Nordisk Exhibit 2538
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00003
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`
`
`TABLE OF ABBREVIATIONS
`
`Abbreviation
`Full Name of Cited Reference
`’366 patent
`U.S. Patent No. 5,164,366
`’462 patent
`U.S. Patent No. 10,335,462
`’674 patent
`U.S. Patent No. 7,022,674
`’727 patent
`U.S. Patent No. 6,284,727
`’833 patent
`U.S. Patent No. 8,114,833
`’924 patent
`U.S. Patent No. 6,458,924
`Deposition of Christine Jensen, M.D., Ph.D. (Nov. 8, 2023) Jensen Dep.
`Knudsen 2004
`Knudsen, Glucagon-Like Peptide-1: The Basis of a New
`Class of Treatment for Type 2 Diabetes, 47 J. MED. CHEM.
`4128 (2004)
`U.S. Patent No. 6,268,343
`Lovshin, Incretin-Based Therapies for Type 2 Diabetes
`Mellitus, 5 NATURE REVIEWS ENDOCRINOLOGY 262 (2009)
`Lund, Emerging GLP-1 Receptor Agonists, 16 EXPERT
`OPINION ON EMERGING DRUGS 607 (2011)
`Madsbad et al., An Overview of Once-Weekly Glucagon-
`Like Peptide-1 Receptor Agonists—Available Efficacy and
`Safety Data and Perspectives
`for
`the Future, 13
`DIABETES, OBESITY & METABOLISM, 394 (2011)
`Boylan, Parenteral Products, in MODERN PHARMACEUTICS
`(Gilbert S. Banker et al. eds., 3d ed. 1996)
`Clinical Trial No. NCT00696657
`Ozempic prescribing information (Oct. 2022)
`REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY
`(Alfonso R. Gennaro ed., 20th ed. 2000)
`Victoza, PHYSICIANS’ DESK REFERENCE (65th ed. 2010)
`WO 00/37098
`WO 03/002136
`WO 2011/058193
`
`Knudsen patent
`Lovshin
`
`Lund
`
`Madsbad 2011
`
`Modern Pharmaceutics
`
`NCT657
`Ozempic label
`Remington
`
`Victoza label
`WO ’098
`WO ’136
`WO ’193
`
`iii
`
`CONFIDENTIAL
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`Novo Nordisk Exhibit 2538
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00004
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`
`
`
`
`TABLE OF ABBREVIATIONS
`(continued)
`
`Full Name of Cited Reference
`WO 2011/073328
`WO 2011/138421
`WO 2006/097537
`
`Abbreviation
`WO ’328
`WO ’421
`WO ’537
`
`4
`
`CONFIDENTIAL
`
`Novo Nordisk Exhibit 2538
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00005
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`
`
`1. My name is Paul Dalby, Ph.D. I have been retained by Dr. Reddy’s
`
`Laboratories, Ltd. and Dr. Reddy’s Laboratories,
`
`Inc.
`
`(“DRL”), Rio
`
`Biopharmaceuticals Inc. and EMS S/A (collectively “Rio”), Sun Pharmaceutical
`
`Industries Ltd. and Sun Pharmaceutical Industries, Inc. (collectively “Sun”), Zydus
`
`Worldwide DMCC, Zydus Pharmaceuticals (USA) Inc., and Zydus Lifesciences
`
`Limited, (collectively “Zydus”), and Mylan Pharmaceuticals Inc. (“MPI”)
`
`(collectively, “Defendants”). Defendants have asked me to provide my expert
`
`opinions regarding the invalidity of claims 4, 5, and 7 of U.S. Patent No. 10,335,462
`
`(“’462 patent”). I understand Novo Nordisk, Inc. and Novo Nordisk A/S
`
`(collectively, “Plaintiffs” or “Novo”) assert that Defendants infringe claims 1, 3, 4,
`
`5, and 7 of the ’462 patent (“the asserted claims”). Because claims 1 and 3 of the
`
`’462 patent relate only to subject matter outside my area of expertise, I have not been
`
`asked to opine on those claims. I therefore address only claims 4, 5, and 7 of the
`
`’462 patent, which relate to my technical area of expertise. I reserve the right to
`
`address the invalidity of any additional claims later asserted by Plaintiffs.
`
`I.
`
`QUALIFICATIONS AND BACKGROUND
`
`A. Education and Experience; Prior Testimony
`
`2.
`
`I earned my doctorate at Cambridge University, UK, in 1998 where I
`
`studied protein folding mechanisms, using protein engineering to alter the relative
`
`stabilities of the native, denatured, intermediate and transition states, and evaluating
`
`1
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`CONFIDENTIAL
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`Novo Nordisk Exhibit 2538
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00006
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`
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`B. Claims 4, 5, and 7 of the ’462 patent would have been obvious over
`WO ’421, NCT657, WO ’537, and/or Lovshin, optionally in view of
`one or more of the ’833 Patent and Madsbad, in view of the
`knowledge of a POSA
`
`140. In my opinion, claims 4, 5, and 7 of the ’462 patent would have been
`
`obvious over WO ’421, NCT657, WO ’537 and/or Lovshin, optionally in view of
`
`one or more of the ’833 Patent and Madsbad 2011, in view of the knowledge of a
`
`person of ordinary skill in the art.
`
`141. In light of the prior art disclosures described here, a POSA would have
`
`been further motivated to formulate this subcutaneous injection as an isotonic
`
`aqueous solution, including a phosphate buffer at a pH in the range of 7.0-9.0, as
`
`required by dependent claim 4. The prior art disclosed semaglutide formulations
`
`having pH ranges within, or that substantially overlap with, the pH values recited in
`
`the dependent claims of the ’462 patent. A POSA would have had a reasonable
`
`expectation of success in making such a formulation using conventional techniques
`
`known in the pharmaceutical industry as stated in the ’833 patent. ’833 patent at
`
`12:64–13:3.
`
`142. As explained here, it is my opinion that a POSA would have been
`
`further motivated to formulate the isotonic aqueous solution to include propylene
`
`glycol and phenol, as required by dependent claims 5 and 7, and would have
`
`53
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`CONFIDENTIAL
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`Novo Nordisk Exhibit 2538
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00007
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`reasonably expected such a formulation to have desirable properties based on the
`
`teachings of the ’833 patent. See id.
`
`143. Finally, a POSA would have had a reasonable expectation of success in
`
`making such a formulation using conventional techniques based on the disclosures
`
`of the ’833 patent. Id. at 12:64–13:3.
`
`1.
`
`The dependent limitations of claim 4 would have been obvious
`
`144. Claim 4 depends from claim 1 and adds the limitation “wherein the
`
`semaglutide is administered in the form of an isotonic aqueous solution comprising
`
`phosphate buffer at a pH in the range of 7.0-9.0.” ’462 patent at 35:49-52. In my
`
`opinion, claim 4 of the ’462 patent would have been obvious in view of the prior art.
`
`145. As explained above, NCT657 and Lovshin both disclosed that
`
`semaglutide had been administered via subcutaneous injection, and therefore taught
`
`that semaglutide could be formulated as an injectable solution. NCT657 at 15;
`
`Lovshin at 263-264. Further, WO ’421 disclosed that GLP-1 analogues, including
`
`semaglutide specifically, could be “prepared according to known formulation
`
`techniques, e.g. using suitable liquid carriers, which usually comprise sterile water,
`
`and, optionally, further additives e.g. for aiding solubility or for preservation or the
`
`like, to obtain injectable solutions or suspensions.” WO ’421 at 39:23-26, 43:13.
`
`Thus, a POSA would have been motivated by WO ’421 to formulate semaglutide as
`
`an injectable solution with a reasonable expectation of success. Further, as explained
`
`54
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`IPR2023-00724
`Page 00008
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`above, a POSA would have been aware that “known formulation techniques” as of
`
`the priority date included preparing injectable formulations as isotonic aqueous
`
`solutions with a pH in the range of 7.0-9.0, and that phosphate buffers were
`
`commonly used. Supra Sections VII.A, VII.D.
`
`146. In addition, WO ’537 expressly disclosed pharmaceutical formulations
`
`comprising GLP-1 compounds, such as semaglutide, along with excipients:
`
`The term “pharmaceutical composition” as used herein
`means a product comprising an active compound or a salt
`thereof together with pharmaceutical excipients such as
`buffer, preservative, and optionally a tonicity modifier
`and/or a stabilizer. Thus a pharmaceutical composition is
`also known in the art as a pharmaceutical formulation.
`
`WO ’537 at 5:32-35. As explained above, WO ’537 disclosed a pharmaceutical
`
`formulation comprising a compound in a concentration from 0.1 mg/ml to 25 mg/ml,
`
`and wherein said formulation has a pH from 3.0 to 9.0. See supra Section VIII.C.
`
`147. Exemplary pH ranges were also provided in WO ’537, include
`
`examples of formulations having a pH from about 7.0 to about 9.5, about 3.0 to about
`
`7.0., about 5.0 to about 7.5. and from about 7.5 to about 9.0. WO ’537 at 24:30 –
`
`25:2; see also ’833 patent at 15:66–22:21; Knudsen patent at 42:59–43:4; supra
`
`Section VIII.C.
`
`148. WO ’537 also disclosed:
`
`In a further embodiment of the invention the buffer is
`selected from the group consisting of sodium acetate,
`
`55
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`CONFIDENTIAL
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`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00009
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`sodium carbonate, citrate, glycylglycine, histidine,
`glycine, lysine, arginine, sodium dihydrogen phosphate,
`disodium hydrogen phosphate, sodium phosphate, and
`tris(hydroxymethyl)-aminomethan, bicine, tricine, malic
`acid, succinate, maleic acid, fumaric acid, tartaric acid,
`aspartic acid or mixtures thereof.
`
`WO ’537 at 25:4-8; see also ’833 patent at 10:47-57; Knudsen patent at 168:1-6
`
`149. WO ’537 also provided a specific example of a pharmaceutical
`
`formulation comprising semaglutide, propylene glycol, phenol, and a phosphate
`
`buffer, where the pH is 8.15.
`
`
`
`WO ’537 at 63:10-15; see also ’833 patent at 16:5-20:41; Knudsen patent at 98:1-8.
`
`150. Accordingly, WO ’057 taught that semaglutide could be formulated
`
`exactly as it is claimed in the ’462 patent. In particular, a POSA would have been
`
`motivated by WO ’537, including in view of WO ’421, Lovshin, and NCT657, to
`
`formulate a 1.0 mg dose of semaglutide in the form of an isotonic aqueous solution
`
`comprising a phosphate buffer at a pH in the range of 7.0-9.0. And a POSA would
`
`56
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`have had a reasonable expectation of success that semaglutide could be formulated
`
`in this way in view of the express teachings of at least WO ’057.
`
`151. Further, the ’833 patent claimed “[a] pharmaceutical formulation
`
`comprising at least one GLP-1 agonist, a disodium phosphate dihydrate buffer and
`
`propylene glycol, wherein said propylene glycol is present in said formulation in a
`
`final concentration of from about 1 mg/ml to about 100 mg/ml and wherein said
`
`formulation has a pH of from about 7.0 to 10.0.” ’833 patent at 22:48-54 (claim 1).
`
`The ’833 patent explains that disodium phosphate dihydrate is a buffer. Id. at 10:47-
`
`57.
`
`152. The ’833 patent further claimed “[t]he formulation according to claim
`
`1, wherein the pH of said formulation is about 7.0 to about 8.3.” Id. at 22:66-67
`
`(claim 6). As described above in Section VIII.E., Examples 1-6 of the ’833 patent
`
`disclosed the use of a phosphate buffer at pH within the range of 7.0-9.0. ’833 patent
`
`at 15:66–22:21.
`
`153. The ’833 patent further disclosed:
`
`Where a buffer is to be included in the formulations of the
`invention, the buffer is selected from the group consisting
`of
`sodium
`acetate,
`sodium
`carbonate,
`citrate,
`glycylglycine, histidine, glycine, lysine, arginin, sodium
`dihydrogen phosphate, disodium hydrogen phosphate,
`sodium
`phosphate,
`and
`tris(hydroxymethyl)-
`aminomethan, or mixtures thereof. . . . In a preferred
`embodiment of the invention, the buffer is glycylglycine,
`
`57
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`CONFIDENTIAL
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`Novo Nordisk Exhibit 2538
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00011
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`sodium dihydrogen phosphate, disodium hydrogen
`phosphate, sodium phosphate or mixtures thereof.
`
`Id. at 10:47-57.
`
`154. The ’833 patent stated that “[t]he inclusion of isotonicity agents in
`
`peptide-containing pharmaceutical formulations is widely known.” Id. at 1:30-31.
`
`The POSA would have known that semaglutide is a GLP-1 analogue, which is a
`
`peptide.
`
`155. Example 3 of the ’833 patent disclosed that “[i]t is believed that similar
`
`results [i.e., ‘no clogging of the needles’] to those obtained with the above-described
`
`propylene glycol-containing formulation would also be obtained if the pH was
`
`adjusted to 7.40, 7.70 or 7.90” and disclosed a pH of “7.40, 7.70, 7.90, or 8.15.” Id.
`
`at 20:6-19. Example 4 disclosed a liraglutide composition with a pH of 7.40
`
`containing sodium dihydrogen phosphate. Id. at 20:29-35. Example 5 of the ’833
`
`patent also disclosed a composition with a pH of 7.4. Id. at 20:67.
`
`156. The ’833 patent also disclosed:
`
`The formulations of the invention may be prepared by
`conventional techniques, e.g. as described in Remington’s
`Pharmaceutical Sciences, 1985 or in Remington: The
`Science and Practice of Pharmacy, 19th edition, 1995,
`where such conventional techniques of the pharmaceutical
`industry involve dissolving and mixing the ingredients as
`appropriate to give the desired end product.
`
`’833 patent at 12:64–13:3.
`
`58
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`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
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`157. Thus, as explained above, the ’833 patent, like WO ’537, expressly
`
`disclosed that injectable solutions of GLP-1 analogues could be formulated as an
`
`isotonic aqueous solution comprising phosphate buffer at a pH in the range of 7.0-
`
`9.0. In my opinion, when WO ’421, NCT657, WO ’537, and/or Lovshin are read in
`
`view of the ’833 patent, a POSA would have been motivated to formulate the 1.0
`
`mg semaglutide solution recited in the asserted claims as an isotonic aqueous
`
`solution comprising phosphate buffer at a pH in the range of 7.0-9.0. And, in my
`
`opinion, a POSA would have had a reasonable expectation of success in view of the
`
`prior art, which expressly taught that GLP-1 analogues could be formulated and
`
`administered consistent with the limitations of dependent claim 4.
`
`158. For at least these reasons, it is my opinion that claim 4 is invalid as
`
`obvious over WO ’421, NCT657, WO ’537 and/or Lovshin optionally in view of the
`
`’833 Patent, optionally in view of Madsbad 2011, and in view of the knowledge of
`
`a POSA.
`
`2.
`
`The dependent limitations of claim 5 would have been obvious
`
`159. Claim 5 depends from claim 4 and adds the limitation “wherein the
`
`solution further comprises propylene glycol and phenol.” ’462 patent at 35:53-54.
`
`For the same reasons discussed above, the elements of claim 4 would have been
`
`obvious over WO ’421, NCT657, WO ’537 and/or Lovshin, optionally in view of
`
`the ’833 Patent, optionally in view of Madsbad 2011, and in view of the knowledge
`
`59
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`IPR2023-00724
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`of a POSA. Further, in my opinion, for many of the same reasons explained above,
`
`a POSA would have been motivated to use propylene glycol and phenol in an
`
`injectable semaglutide solution.
`
`160. First, WO ’537 expressly taught a pharmaceutical formulation that
`
`included semaglutide, propylene glycol, phenol, and a phosphate buffer, where the
`
`pH is 8.15.
`
`
`
`WO ’537 at 63:10-15. Indeed, WO ’537 disclosed that phenol could be used as a
`
`preservative. Id. at 25:11-13. WO ’537 further disclosed that propylene glycol could
`
`be used as an isotonicity agent. Id. at 25:34-35. Thus, in my opinion, a POSA would
`
`have been motivated to use propylene glycol and phenol in view of WO ’537, and
`
`would have had a reasonable expectation of success.
`
`161. Second, the ’833 patent disclosed the use of propylene glycol as an
`
`isotonicity agent in aqueous solutions containing GLP-1 agonists. See ’833 patent at
`
`24:7-14 (claim 23); see also id. at 19:44 (disclosing the use of propylene glycol as
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`
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`an isotonicity agent). A POSA would have known that semaglutide is a GLP-1
`
`agonist. Supra Section VII.B.
`
`162. The ’833 patent disclosed that the use of a preservative in
`
`pharmaceutical compositions is well-known to the skilled artisan. ’833 patent at
`
`10:58-67. In particular, the ’833 patent disclosed the use of “phenol (5.0 or 5.5
`
`mg/ml)” as a preservative. Id. at 20:14. The ’833 patent also disclosed that “[i]n a
`
`preferred embodiment of the invention the preservative is phenol or m-cresol.” Id.
`
`at 10:65-67.
`
`163. The ’833 patent further disclosed “that peptide formulations containing
`
`propylene glycol at certain concentrations exhibit reduced deposits in production
`
`equipment and in the final product and also exhibit reduced clogging of injection
`
`devices.” Id. at 1:53-57; see also id. at 13:43-45 (Disclosing “the ability of propylene
`
`glycol to reduce clogging of injection devices when compared to other isotonic
`
`agents and to mannitol in particular.”). The ’833 patent also disclosed that “[t]he
`
`present invention further relates to a method for reducing the clogging of injection
`
`devices by a peptide formulation, where the method comprises replacing the
`
`isotonicity agent previously utilized in said formulation with propylene glycol at a
`
`concentration of between 1-100 mg/ml.” Id. at 2:58-62.
`
`164. Accordingly, in my opinion, a POSA would have been highly
`
`motivated to use propylene glycol in a semaglutide solution formulation in view of
`
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`IPR2023-00724
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`the ’833 patent. Further, it is my opinion that a POSA would have been motivated
`
`to use both phenol and propylene glycol in view of the ’833 patent, and would have
`
`had a reasonable expectation of success.
`
`165. For at least these reasons, and the reasons discussed above with respect
`
`to claim 4, claim 5 is invalid as obvious over WO ’421, NCT657, WO ’537 and/or
`
`Lovshin, optionally in view of the ’833 Patent, optionally in view of Madsbad 2011,
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`and in view of the knowledge of a POSA.
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`3.
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`The dependent limitations of claim 7 would have been obvious
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`166. Claim 6 depends from claim 4 and adds the limitation “wherein the pH
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`is 7.4.” ’462 patent at claim 6. Claim 7 depends from claim 6 and adds the limitation
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`“wherein the solution further comprises propylene glycol and phenol.” ’462 patent
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`at claim 7. Thus, I understand claim 7 of the ’462 patent requires the solution of
`
`claim 4 to include propylene glycol and phenol, and to have a pH of 7.4.
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`167. For the same reasons set forth above, it is my opinion that a POSA
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`would have been motivated to use both propylene glycol and phenol, and would have
`
`had a reasonable expectation of success, in view of WO ’421, NCT657, WO ’537
`
`and/or Lovshin, optionally in view of the ’833 Patent, optionally in view of Madsbad
`
`2011, and in view of the knowledge of a POSA. Supra Section IX.B.2. Further, in
`
`my opinion, a POSA would have been motivated to prepare the semaglutide solution
`
`having a pH of 7.4 in view of the prior art.
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`IPR2023-00724
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`168. First, WO ’537 disclosed exemplary pH ranges for a semaglutide
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`formulation:
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`In another embodiment of the invention the pH of the
`formulation is from about 7.0 to about 9.5. In another
`embodiment of the invention the pH of the formulation is
`from about 3.0 to about 7.0. In another embodiment of the
`invention the pH of the formulation is from about 5.0 to
`about 7.5. In another embodiment of the invention the pH
`of the formulation is from about 7.5 to about 9.0. In
`another embodiment of the invention the pH of the
`formulation is from about 7.5 to about 8.5. In another
`embodiment of the invention the pH of the formulation is
`from about 6.0 to about 7.5. In another embodiment of the
`invention the pH of the formulation is from about 6.0 to
`about 7.0. In another embodiment the pharmaceutical
`formulation is from 8.0 to 8.5.
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`Id. at 24:30–25:2. Accordingly, a POSA would have understood from WO ’537 that
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`one pH suitable for a semaglutide solution would be 7.4.
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`169. Second, as explained above, Example 3 of the ’833 patent disclosed
`
`that “similar results [i.e., ‘no clogging of the needles’]” if the pH was adjusted to
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`7.40, 7.70 or 7.90 and disclosed a pH of “7.40, 7.70, 7.90, or 8.15.” ’833 patent at
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`20:6-19. Example 4 disclosed a liraglutide composition with a pH of 7.40 containing
`
`sodium dihydrogen phosphate (20:29-35) and Example 5 disclosed a pH of 7.4
`
`(20:67). Examples 1-6 of the ’833 patent (each exemplary formulation) further
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`disclosed the use of a phosphate buffer at pH within the range of 7.0-9.0. Id. at
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`15:66–22:21.
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`IPR2023-00724
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`170. Accordingly, in my opinion, a POSA would have been motivated to use
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`a pH of 7.4 in view of the ’833 patent, and would have had a reasonable expectation
`
`of success. In particular, it is my opinion that a POSA would have been motivated
`
`to use a pH of 7.4 in a semaglutide solution, and would have had a reasonable
`
`expectation of success, in view of WO ’421, NCT657, WO ’537 and/or Lovshin,
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`optionally in view of the ’833 Patent, optionally in view of Madsbad 2011, and in
`
`view of the knowledge of a POSA.
`
`171. In my opinion, for at least these reasons, and the reasons discussed
`
`above with respect to claims 4 and 5, claim 7 is invalid as obvious over WO ’421,
`
`NCT657, WO ’537 and/or Lovshin in view of the ’833 Patent, optionally in view of
`
`Madsbad 2011, and in view of the knowledge of a person of ordinary skill in the art.
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`4.
`
`Conclusion
`
`172. For each of claims 4, 5, and 7 of the ’462 patent, it is my opinion that a
`
`POSA would have been motivated to formulate the claimed semaglutide dose into
`
`an isotonic aqueous solution that includes a phosphate buffer, propylene glycol, and
`
`phenol, at a pH in the range of 7.0-9.0, specifically at a pH of 7.4. Indeed, the prior
`
`art expressly disclosed semaglutide formulations having these ingredients and
`
`properties (i.e., the claimed excipients, aqueous isotonic solutions, pH ranges within,
`
`or that overlap with, the claimed pH values recited in the dependent claims of the
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`’462 patent). And a POSA would have had a reasonable expectation of success of
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`making such a formulation using conventional techniques known to a POSA. My
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`opinions are limited to the formulation elements in claims 4, 5, and 7 of the ’462
`
`patent. However, Defendants’ medical and clinical experts’ opinions are that WO
`
`’537 disclosed all treatment-related elements of the asserted claims of the ’462
`
`patent. Thus, the asserted claims of the ’462 patent would have been obvious over
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`WO ’421, NCT657, WO ’537, and/or Lovshin, optionally in view of one or more of
`
`the ’833 Patent and Madsbad, in view of the knowledge of a person of ordinary skill
`
`in the art.
`
`C. Claims 4, 5, and 7 of the ’462 patent would have been obvious over
`WO ’421 alone or in view of the ’833 patent
`
`173. As explained above, claims 4, 5, and 7 of the ’462 patent recite a
`
`method for treating type 2 diabetes, comprising once-weekly administration of 1.0
`
`mg of semaglutide with the following properties and excipients: (1) as an isotonic
`
`aqueous solution for subcutaneous injection; (2) with propylene glycol and phenol;
`
`(3) with a phosphate buffer; and/or (4) with a pH in the range of 7.0-9.0, and at 7.4
`
`specifically. In my opinion, a POSA would have been motivated to formulate the
`
`claimed dose of semaglutide with the claimed excipients and properties in view of
`
`WO ’421 further in view of the ’833 patent.
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`174. First, I explained above why the limitations of claims 4, 5, and 7 would
`
`have been obvious in view of the ’833 patent. Supra Section IX.B. For those same
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`reasons, it is my opinion that a POSA would have been motivated by the ’833 patent
`
`to formulate semaglutide with the excipients and properties recited in the
`
`formulation claims.
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`175. In addition, in my opinion, when WO ’421 is read in view of the ’833
`
`patent, the formulations claims would have been obvious. WO ’421 disclosed
`
`“methods for treating and/or preventing metabolic diseases, especially type 2
`
`diabetes mellitus, obesity and/or conditions related
`
`thereto (e.g. diabetic
`
`complications) comprising the combined administration of a GLP-1 receptor agonist
`
`(e.g. exogenous GLP-1 or a GLP-1 analogue) and a certain DPP-4 inhibitor.” WO
`
`’421 at 1:4-7. WO ’421 further disclosed that “[p]referred examples of GLP-1
`
`receptor agonists (GLP-1 analogues) of this invention are exenatide, exenatide LAR,
`
`liraglutide, taspoglutide, semaglutide, albiglutide, lixisenatide and dulaglutide.” Id.
`
`at 33:20-22 (emphasis added).
`
`176. Further, as explained above, WO ’421 disclosed that injectable
`
`formulations of GLP-1 receptor agonists “may be prepared according to known
`
`formulation techniques, e.g. using suitable liquid carriers, which usually comprise
`
`sterile water, and, optionally, further additives e.g. for aiding solubility or for
`
`preservation or the like, to obtain injectable solutions or suspensions.” WO ’421 at
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`39:23-26. And WO ’421 disclosed that injectable formulations of GLP-1 receptor
`
`agonists “may be prepared according to known formulation techniques, e.g. using
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`IPR2023-00724
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`suitable liquid carriers, which usually comprise sterile water, and, optionally, further
`
`additives e.g. for aiding solubility or for preservation or the like, to obtain injectable
`
`solutions or suspensions.” Id. at 39:23-26. Thus, a POSA would have been motivated
`
`by WO ’421 to formulate semaglutide as an injectable solution with a reasonable
`
`expectation of success. Further, as explained above, a POSA would have been aware
`
`that “known formulation techniques” as of the priority date included preparing
`
`injectable formulations as isotonic aqueous solutions with a pH in the range of 7.0-
`
`9.0, and that phosphate buffers were commonly used. Supra Sections VII.A, VII.D,
`
`IX.A.
`
`177. Accordingly, in my opinion, the formulation claims would have been
`
`obvious in view of WO ’421 and the ’833 patent. In my opinion, a POSA would
`
`have been motivated to formulate the claimed semaglutide dose into an isotonic
`
`aqueous solution that includes a phosphate buffer, propylene glycol, and phenol, at
`
`a pH in the range of 7.0-9.0, including at a pH of 7.4 specifically. Indeed, the prior
`
`art expressly disclosed semaglutide formulations having these ingredients and
`
`properties (i.e., the claimed excipients, aqueous isotonic solutions, pH ranges within,
`
`or that overlap with, the claimed pH values recited in the dependent claims of the
`
`’462 patent). And a POSA would have had a reasonable expectation of success of
`
`making such a formulation using conventional techniques known to a POSA.
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