I.
`
`INTRODUCTION
`
`Mylan InstitutionalFresenius Kabi USA, LLC (“Petitioner”) petitions for
`
`Inter Partes Review (“IPR”) of claims 1-31 of U.S. Patent No. 8,114,833 (“the ’833
`
`patent”) (Ex. 1001), which is assigned to Novo Nordisk A/S (“Patent Owner”), under
`
`35 U.S.C. §§ 311-319 and 37 C.F.R. § 42 and seeks a determination that all claims
`
`(1-31) of the ’833 patent be canceled as unpatentable.
`
`II. MANDATORY NOTICES
`
`This Petition is filed in accordance with 37 C.F.R. § 42.106(a). Filed herewith
`
`is a power of attorney and exhibit list per § 42.10(b) and § 42.63(e). Pursuant to
`
`37Petitioner authorizes the U.S. Patent & Trademark Office to charge Deposit
`
`Account No. 506989 for any necessary fees.
`
`A. Real Parties-In-Interest – 37 C.F.R. § 42.103, the fee set forth in §
`42.15(e) accompanies this Petition42.8(b)(1).
`
`A. Real Parties-In-Interest
`In accordance with 37 C.F.R. § 42.8(b)(1), the real parties-in-interest for
`
`Petitioner are Mylan Institutional LLC, Mylan Inc., and Mylan N.Vand in
`
`abundance of caution, Fresenius Kabi, LLC may be a real party-in-interest.
`
`B. Related Matters – 37 C.F.R. § 42.8(b)(2).
`
`In accordance with 37 C.F.R. § 42.8(b)(2), Petitioner is not aware of any
`
`reexamination certificates or pending prosecution concerning the ’833 patent.
`
`Petitioner is the defendant in the following litigation involving the ’833 patent:
`
`Novo Nordisk Inc. v. Mylan Institutional LLC, C.A. No. 19-cv-01551-CMC
`(D. Del.).
`The ’833 patent is the subject of the following litigations: Novo Nordisk
`
`Inc. et al v. Sandoz Inc., Case No. 1:20-cv-00747 (D. Del.) (“Sandoz Litigation”),
`
`Novo Nordisk Inc. et al v. Teva Pharmaceuticals, Inc. et al, Case No. 1:21-cv-
`
`01782 (D. Del.), and Novo Nordisk Inc. et al v. Hikma Pharmaceuticals USA Inc.,
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`FRESENIUS EXHIBIT 1077
`Page 1 of 72
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`
`
`INTRODUCTION
`
`Mylan InstitutionalFresenius Kabi USA, LLC (“Petitioner”) petitions for
`
`Inter Partes Review (“IPR”) of claims 1-31 of U.S. Patent No. 8,114,833 (“the ’833
`
`patent”) (Ex. 1001), which is assigned to Novo Nordisk A/S (“Patent Owner”), under
`
`35 U.S.C. §§ 311-319 and 37 C.F.R. § 42 and seeks a determination that all claims
`
`(1-31) of the ’833 patent be canceled as unpatentable.
`
`II. MANDATORY NOTICES
`
`This Petition is filed in accordance with 37 C.F.R. § 42.106(a). Filed herewith
`
`is a power of attorney and exhibit list per § 42.10(b) and § 42.63(e). Pursuant to
`
`37Petitioner authorizes the U.S. Patent & Trademark Office to charge Deposit
`
`Account No. 506989 for any necessary fees.
`
`A. Real Parties-In-Interest – 37 C.F.R. § 42.103, the fee set forth in §
`42.15(e) accompanies this Petition42.8(b)(1).
`
`A. Real Parties-In-Interest
`In accordance with 37 C.F.R. § 42.8(b)(1), the real parties-in-interest for
`
`Petitioner are Mylan Institutional LLC, Mylan Inc., and Mylan N.Vand in
`
`abundance of caution, Fresenius Kabi, LLC may be a real party-in-interest.
`
`B. Related Matters – 37 C.F.R. § 42.8(b)(2).
`
`In accordance with 37 C.F.R. § 42.8(b)(2), Petitioner is not aware of any
`
`reexamination certificates or pending prosecution concerning the ’833 patent.
`
`Petitioner is the defendant in the following litigation involving the ’833 patent:
`
`Novo Nordisk Inc. v. Mylan Institutional LLC, C.A. No. 19-cv-01551-CMC
`(D. Del.).
`The ’833 patent is the subject of the following litigations: Novo Nordisk
`
`Inc. et al v. Sandoz Inc., Case No. 1:20-cv-00747 (D. Del.) (“Sandoz Litigation”),
`
`Novo Nordisk Inc. et al v. Teva Pharmaceuticals, Inc. et al, Case No. 1:21-cv-
`
`01782 (D. Del.), and Novo Nordisk Inc. et al v. Hikma Pharmaceuticals USA Inc.,
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`Case No. 1:21-cv-01783 (D. Del.). Trial is scheduled in the Sandoz litigation to
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`begin in April 2022. No schedule has been entered in the other litigations.
`
`The ’833 patent was the subject of two Inter Partes Review proceedings:
`
`Mylan Institutional LLC v. Novo Nordisk A/S, IPR2020-00324, and Pfizer Inc. v.
`
`Novo Nordisk A/S, IPR2020-01252. These petitions were instituted and joined,
`
`but both settled before issuance of a Final Written Decision. This petition
`
`presents the same grounds of unpatentability as IPR2020-00324 and IPR2020-
`
`01252.
`
`Petitioner is not aware of any other pending litigation, or any pendingjudicial
`
`or administrative matter that would affect or be affected by a decision in this
`
`IPR.
`
`proceedings in front of the Patent Trial and Appeal Board.
`A patent application in the same patent family is pending as U.S. Patent
`
`Application No. 16/260,204910,945, filed on Jan. 29June 24, 20192020.
`
`C.
`
`Identification ofLead and Backup Counsel (– 37 C.F.R. § 42.8(b)(3))
`
`Petitioner designates the following lead and backup counsel:
`
`Lead Counsel
`Brandon M. WhiteLinnea Cipriano
`(Reg. No. 52,354) Perkins Coie
`LLP67,729)
`700 Thirteenth Street, N.W. Suite
`600
`Washington, D.C. 20005
`Goodwin Procter LLP
`620 Eighth Avenue
`New York, NY 10018
`TelephonePhone: (202212) 654-
`6206813-8800
`Fax: (212) 355-3333
`Facsimile: (202) 654-9681
`BMWhite@perkinscoie.comlcipriano@
`goodwinlaw.com
`
`Back-UpBack-up Counsel
`Lara Dueppen (Reg. No. 65,002)
`Perkins Coie LLP
`1888 Century Park East Suite
`1700
`Los Angeles, CA 90067
`Telephone: (310) 788-3349
`Daryl Wiesen (pro hac vice application
`to be filed)
`Goodwin Procter LLP
`100 Northern Avenue
`Boston, MA 02210
`Phone: (617) 570-1000
`Fax: (617) 523-1231
`788-3399
`Facsimile:
`(310)
`LDueppen@perkinscoie.comdwiesen@
`goodwinlaw.com
`
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`D. Service Information
`Service Information – 37 C.F.R. § 42.8(b)(4)
`D.
`
`Pursuant to 37 C.F.R. § 42.8(b)(4), Petitioner respectfully requests that all
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`correspondence be directed to lead counsel and back-up counsel at the contact
`
`information provided above. Petitioner consents to electronic service by e-mail at the
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`following email addresses:
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`White-ptab@perkinscoie.com; Dueppen-ptab@perkinscoie.com; and
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`Liraglutide@perkinscoie.com.
`
`lcipriano@goodwinlaw.com
`
`dwiesen@goodwinlaw.com
`
`III.
`
`III. GROUNDS FOR STANDING
`
`Pursuant to 37 C.F.R. § 42.104(a), Petitioner certifies that the ’833 patent is
`
`available for inter partes reviewIPR and that Petitioner is not barred or estopped
`
`from requesting inter partes reviewIPR on the grounds identified herein.
`
`IV.
`
`2
`IV. IDENTIFICATION OF CHALLENGE AND STATEMENT OF
`PRECISE RELIEF REQUESTED
`Pursuant to 37 C.F.R. § 42.22(a) and 37 C.F.R. § 42.104(b), Petitioner requests
`
`inter partes review and cancellation of claims 1-31 on the following grounds:
`
`Ground 1: Claims 1-15 of the ’833 patent were anticipated by Flink (Ex.
` 1004).
`
`Ground 2: Claims 1-15 of the ’833 patent would have been obvious over
`Flink
` (Ex. 1004).
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`Ground 3: Claims 1-31 of the ’833 patent would have been obvious over
`Flink
` (Ex. 1004) in view Betz (Ex. 1005).
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`Petitioner’s statement of the reasons for the relief is set forth below. In support
`
`of these grounds for unpatentability, Petitioner submits the declaration of Laird
`
`Forrest, Ph.D., and relies on the Exhibits identified in the concurrently-filed Listing
`
`of Exhibits (Ex. 1002).
`
`Statement of No Redundancy: This is the first petition for inter partes review
`of the ’833 patent by Petitioner. Grounds 1-3 presented in this Petition have not
`
`previously been before the Board.
`
`V. V. THRESHOLD REQUIREMENT FOR INTER PARTES
`REVIEW
`A petition for inter partes review must demonstrate a “reasonable likelihood
`
`that the petitioner would prevail with respect to at least 1 of the claims challenged
`
`3
`in the petition.” 35 U.S.C. § 314(a). ThisAs explained in detail herein, this
`
`Petition clears thatthe threshold. There for institution because there is a reasonable
`
`likelihood that Petitioner will prevail with respect to at least one of the challenged
`
`claims. 35 U.S.C. § 314(a).
`
`VI. STATEMENT OF REASONS FOR THE RELIEF REQUESTED.
`Summary of the Argument
`A.
`
`The challenged claims relate to a formulation containing a glucagon-like
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`peptide 1 (“GLP-1”) agonist, a standard buffer to stabilize the pH of the formulation,
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`and a common tonicity agent. This same formulation was, however, already
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`disclosed in the prior art, including in the Flink reference relied on here. The claims
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`offer nothing new over the prior art, rendering them unpatentable.
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`Level of Ordinary Skill in the Art
`
`B.
`A person of ordinary skill in the art (“POSA”)1 1 would have had (1) a Pharm.
`
`D., or a Ph.D. in pharmacy, chemical engineering, bioengineering, chemistry, or
`
`related discipline; (2) at least two years of experience in the area of protein or peptide
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`therapeutic development and/or manufacturing; and (3) experience with the
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`development, design, manufacture, or formulation of therapeutic agents, and the
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`literature concerning protein or peptide formulation and design. Ex. 1002, ¶¶26-27.
`
`1 All references herein to the knowledge or understanding of a POSA or a
`POSA’s interpretation or understanding of a prior art reference are as of the earliest
`possible priority date claimed on the face of the ’833 patent, November 20, 2003,
`unless specifically stated otherwise.
`
`4
` In view of the relatively high level of skill and the clear teachings in the prior
`
`art, the level of skill of the POSA is not dispositive of any issue raised in this
`
`Petition.
`
`C. The ’833 Patent and Its Prosecution
`
`1.
`
`THEThe ’833 PATENT DISCLOSURESPatent Disclosures
`
`
`1 All references herein to the knowledge or understanding of a POSA or a POSA’s
`
`interpretation or understanding of a prior art reference are as of the earliest possible
`
`priority date claimed on the face of the ’833 patent, November 20, 2003, unless
`
`specifically stated otherwise.
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`The ’833 patent is titled “Propylene Glycol-Containing Peptide Formulations
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`Which Are Optimal for Production and For Use in Injection Devices.” Ex. 1001. The
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`’833 patent is directed to pharmaceutical formulations containing a peptide and
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`propylene glycol as a tonicity agent instead of one of the other tonicity agents known
`
`to be prone to crystallization. Ex. 1001, 1:18-22. According to the ’833 patent, using
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`propylene glycol as the tonicity agent, rather than an alternative like mannitol,
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`reduces crystallization of the formulation, thereby reducing the formation of deposits
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`on production equipment and the clogging of needles. Ex. 1001, 1:23-26, 53-57.
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`The patent teaches that formulations containing propylene glycol “may be
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`formulated with any peptide” to achieve the same purported advantages. Ex. 1001,
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`1:57-58 (emphasis added). .2 The specification discloses many peptides that may be
`
`used in the formulations (Ex. 1001, 3:49-4:2), and the claims as originally filed were
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`directed to formulations that include GLP-1 agonists, insulin, human growth hormone
`
`(“hGH”), and analogues or derivatives of those peptides (Ex. 1003, 33-35). The
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`specification describes a genus of GLP-1 agonists, GLP-1 analogues, and
`
`5
` derivatives thereof, including Arg34, Lys26(Nε-(γ-Glu(Nα-hexadecanoyl)))-
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`GLP-1(7- 37), known as liraglutide. Ex. 1001, 4:25-37, 4:53-7:64.
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`The patent includes six working examples disclosing studies comparing the
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`effect of different tonicity agents on deposit formation and needle clogging. Based on
`
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`2 All emphasis is added unless otherwise noted.
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`results of the tests run in the first example, the patentee determined several tonicity
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`agents were equally suitable candidates to replace mannitol in peptide formulations.
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`Id. at 17:66-18:67. But the patentee chose only propylene glycol for further studies in
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`formulations with a placebo, liraglutide, and insulin. Id. at 15:64- 18:67.
`
`2.
`
`2. THEThe ’833 PATENT PRIORITY DATEPatent Priority
`Date
`
`The ’833 patent issued February 14, 2012, from U.S. Application No.
`
`11/435,977 (“’977 application”), filed on May 17, 2006. Ex. 1001 ¶¶(21), (22). The
`
`’833 patent names Tina Bjeldskov Pedersen, Claude Bonde, and Dorthe Kot
`
`Engelund as inventors and Novo Nordisk A/S as assignee. Id. ¶(75).
`
`The ’977 application is a continuation of International Application No.
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`PCT/DK2004/000792 (“’792 PCT”), filed November 18, 2004, and purports to claim
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`priority to (i) U.S. Provisional Application No. 60/524,653 (“’653 provisional”) filed
`
`November 24, 2003, and (ii) Danish Patent Application No. DK 200301719 (“Danish
`
`priority application”) filed November 20, 2003. But the Examiner confirmed during
`
`prosecution of the ’977 application (see Section VI.C.4)
`
`6
` that the ’792 PCT fails to include a priority claim to the ’653 provisional, and
`
`can only claim priority to the Danish priority application. Ex. 1003, 163. And, the
`
`’833 patent cannot claim priority to the ’653 provisional because the ’977 application
`
`was filed more than twelve months after the provisional. Thus, for purposes of pre-
`
`AIA 35 U.S.C. § 102(b), the ’833 patent’s priority date is November 18,
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`
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`2004.22004.3
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`3.
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`3. THEThe ’833 PATENT CLAIMSPatent Claims
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`The ’833 patent’s independent claims recite GLP-1 agonist formulations (claim
`
`1), and methods of preparing GLP-1 agonist formulations (claim 16), reducing
`
`deposits during the production of such formulations (claims 23 and 26), and reducing
`
`clogging of injection devices by such formulations (claim 29). Ex. 1001, 22:49-54,
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`23:37-53, 24:7-13, 24:26-32, 24:45-50; Ex. 1002, ¶29. Independent
`
` claim 1 is representative of the formulation claims:
`
`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 about 10.0.
`
`
`3 The ’833 patent cannot claim priority to the ’653 provisional. Thus, the only proper
`
`priority claim for the ’833 patent is to the Danish application filed on November 20,
`
`2003. Under pre-AIA 35 U.S.C. § 102(b), the relevant date is the filing of a patent
`
`application “in this country,” which includes PCT applications, but not foreign
`
`priority documents. See 35 U.S.C. § 119(a) (pre-AIA); see also MPEP 706.02. Here,
`
`“the actual filing of the application in this country” is no earlier than November 18,
`
`2004, PCT/DK2004/000792’s filing date. Therefore, references that pre-date
`
`November 18, 2003, are § 102(b) prior art. MPEP 2123(II); In re Katz, 687 F.2d 450,
`
`454 (CCPA 1982).
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`2 The ’833 patent cannot claim priority to the ’653 provisional. Thus, the only proper
`priority claim for the ’833 patent is to the Danish application filed on November
`20, 2003. Under pre-AIA 35 U.S.C. § 102(b), the relevant date is the filing of a
`patent application “in this country,” which includes PCT applications, but not foreign
`priority documents. See 35 U.S.C. § 119(a) (pre-AIA); see also MPEP
`706.02. Here, “the actual filing of the application in this country” is no earlier than
`November 18, 2004, PCT/DK2004/000792’s filing date. Therefore, references that
`pre-date November 18, 2003, are § 102(b) prior art. MPEP 2123(II); In re Katz, 687
`F.2d 450, 454 (CCPA 1982).
`
`7
`Ex. 1001, 22:49-54; Ex. 1002, ¶30. The method of preparing the formulations recited
`
`in independent claim 16 relates to a formulation like that of claim 1 with the addition
`
`of a preservative. Ex. 1002, ¶32.
`
`Claims depending from claims 1 and 16 are directed to narrowing
`
`concentration ranges of propylene glycol (claims 2-4, and 17-19), narrowing pH
`
`ranges (claims 5-7 and 20-22), adding a preservative (claims 8-9), and specific GLP-
`
`1 agonists, analogues and derivatives (claims 10-15). Ex. 1002, ¶¶27, 31, 33.
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`Liraglutide formulations are specifically claimed in claim 14.
`
`Independent claims 23, 26, and 29 are directed to methods of replacing the
`
`isotonic agent of the formulation containing a disodium phosphate dihydrate buffer
`
`with propylene glycol. Claims 23 and 26 specify that the method is intended to
`
`reduce deposits on production equipment and in the final product, respectively,
`
`during production of the formulation. Ex. 1002, ¶¶34, 36. Claim 29 specifies that the
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`method is intended to reduce clogging of injection devices. Ex. 1002, ¶38. Claims 24,
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`27, and 30 depend from claims 23, 26, and 29, respectively, each of which is directed
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`to how the reduction of deposits or clogging is measured. Ex. 1002, ¶¶35, 37, 39.
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`Claims 25, 28, and 31 also depend from claims 23, 26, and 29, respectively, and
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`specify the isotonic agent that propylene glycol replaces. Id.
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`4.
`
`8
`4. PROSECUTION HISTORY OF THEProsecution History of
`the ’833 PATENTPatent
`
`After a restriction requirement (Ex. 1003, 117-26), the Examiner issued only
`
`two substantive Office actions. In each, the Examiner raised issues of priority,
`
`novelty, obviousness, and double patenting.
`
`As explained above, the Examiner first confirmed that, although apparently
`
`claiming priority to the ’653 provisional, the ’977 application is not entitled to that
`
`priority because (i) the ’977 application was filed more than twelve months after the
`
`’653 provisional was filed, and (ii) the PCT application to which the ’977 application
`
`claims priority does not claim priority to the ’653 provisional. Id., 130.3130.4
`
`With respect to novelty, the Examiner rejected most of the claims under
` § 102(e) over US20060287221 (“Knudsen”). Id., 131-33, 164-66. To
`
`overcome this rejection, the applicant amended the claims to require “a disodium
`
`phosphate dihydrate buffer.” Id., 188, 191-92.
`
`The Examiner also rejected the claims as obvious over Knudsen or
`
`
`4 The WIPO Patentscope bibliography data confirms that no priority claim was made
`
`to the ’653 provisional. Ex. 1076 (identifying “priority data” as “PA 2003 01719
`
`20.11.2003 DK”).
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`US20060084605 (“Engelund”). Id., 134-36. Those rejections were withdrawn in
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`view the applicant’s response that the claimed subject matter was owned by the same
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`entities as Knudsen and Engelund. Id., 167.
`
`3 The WIPO Patentscope bibliography data confirms that no priority claim was made
`to the ’653 provisional. Ex. 1076 (identifying “priority data” as “PA 2003 01719
`20.11.2003 DK”).
`
`9
`The Examiner issued a Notice of Allowance on December 16, 2009, stating the
`
`rejections over Knudsen were overcome by applicant’s claim amendments requiring
`
`the claimed formulation to include a disodium phosphate dihydrate buffer because (i)
`
`the claims are not anticipated because Knudsen “teaches phosphate buffer which is
`
`generic to the species disodium phosphate dihydrate buffer now claimed” and (ii)
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`Knudsen “is disqualified as prior art under 35 U.S.C. 103(c).” Id., 204.
`
`D. D. Claim Construction (37 C.F.R. §§ 42.100(b), 42.104(b)(3))
`
`Under 37 C.F.R. § 42.100(b), patent claims “shall be construed using the same
`
`claim construction standard that would be used to construe the claim in a civil action
`
`under 35 U.S.C. § 282(b), including construing the claim in accordance with the
`
`ordinary and customary meaning of such claim as understood by one of ordinary skill
`
`in the art and the prosecution history pertaining to the patent.” Petitioner submits, for
`
`the purposes of this Petition only, that no claim terms currently require construction,
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`and all terms have their plain meaning.45
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`Petitioner submits, however, that the preambles of claims 23, 26 and 29 should
`
`be construed as nonlimiting. Ex. 1002, ¶40. The preambles of claims 23, 26, and 29
`
`recite statements of purpose and intended result. Claim 23 recites “[a] method
`
`4 Petitioner may contend in district court that certain claim terms are indefinite.
`By filing this Petition, Petitioner does not relinquish its indefiniteness positions.
`10
` for reducing deposits on production equipment during production of a GLP-1
`
`agonist formulation….” Claim 26 recites “[a] method for reducing deposits in the
`
`final product during production of a GLP-1 agonist formulation….” Claim 29 recites
`
`“[a] method for reducing the clogging of injection devices by a GLP-1 agonist
`
`formulation….”
`
`These preambles state the inherent intended result of using a GLP-1 agonist
`
`formulation containing propylene glycol as an isotonic agent. None of the preambles
`
`result in a manipulative difference in the steps of the claim. Whether one wants to
`
`reduce deposits or reduce clogging, the method to achieve each purpose is identical.
`
`See Catalina Mktg. Int’l, Inc. v. Coolsavings.com, Inc., 289 F.3d 801, 809 (Fed. Cir.
`
`2002) (“[P]reambles describing the use of an invention generally do not limit the
`
`claims….” (citation omitted)); Braintree Labs., Inc. v. Novel Labs., Inc., 749 F.3d
`
`1349, 1357 (Fed. Cir. 2014) (finding preambles nonlimiting where claim defines a
`
`
`5 Petitioner reserves the right to contend that claim terms are indefinite in
`
`separate proceedings.
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`structurally complete invention); In re: Copaxone Consol. Cases, 906 F.3d 1013,
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`1023 (Fed. Cir. 2018), (preambles nonlimiting when they did not alter the single
`
`manipulative step recited in the claims). Thus, the preambles are nonlimiting. And
`
`each claim is unpatentable as explained below. However, even if the Board finds the
`
`preambles limiting, these claims are still unpatentable as explained below.
`
`11
`The POSA’s Knowledge of GLP-1 Agonists and Drug Formulation
`
`E.
`
`The ’833 patent relates to a formulation containing a GLP-1 agonist. By the
`
`priority date, GLP-1 agonists and their parenteral formulations were established in
`
`the art, having been disclosed and described in dozens of prior art references. The
`
`POSA looking to develop a GLP-1 agonist formulation would find no shortage of
`
`successful examples of these types of formulations in the art, including formulations
`
`identical to those claimed in the ’833 patent.
`
`The POSA would have confronted the task of developing a parenteral
`
`formulation containing a GLP-1 with a wealth of background knowledge informing
`
`the desirable properties of a successful parenteral formulation, coupled with a deep
`
`understanding of the characteristics of conventional excipients and their established
`
`roles in such formulations (e.g., buffering the solution or adjusting the tonicity of the
`
`formulation). By the priority date, the POSA would have been well versed in
`
`designing formulations like those claimed in the ’833 patent, as discussed herein and
`
`in the declaration of Laird Forrest, Ph.D. (Ex. 1002). See, e.g., Ex. 1002, ¶¶99-147.
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`1. GLP-1 AGONISTS WERE WELL KNOWN IN THE ARTAgonists
`Were Well Known in the Art
`
`By the priority date, GLP-1 agonists5 agonists6 were well known in the art.
`Ex. 1002,
` ¶¶41-42. The ’833 patent itself identifies numerous disclosures of prior art
`GLP-1
`5 Human GLP-1 is a 37-amino acid peptide hormone (“GLP-1(1-37)”)
`originating from preproglucagon. Processing of preproglucagon yields two shorter
`12
` agonists. Id., ¶42; see also Ex. 1001, 4:38-52 (citing WO93/19175,
`
`WO99/43705, WO 99/43706, WO99/43707, WO98/08871, WO02/46227,
`
`WO99/43708, WO99/43341, WO87/06941, WO90/11296, WO91/11457,
`
`WO98/43658, EP0708179, EP0699686, and WO01/98331) (Exs. 1031-1045,
`
`respectively); see also Ex. 1006, 268:15-16 (claiming liraglutide) and Ex. 1020,
`
`199:66-67 (claiming liraglutide).
`
`
`6 Human GLP-1 is a 37-amino acid peptide hormone (“GLP-1(1-37)”)
`
`originating from preproglucagon. Processing of preproglucagon yields two shorter
`
`forms of GLP-1: GLP-1(7-36)amide and GLP-1(7-37). Ex. 1006, 4:17-24. GLP-1(7-
`
`36) and GLP-1(7-37) have the following sequence:
`
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-
`
`Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-X
`
`where X is hydrogen for GLP-1(7-36) and Gly for GLP-1(7-37). Ex. 1006, 4:50-60.
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`FRESENIUS EXHIBIT 1077
`Page 14 of 72
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`2.
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`THE POSA’S KNOWLEDGE OF PARENTERAL DOSAGE
`FORMSThe POSA’s Knowledge of Parenteral Dosage Forms
`
`a.
`
`Parenteral dosage forms are preferred for peptide-based
`drugs
`
`Parenteral dosage forms are administered by injection (e.g., subcutaneous,
`
`intramuscular, intravenous, and intraarterial) and have certain advantages for treating
`
`patients. Ex. 1002, ¶¶43-45; Ex. 1013, 354-56. The POSA would have known that
`
`parenteral dosage forms need not pass through the digestive tract, unlike oral drugs
`
`that pass through the stomach and into the intestines before they are absorbed into the
`
`blood. Ex. 1002, ¶44; Ex. 1013, 157-60; Ex. 1012 at 29-39, 109- 12109-12, 247-50.
`
`POSAs also knew that parenteral dosage forms, especially subcutaneous
`
`forms of GLP-1: GLP-1(7-36)amide and GLP-1(7-37). Ex. 1006, 4:17-24. GLP-
`1(7-36) and GLP-1(7-37) have the following sequence:
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-
`Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-X
`where X is hydrogen for GLP-1(7-36) and Gly for GLP-1(7-37). Ex. 1006, 4:50-60.
`13
` and intramuscular, offer advantages for peptide-based drugs. Ex. 1002, ¶45.
`
`Peptide- basedPeptide-based drugs generally are indistinguishable from other
`
`peptides and proteins that the intestines encounter in the digestion of food; so, if they
`
`were administered orally, they may be broken down into component amino acids and
`
`absorbed with other nutrients, eliminating their therapeutic activity. Ex. 1002, ¶44-
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`45; Ex. 1013, 157, 177-78, 200-01; 296-303; Ex. 1012, 41-44, 109-14, 126. POSAs
`
`knew that parenteral formulations maximize the amount of peptide-based drug that
`
`reaches the blood. Ex. 1002, ¶45; Ex. 1053, 8; Ex. 1013, 158-59; 296-303; Ex. 1052,
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`FRESENIUS EXHIBIT 1077
`Page 15 of 72
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`1, 3; Ex. 1055, 1. Injections for subcutaneous administration (unlike for intravenous
`
`formulations) allow a patient to self-administer the drug, in addition to offering other
`
`therapeutic advantages. Ex. 1002, ¶46; Ex. 1013, 153-64, 379-87; Ex. 1050, 1, 3-4;
`
`Ex. 1051, 1-2; see also Ex. 1030 (U.S. Patent 5,514,097); Ex. 1024, 53-54.
`
`b.
`
`b. Stability of Peptide Formulationspeptide formulations
`
`Ensuring that protein and peptide formulations remain stable in aqueous
`
`solutions is an important, albeit conventional, aspect of formulation development.
`
`See, e.g., Ex. 1024, 4-5; Ex. 1002, ¶63. Environmental factors e.g., temperature or
`
`pH—may impact a protein or peptide’s conformational state and its stability. See id.,
`
`3-8; Ex. 1002, ¶63. Stability of peptide formulations can also be impacted by
`
`chemical and physical issues. Ex. 1024, 8 (Table III); Ex. 1002, ¶63. Chemical
`
`instabilities affecting certain amino acids of the peptide are dependent on pH and
`
`14
`exposure to oxygen, light, high temperature, metal ions, and free radicals. See, e.g.,
`
`id., 16-25; Ex. 1002, ¶63. Physical instabilities manifested by aggregation or
`
`precipitation can result from changes to the structure of the peptide caused by, for
`
`example, a change in pH or temperature, or exposure to certain chemicals. See, e.g.,
`
`id., 25-29; Ex. 1002, ¶63. To ensure that a protein or peptide drug remains safe and
`
`effective over its entire shelf life, POSAs consider how the drug is to be administered
`
`and design formulations to best stabilize the protein.
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`
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`FRESENIUS EXHIBIT 1077
`Page 16 of 72
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`c.
`
`c. Formulation Design for Peptide-Containing
`Parenteral Formulationsdesign for peptide-containing
`parenteral formulations
`
`A POSA would have known that despite the numerous advantages of parenteral
`
`dosage, they also require unique considerations in developing a successful
`
`formulation. Ex. 1002, ¶47; Ex. 1013, 354-60, 376-77; 390-91; Ex. 1012, 187-188,
`
` 283-85. For example, if a dosage form is intended for multiple uses, a POSA
`
`would appreciate that anti-microbial excipients may be necessary. Ex. 1002, ¶48; Ex.
`
`1013, 359; Ex. 1024, 36-40. And, for protein and peptide formulations, a POSA
`
`would have understood that stabilizers may be needed to ensure the drug’s safety and
`
`efficacy over time. Ex. 1002, ¶¶122, 127; Ex. 1024, 16-21, 29-42; Ex. 1026, 22-29.
`
`Consequently, POSAs knew that parenteral formulations must be designed so that the
`
`physical and chemical stability of the formulation is maintained throughout its useful
`
`life. Ex. 1002, ¶48; Ex. 1013, 157-59, 354-60, 362-64. POSAs would also consider
`
`other factors that may impact the design of a parenteral formulation,
`
`15
` including pH, buffering capacity, avoidance of particulates, biocompatibility
`
`of the vehicle, osmolarity, sterility, and choice of excipients. Ex. 1002, ¶49; Ex. 1013
`
`at 54-55, 355-56; 358-59, 376-77; Ex. 1012 at 283-85; Ex. 1024 at 29-42.
`
`i.(i) pH and Buffering Capacity
`A buffering system contains a weak acid and its conjugate base or a weak base
`
`and its conjugate acid. Ex. 1028, 3-4. A buffer is “[a] solution that resists change in
`
`pH when an acid or alkali is added or when the solution is diluted.” Id., 3; Ex. 1002,
`
`
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`FRESENIUS EXHIBIT 1077
`Page 17 of 72
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`¶50. Buffers thus establish and maintain the product pH. Ex. 1027, 20. POSAs would
`
`design parenteral formulations to have and to maintain a narrow pH range until the
`
`drug is administered. Ex. 1002, ¶¶51, 54-55; Ex. 1013, 54-55; Ex. 1012 at 146-51,
`
`180, 262, 279. The POSA would understand that parenterally administered products
`
`should have a pH between about 5 and 9 for intravenous, intramuscular, and
`
`subcutaneous routes, and ideally close to 7.4 to minimize pain and tissue irritation.
`
`Ex. 1002, ¶¶47, 51-55; Ex. 1024, 4, 16-17; Ex. 1060, 1-2, 4-5;
`
`4-
`
` Ex. 1012 at 283-285; Ex. 1047, 1, 3-4; Ex. 1056, 1-3; Ex. 1058 at 26; Ex. 1054,
`
`4-88. A pH of 7.4–—often referred to as physiological pH–ispH—is desirable
`
`because that is the approximate pH of blood and other tissues. Id.; Ex. 1048, 2; Ex.
`
`1013, 128; Ex. 1049, 1; Ex. 1057, 30; Ex. 1047, 1.
`
`16
`ii.(ii) Vehicles and Diluents
`A POSA developing a parenteral formulation would have known that vehicles
`
`and/or diluents are necessary for most parenteral delivery routes. Ex. 1002, ¶57. The
`
`vehicle in parenteral formulations provides a liquid carrier for the drug. The vehicle
`
`may be composed of solvents, such as water; organic solvents (like propylene glycol,
`
`glycerin, ethanol or sesame oil); or combinations of these. Ex. 1002, ¶57. Water-
`
`based vehicles are often preferred when possible due to the high solubility of many
`
`drugs in water and the safety of aqueous vehicles. Ex. 1002, ¶57; Ex. 1013, 234-38.
`
`However, POSAs knew that water alone is often insufficient, in which case an
`
`organic co-solvent may be used. Ex. 1002, ¶57. A POSA would appreciate that
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`FRESENIUS EXHIBIT 1077
`Page 18 of 72
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`several organic solvents have been used in FDA-approved drug formulations to
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`improve solubility, and common texts such as Remington’s provide guidance on the
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`use of organic solvents in parenteral formulations. Ex. 1002, ¶58; Ex. 1013, 234-51,
`
`354-60.
`
`iii.(iii) Tonicity and Osmolarity
`Tonicity of a formulation relates to its osmotic pressure (i.e., osmolarity and
`
`osmolality) as compared to that of a physiological fluid. Ex. 1013, 305; Ex. 1002,
`
` ¶60. A POSA would have appreciated that every ingredient that is not water
`
`contributes to the osmolarity (and thus tonicity) of a formulation. Ex. 1002, ¶59.
`
`Hypertonic or hypotonic formulations can cause pain and irritation at the site of
`
`17
` administration and complications like hemolysis and tissue damage. Ex. 1026,
`
`29; Ex. 1013, 308; Ex. 1027, 13; Ex. 1002, ¶¶47, 60. As such, a POSA would have
`
`appreciated that a formulation intended to be delivered parenterally should be
`
`“isotonic” with body fluids to minimize these risks. Ex. 1002, ¶¶60-62; Id.
`
`iv.(iv) Particulates
`The presence of particulates in formulations is generally undesirable because
`
`particulates may indicate the presence of foreign material that has compromised the
`
`sterility of the product or it may indicate that an excipient or drug has precipitated
`
`due to physical instabilities. Ex. 1002, ¶56. Unintended introduction of particulates
`
`into a parenteral formulation could lead to loss of drug activity, irritation at the
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`patient’s injection site, immunological sensitization to the medicant and/or the
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`FRESENIUS EXHIBIT 1077
`Page 19 of 72
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`excipients, or even endanger the patient if the particulate enters the blood. Ex. 1002
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`, ¶56; Ex. 1013, 376-77; Ex. 1067, 8. Proteins and peptides are particularly
`
`vulnerable to precipitating out of a formulation. Ex. 1002, ¶63.
`
`v.(v) Excipient Selection
`Designing formulations for protein and peptide drugs further involves careful
`
`consideration of excipients, including buffers and isotonicity agents. See, e.g., Ex.
`
`1024, 16-42; Ex. 1002, ¶¶34-65. Regulatory agencies like the FDA require the role
`
`and amount of each excipient to be justified, require the developer to ensure there are
`
`no incompatibilities between the excipients and the active drug, and require
`
`18
`ongoing quality control of each excipient during manufacturing. Ex. 1029, 15-36; Ex.
`
`1002, ¶66. POSAs thus knew that it was desirable to keep protein/peptide
`
`formulations “as simple as possible…and, if possible, to use excipients that have
`
`previously been used in [FDA]-approved formulations.” Ex. 1002, ¶67; Ex. 1024, 7;
`
`Ex. 1005, 4. Consequently, POSAs knew that it would be most preferable to
`
`minimize the number of excipients used. Ex. 1002, ¶67; Ex. 1005, 4, 7.
`
`d.
`
`Propylene Glycol Offers Several Advantages in a Peptide
`Formulationglycol is advantageous in a peptide
`formulation
`
`i.(i) Propylene Glycol is a Multi-functional Excipient
`Propylene glycol was well known to function as an isotonicity agent in liquid
`
`formulations. Ex. 1002, ¶69; Ex. 1025, 28:24-27; Ex. 1017, 31 (21:66-22:4); Ex.
`
` 1007, ¶[0014]; Ex. 1013, 312; Ex. 1063 (U.S. Patent No. 4,425,346); Ex. 1064
`
`(U.S.
`
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`FRESENIUS EXHIBIT 1077
`Page 20 of 72
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` Patent No. 6,207,684); Ex. 1065 (
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