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`BCDCEBFEGHIJKEKGKFLJKEMFLKBKGNJOPEGCEGKPEH
`QRSTRUVWXWYXQUSUZSU[\X]XY^XW\_X`a\_bRcdVZXeSb_SfXg_^_VbUVWTXgShXi_bbjkTXlUmYSUWYSd_TfX
`lWbhXUVbXgShXi_bbjkTXlUmYSUWYSd_TfXnVahXopgilqrfXsctYZ_VfXnVahXopsctYZ_VqrfXidYX
`udY[\USvUa_RWdaUcTXnVahXUVbXwx`X`ysXoaYcc_aWdt_cjfXpidYqrfX`RVXQ\USvUa_RWdaUcXnVbRTWSd_TXl72'
`UVbX`RVXQ\USvUa_RWdaUcXnVbRTWSd_TfXnVahXoaYcc_aWdt_cjfXp`RVqrfXUVbXzjbRTX{YScb|db_Xgx}}fX
`zjbRTXQ\USvUa_RWdaUcTXo~`srXnVahfXzjbRTXld^_Tad_Va_TXldvdW_bfXoaYcc_aWdt_cjfXpzjbRTqrfXUVbX
`xjcUVXQ\USvUa_RWdaUcTXnVahXopxQnqrXo_Ua\XdVbdtdbRUccjXUXpg_^_VbUVWXSYR[qXUVbXaYcc_aWdt_cjfX
`pg_^_VbUVWTqrX\_S_mjXTRmvdWXWYXQcUdVWd^^TX€YtYX€YSbdTXnVahXUVbX€YtYX€YSbdTXsy`XoaYcc_aWdt_cjfX
`p€YtYqrXdWTXdVtUcdbdWjXaYVW_VWdYVTX^YSXW\_XUTT_SW_bXacUdvTXY^X~VdW_bX`WUW_TXQUW_VWX€YThX‚fƒƒ„f‚……X
`
`Novo Nordisk Exhibit 2001
`Dr. Reddy's Laboratories v. Novo Nordisk A/S
`IPR2024-00009
`Page 00001
`
`

`

`
`
`claim limitation is anticipated by, and therefore not patentably distinct from, an earlier species
`
`claim.”).
`
`For at least these reasons, claims 1-3 are are invalid as anticipated under 35 U.S.C. § 102.
`
`See Akamai Techs., Inc. v. Cable & Wireless Internet Servs., Inc., 344 F.3d 1186, 1192 (Fed. Cir.
`
`2003).
`
`
`
`Obviousness of the ’462 Patent
`
`B.
`All of the claims of the ’462 patent are invalid as obvious under 35 U.S.C. § 103(a) because
`
`the differences between the claimed subject matter and the prior art would have been obvious to a
`
`person of ordinary skill in the art before the effective filing date of this patent.
`
`The prior art, taken as a whole, discloses, teaches, and/or suggests each and every element
`
`recited in the claims of the ’462 patent. In addition, there was motivation to modify the prior art
`
`to arrive at the claimed inventions of the ’462 patent, and to do so with a reasonable expectation
`
`of success.
`
`A method of treatment claim does not require a lead compound analysis. Novartis Pharms.
`
`Corp., 923 F.3d at 1060. Such claims are subject to the usual scrutiny under the Graham factors.
`
`Id. An examination of the Graham factors shows the obviousness of the ’462 patent’s claims, all
`
`of which are directed to a method of treating type 2 diabetes by a once-weekly administration of
`
`1.0 mg semaglutide.
`
`1.
`
`Claims 1-3 are obvious over WO ’421, NCT00696657, WO ’537
`and/or Lovshin 2009, optionally in view of one or more of WO ’530,
`the ’833 Patent, WO ’471, and Madsbad 2011, in view of the
`knowledge of a person of ordinary skill in the art
`
`Claim 1 reads:
`
`1.
`
`A method for treating type 2 diabetes, comprising administering semaglutide once
`weekly in an amount of 1.0 mg to a subject in need thereof.
`
`(’462 patent at col. 35 ll. 42-44.)
`
`
`
`187
`
`Novo Nordisk Exhibit 2001
`Dr. Reddy's Laboratories v. Novo Nordisk A/S
`IPR2024-00009
`Page 00002
`
`

`

`
`
`Claim 2 depends from claim 1 and adds the limitation “wherein the semaglutide is
`
`administered by parenteral administration;” claim 3 depends from claim 2 and adds the limitation
`
`“wherein the solution is administered by subcutaneous injection.” (Id. at col. 35 ll. 45-48.)
`
`As of the relevant priority date, it was well known that GLP-1 analogues such as
`
`semaglutide could be therapeutically useful for treating type 2 diabetes. WO ’421 discloses
`
`“[m]ethods 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.) NCT00696657 discloses a Phase 2 interventional
`
`trial entitled “Investigation of Safety and Efficacy of Five Doses of Semaglutide Versus Placebo
`
`and Open-label Liraglutide, as Add on Therapy, in Subjects Diagnosed With Type 2 Diabetes
`
`Currently Treated With Metformin or Controlled With Diet and Exercise.” (NCT00696657 at 2.)
`
`Under “Condition or disease,” NCT00696657 identifies both “Diabetes” and “Diabetes Mellitus,
`
`Type 2.” (Id.) Lovshin 2009 discloses that “[i]ncretin-based drugs, such as glucagon-like peptide-
`
`1 receptor agonists and dipeptidyl peptidase 4 inhibitors, are now routinely used to treat type 2
`
`diabetes mellitus.” (Lovshin 2009 at 262.)
`
`WO ’537 (or US ’478 or the ’343 patent) discloses “[a]n embodiment provides the use of
`
`a [GLP-1] compound according to any one of the embodiments . . . for the preparation of a
`
`medicament for the treatment or prevention of hyperglycemia, type 2 diabetes, impaired glucose
`
`tolerance, type 1 diabetes, obesity,” or “for delaying or preventing disease progression in type 2
`
`diabetes.” (WO ’537 at 22:24 – 23:3; US ’478 at [0129]-[0130]; ’343 patent at col. 40 ll. 36-48.)
`
`WO ’537 (or US ’478 or the ’343 patent) further discloses, “[i]n one embodiment a compound
`
`according to the invention is used for the preparation of a medicament for the treatment or
`
`
`
`188
`
`Novo Nordisk Exhibit 2001
`Dr. Reddy's Laboratories v. Novo Nordisk A/S
`IPR2024-00009
`Page 00003
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`

`

`
`
`prevention of hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity
`
`. . . .” (WO ’537 at 37:34-36; US ’478 at [0191]; ’343 patent at col. 53 ll. 4-7.)
`
`WO ’421 discloses 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,” each of which was disclosed to have “significant
`
`sequence identity to GLP-1.” (WO ’421 at 33:20-26 (emphasis added).) NCT00696657 further
`
`discloses that trial “participants were randomised evenly to treatment with semaglutide (0.1 mg
`
`QW – 1.6 mg QW[)], 6 treatment arms, placebo or liraglutide (1.2 mg QD, or 1.8 mg QD).”
`
`(NCT00696657 at 2; see also WO ’421 at 43:7-19 (disclosing overlapping dosage amounts for
`
`several GLP-1 receptor agonists, including liraglutide and semaglutide).) Lovshin 2009 discloses
`
`investigation of the treatment of type 2 diabetes with the agent NN9535 by subcutaneous injection.
`
` (Lovshin 2009 at 263 (Table 1).) NN9535 is and was known to be semaglutide. (See
`
`NCT00696657 (NN9535 is semaglutide).)
`
`WO ’537 (or US ’478 or the ’343 patent) is directed to therapeutic peptides, i.e., new
`
`protracted GLP-1 compounds. (WO ’537 at 1:5-6; US ’478 at [0001]; ’343 patent at col. 1 ll. 16-
`
`17.) Specifically, WO ’537 (or US ’478 or the ’343 patent) discloses the structure of semaglutide.
`
`Example 4
`N-c26-[2-(2-[2-(2-[2-(2-[4-(17-Carboxyheptadecanoylamino )-4(8)-
`carboxybutyrylamino ]ethoxy)ethoxy]acetylamino )ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-
`37)peptide.
`
`-,- H- ~~
`
`e G T F r s D v s s v L e G o A A- V
`
`e F I A w L v R G R G -=
`
`H,C CH~ Y OH
`
`O
`
`\
`
`HO
`
`--.,,, ,....,,,. ,_,,,
`
`~~
`
`~
`
`0
`
`0 ~
`
`o-Jlr(""o---./'0 " ' ! (NH
`0
`
`
`
`(WO ’537 at 47:4-8; US ’478 at [0265]; ’343 patent at col. 61 ll. 1-28.)
`
`
`
`189
`
`Novo Nordisk Exhibit 2001
`Dr. Reddy's Laboratories v. Novo Nordisk A/S
`IPR2024-00009
`Page 00004
`
`

`

`
`
`WO ’537 (or US ’478 or the ’343 patent) discloses once weekly administration of GLP-1
`
`peptides, including semaglutide. “One aspect of this invention is to prepare GLP-1
`
`analogues/derivatives with extended plasma half-lives that are suitable for once weekly
`
`administration.” (WO ’537 at 59:24-25; US ’478 at [0354]; ’343 patent at col. 94 ll. 45-47.)
`
`Pharmacokinetic Screening of Once Weekly GLP-1 Analogues
`
`Pharmacokinetic screening of GLP-1 analogues for identification of
`suitable once weekly candidates were performed on candidates that
`according to the project screenings plan were shown to be
`sufficiently potent with respect to glucose lowering potential in a
`diabetic mouse model (db/db mice) and subsequently had a time of
`duration of 48 hours or more in the db/db mouse model.
`
`(WO ’537 at 59:28-32; US ’478 at [0355]; ’343 patent at col. 94 ll. 50-58.)
`
`WO ’537 (or US ’478 or the ’343 patent) further discloses that “[p]arenteral administration
`
`may be performed by subcutaneous, intramuscular, intraperitoneal or intravenous injection by
`
`means of a syringe, optionally a pen-like syringe.” (WO ’537 at 34:15-16; US ’478 at [0175];
`
`’343 patent at col. 50 ll. 29-31; see also WO ’537 at 34:3-4 (“Even more preferably, are controlled
`
`release and sustained release systems administered subcutaneous.”); US ’478 at [0174] (same);
`
`’343 patent at col. 50 ll. 11-12 (same).)
`
`The ’833 patent also discloses:
`
`[I]n a preferred embodiment, the formulations of the invention are
`to be administered parenterally to a patient in need thereof.
`Parenteral administration may be performed by subcutaneous,
`intramuscular or intravenous injection by means of a syringe,
`optionally a pen-like syringe.
`
`(’833 patent at col. 13 ll. 45-50.)
`
`WO ’530 describes pharmaceutical compositions for the treatment of type 2 diabtetes
`
`comprising therapeutic peptides, such as semaglutide, that “may be administred orally,
`
`parenterally (e.g., via intravenous, subcutaneous, intracutaneous, intramuscular, intraarticular,
`
`
`
`190
`
`Novo Nordisk Exhibit 2001
`Dr. Reddy's Laboratories v. Novo Nordisk A/S
`IPR2024-00009
`Page 00005
`
`

`

`
`
`intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, intraocular, or intracranial
`
`injection).” (WO ’530 at 88-89, 143; see also id. at 144 (“In some cases, in order to prolong the
`
`effect of a drug, it is desirable to slow the absorption of the agent from subcutaneous or
`
`intramuscular injection.”).)
`
`WO ’471 discloses the use of a parenteral formulation of semaglutide for the treatment of
`
`type 2 diabetes. (See WO ’471 at 18:7-19, 24:30-31.)
`
`Madsbad 2011 discloses that the “once-weekly GLP-1 receptor analogues are promising
`
`candidates for the treatment of type 2 diabetes.” (Madsbad 2011 at 394.)
`
`Madsbad 2011 discloses dosing regimens for several GLP-1 receptor agonists, including
`
`semaglutide, which is administered by subcutaneous (sc) injection:
`
`GLP• 1 receptor agonists
`SC administered peptides
`
`I
`I Human GLP-1 backllonq
`
`I
`
`I Exendin-4 backbone I
`
`Wookly
`
`OnCG-<laily
`
`W-ly
`
`OD BID
`
`I Taspoglutide I .! Liraalutide
`
`I
`
`I Albialutide ~
`
`I LY2189265 I
`I CJC-1131 ~
`I Semaalutide I
`
`I Exenatide OW 7. Exenatide
`I
`I CJC.1134.pe '" .... Lix.isenatide I
`
`Figure 1. Shows the gtucagon-like peptide-I (GLP-1) receptor agonists,
`which have already been approved (exenatide BID and liraglutide). The
`agonists are subdivided in relation to whether the backbone of the
`compound is human GLP. 1 or exenatide. and in relation to the frequency
`of administration (once weekl}' o r once dail}' or twke daiJy). The once.
`weekl}' GLP.J receptor agonists illustrated with yellow are discussed in
`details in the present review.
`
`
`
`(Id. at 395.)
`
`
`
`191
`
`Novo Nordisk Exhibit 2001
`Dr. Reddy's Laboratories v. Novo Nordisk A/S
`IPR2024-00009
`Page 00006
`
`

`

`
`
`Madsbad 2011 discloses that “[i]ncretin-based therapies, such as the injectable glucagon-
`
`like peptide-1 (GLP-1) receptor agonists and orally administered dipeptidyl peptidase-4 (DPP-4)
`
`inhibitors, have recently been introduced into clinical practice. . . . Several once-weekly GLP-1
`
`receptor agonists are in phase 3 development.” (Id. at 394.)
`
`WO ’421 discloses that “[s]emaglutide is administered once weekly by subcutaneous
`
`injection (0.1-1.6 mg).” (WO ’421 at 43:13.) NCT00696657 discloses that trial “participants were
`
`randomised evenly to treatment with semaglutide (0.1 mg QW – 1.6 mg QW[)], 6 treatment arms,
`
`placebo or liraglutide (1.2 mg QD, or 1.8 mg QD).” (NCT00696657 at 2.) The NCT00696657
`
`trial included treatment with semaglutide at six different dosages, including 0.8 and 1.6 mg. (See
`
`Arms
`
`id. at 3.)
`
`Experimental: A
`
`Experimental: B
`
`Experimental: C
`
`Experimental: D
`
`Experimental: E
`
`Experimental: F
`
`Assigned Interventions
`
`Drug semaglutide
`0.1 mg, once weekly, ~ injection
`
`Drug: semaglutide
`0.2 mg, once weekly, ~ injection
`
`Drug: semaglutide
`0.4 mg, once weekly, ~ injection
`
`Drug: semaglutide
`0.8 mg, once weekly, ~ injection
`
`Drug: semaglutide
`0.8 mg with titration, once weekly, ~ injection
`
`Drug: semaglutide
`1.6 mg with titration, once weekly, ~ injection
`
`
`
`(Id. (disclosing administration of semaglutide once weekly by subcutaneous injection).) Lovshin
`
`2009 discloses treatment at a dosage of 0.1 to 1.6 mg semaglutide once per week. (Lovshin 2009
`
`at 263 (Table 1).) WO ’537 (or US ’478 or the ’343 patent) further discloses that formulations can
`
`be prepared a variety of different concentrations, such as from 0.1 mg/mL to 25 mg/mL. (’537 at
`
`24:11-13; US ’478 at [144]; ’343 patent at col. 41 ll. 60-63.)
`
`
`
`192
`
`Novo Nordisk Exhibit 2001
`Dr. Reddy's Laboratories v. Novo Nordisk A/S
`IPR2024-00009
`Page 00007
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`

`

`
`
`A POSA would have understood these to be disclosures of ranges of semaglutide doses
`
`including 1.0 mg once weekly. See Bristol-Myers Squibb, 246 F.3d at 1380; ClearValue, 668 F.3d
`
`at 1345. Alternatively, the dosage range disclosed by Lovshin 2009 renders the claimed 1.0 mg
`
`dosage obvious. By routine testing of this range of dosages, a POSA would have been motivated
`
`with a reasonable expectation of success to use a weekly dose of 1.0 mg semaglutide by
`
`subcutaneous injection to treat type 2 diabetes. See In re Peterson, 315 F.3d 1325, 1329-30 (Fed.
`
`Cir. 2003) (“A prima facie case of obviousness typically exists when the ranges of a claimed
`
`composition overlap the ranges disclosed in the prior art. . . . In fact, when, as here, the claimed
`
`ranges are completely encompassed by the prior art, the conclusion is even more compelling than
`
`in cases of mere overlap. The normal desire of scientists or artisans to improve upon what is
`
`already generally known provides the motivation to determine where in a disclosed set of
`
`percentage ranges is the optimum combination of percentages.”); E.I. DuPont de Nemours & Co.
`
`v. Synvina C.V., 904 F.3d 996, 1006 (Fed. Cir. 2018) (“For decades, [the Federal Circuit] and its
`
`predecessor have recognized that where the general conditions of a claim are disclosed in the prior
`
`art, it is not inventive to discover the optimum or workable ranges by routine experimentation.”)
`
`(internal quotation omitted); see also Valeant Pharms. Int’l, Inc. v. Mylan Pharms. Inc., 955 F.3d
`
`25, 31 (Fed. Cir. 2020) (“[T]his court [has] recognized that ‘[a] prima facie case of obviousness
`
`typically exists when the ranges of a claimed composition overlap the ranges disclosed in the prior
`
`art.’”) (quoting In re Peterson, 315 F.3d at 1329); see also In re Aller, 220 F.2d 454, 458 (C.C.P.A.
`
`1955) (“No invention is involved in discovering optimum ranges of a process by routine
`
`experimentation.”).
`
`The ability of a POSA to determine an optimal dosage from a range is reinforced by the
`
`’833 patent, which discloses:
`
`
`
`193
`
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`IPR2024-00009
`Page 00008
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`

`

`
`
`[I]t is understood that depending on the peptide or peptides included
`in the formulations of the invention, the formulations may be used
`in methods of treatment of diseases or conditions for which use of
`the peptide is indicated. . . . It is to be understood that “an effective
`amount” is the effective dose to be determined by a qualified
`practitioner, who may titrate dosages to achieve the desired
`response. Factors for consideration of dose will include potency,
`bioavailability,
`desired
`pharmacokinetic/pharmacodynamic
`profiles, the condition or disease to be treated (e.g. diabetes, obesity,
`weight loss, gastric ulcers), patient-related factors (e.g. weight,
`health, age, etc.) presence of co-adminsitered medications (e.g.
`insulin), time of administration, or other factors known to a medical
`practitioner.
`
`(’833 patent at col. 13 l. 60 – col. 14 l. 15 (emphasis added).)
`
`A POSA would have known how to formulate a semaglutide solution suitable for
`
`subcutaneous injection. For example, WO ’421 discloses:
`
`Injectable formulations of the GLP-1 receptor agonists of this
`invention 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.
`
`(Id. at 39:23-26.) Moreover, a POSA would have been aware of knowledge in the art regarding
`
`subcutaneous pharmaceutical formulations. (See, e.g., WO ’537 at 63:10-15 (disclosing an
`
`exemplary semaglutide formulation with a concentration of 6.25 mg/ml semaglutide); US ’478 at
`
`[0385] (same); ’343 patent at col. 98 ll. 1-8 (same); WO ’537 at 5:32-35 (disclosing pharmaceutical
`
`formulations comprising GLP-1 compounds, such as semaglutide, along with excipients); US ’478
`
`at [0031] (same); ’343 patent at col. 4 ll. 57-62 (same).)
`
`WO ’537 (or US ’478 or the ’343 patent) discloses that “[c]ompositions of the current
`
`invention are specifically useful in formulation of controlled, sustained, protracting, retarded and
`
`slow release drug delivery systems. More specifically, but not limited to, compositions are useful
`
`
`
`194
`
`Novo Nordisk Exhibit 2001
`Dr. Reddy's Laboratories v. Novo Nordisk A/S
`IPR2024-00009
`Page 00009
`
`

`

`
`
`in formulation of parenteral controlled release and sustained release systems.” (WO ’537 at 33:35
`
`– 34:2; US ’478 at [0174]; ’343 patent at col. 50 ll. 4-9.)
`
`A POSA would have been motivated to combine the teachings of WO ’421,
`
`NCT00696657, Lovshin 2009, WO ’537,13 WO ’530, the ’833 Patent, WO ’471, and Madsbad
`
`2011 because they are all directed to the use of GLP-1 agonists, including semaglutide, for the
`
`treatment of diabetes, including in parenteral formulations for subcutaneous injection.
`
`A POSA viewing the teachings of WO ’421, NCT00696657, and/or Lovshin 2009,
`
`optionally in view of one or more of WO ’537, WO ’530, the ’833 Patent, WO ’471, and Madsbad
`
`2011, in light of the POSA’s knowledge would have been motivated with a reasonable expectation
`
`of success to utilize parenteral administration of 1.0 mg semaglutide by subcutaneous injection
`
`once weekly for the treatment of type 2 diabetes.
`
`Claims 1-3 of the ’462 patent thus claim nothing more than the use of an old compound for
`
`a known purpose at a dose that falls within the prior art-disclosed range. That cannot make the
`
`claims nonobvious. See Galderma Lab’ys, L.P. v. Tolmar, Inc., 737 F.3d 731, 737 (Fed. Cir.
`
`2013); see also id. at 738 (“[W]here there is a range disclosed in the prior art, and the claimed
`
`invention falls within that range, the burden of production falls upon the patentee to come forward
`
`with evidence that (1) the prior art taught away from the claimed invention; (2) there were new
`
`and unexpected results relative to the prior art; or (3) there are other pertinent secondary
`
`considerations.”).
`
`For at least these reasons, claims 1-3 are invalid under 35 U.S.C. § 103 as obvious over
`
`WO ’421, NCT00696657, WO ’537 and/or Lovshin 2009, optionally in view of one or more of,
`
`
`13 “WO ’537” referes to WO ’537 or US ’478 or the ’343 patent, here and below.
`
`
`
`195
`
`Novo Nordisk Exhibit 2001
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`IPR2024-00009
`Page 00010
`
`

`

`
`
`WO ’530, the ’833 Patent, WO ’471, and Madsbad 2011, in view of the knowledge of a person of
`
`ordinary skill in the art.
`
`2.
`
`Claim 4 is obvious over WO ’421, NCT00696657, WO ’537 and/or
`Lovshin 2009 in combination with one or more of WO ’530, the ’833
`Patent, and WO ’471, optionally in view of Madsbad 2011, in view of
`the knowledge of a person of ordinary skill in the art
`
`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 col. 35 ll. 49-52.)
`
`The ’833 patent 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 10.0.” (’833 patent at col. 22
`
`ll. 48-54 (claim 1).) A POSA would have understood that a disodium phosphate dihydrate buffer
`
`is an example of a phosphate buffer.
`
`The ’833 patent further claims “[t]he formulation according to claim 1, wherein the pH of
`
`said formulation is about 7.0 to about 8.3.” (Id. at col. 22 ll. 66-67 (claim 6).) Examples 1-6 of
`
`the ’833 patent (each exemplary formulation) further disclose the use of a phosphate buffer at pH
`
`within the range of 7.0-9.0. (Id. at col. 15 l. 66 – col. 22 l. 21.)
`
`The ’833 publication further discloses:
`
`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, sodium dihydrogen
`phosphate, disodium hydrogen phosphate, sodium phosphate or
`mixtures thereof.
`
`
`
`196
`
`Novo Nordisk Exhibit 2001
`Dr. Reddy's Laboratories v. Novo Nordisk A/S
`IPR2024-00009
`Page 00011
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`(Id. at col. 10 ll. 47-57.)
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`The ’833 patent also discloses that “[t]he inclusion of isotonicity agents in peptide-
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`containing pharmaceutical formulations is widely known.” (Id. at col. 1 ll. 30-31.) The POSA
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`would have known that semaglutide is a peptide.
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`Example 3 of the ’833 patent teaches that “[i]t is believed that similar results [i.e.,‘no
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`clogging of the needles’] to those obtained with the above-described propylene glycol-containing
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`formulation would also be obtained if the pH was adjusted to 7.40, 7.70 or 7.90” and discloses a
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`pH of “7.40, 7.70, 7.90, or 8.15.” (Id. at col. 20 ll. 6-19.) In Example 4, the ’833 patent discloses
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`a liraglutide composition with a pH of 7.40 containing sodium dihydrogen phosphate. (Id. at col.
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`20 ll. 29-35.) Example 5 of the ’833 patent also discloses a composition with a pH of 7.4. (Id. at
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`col. 20 l. 67.)
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`WO ’537 (or US ’478 or the ’343 patent) discloses pharmaceutical formulations
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`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; US ’478 at [0031]; ’343 patent at col. 4 ll. 57-62.)
`
`to provide a
`is
`invention
`the present
`Another object of
`pharmaceutical formulation comprising a compound according to
`the present invention which is present 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. The formulation may further comprise a buffer system,
`preservative(s), tonicity agent(s), chelating agent(s), stabilizers and
`surfactants. In one embodiment of the invention the pharmaceutical
`formulation is an aqueous formulation, i.e. formulation comprising
`water.
`
`(WO ’537 at 24:11-16; US ’478 at [0144]; ’343 patent at col. 41 l. 60 – col. 42 l. 38.)
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`
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`IPR2024-00009
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`Exemplary pH ranges are provided in WO ’537, US ’478, and the ’343 patent:
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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.
`
`(WO ’537 at 24:30 – 25:2; US ’478 at [0148]; ’343 patent at col. 42 l. 59 – col. 43 l. 4.)
`
`WO ’537 (or US ’478 or the ’343 patent) also discloses:
`
`In a further embodiment of the invention the buffer is selected from
`the group consisting of sodium acetate, 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; US ’478 at [0149]; ’343 patent at col. 43 ll. 5-11.) Further, WO ’537 (or US
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`’478 or the ’343 patent) provides a specific example of a pharmaceutical formulation comprising
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`semaglutide, propylene glycol, phenol, and a phosphate buffer, where the pH is 8.15.
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`Pharmaceutical formulation:
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`A compound of the invention may be formulated as:
`
`Compound of example 4
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`6,25 mg/ml
`
`Propyleneglycol
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`14,0 mg/ml
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`Phenol
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`5.5 mg/ml
`
`Phosphate Buffer pH 8.15
`
`
`
`(WO ’537 at 63:10-15; US ’478 at [0385]; ’343 patent at col. 98 ll. 1-8.)
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`IPR2024-00009
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`WO ’530 discloses the use of phosphate buffers and isotonicity agents, and expresses the
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`goal of creating a pharmaceutical composition for parenteral administration that is “isotonic with
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`the blood of the intended recipient.” (WO ’530 at 53-54, 141, 143-44.)
`
`WO ’471 discloses the use of the claimed propylene glycol, phenol, disodium hydrogen
`
`phosphate buffer, and pH 7.4 for a parenteral formulation of semaglutide for the treatment of type
`
`2 diabetes. (WO ’471 at 18:7-19, 24:30-31.)
`
`The ’833 patent also discloses:
`
`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 col. 12 l. 64 – col. 13 l. 3.)
`
`As described above with respect to claims 1-3, as of the earliest priority date to which the
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`claims of the ’462 patent may be entitled, a POSA would have been motivated with a reasonable
`
`expectation of success to treat type 2 diabetes by administering semaglutide by subcutaneous
`
`injection, a form of parenteral administration, once weekly in an amount of 1.0 mg to a subject in
`
`need thereof. 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
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`phosphate buffer at a pH in the range of 7.0-9.0. The prior art discloses semaglutide formulation
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`pH ranges that substantially overlap with the claimed pH values recited in the dependent claims of
`
`the ’462 patent. Valeant Pharms. Int’l, Inc., 955 F.3d at 31 (“[T]his court [has] recognized that
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`‘[a] prima facie case of obviousness typically exists when the ranges of a claimed composition
`
`overlap the ranges disclosed in the prior art.’”) (quoting In re Peterson, 315 F.3d at 1329). A
`
`POSA would have had a reasonable expectation of success in making such a formulation using
`
`
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`IPR2024-00009
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`conventional techniques of the pharmaceutical industry as taught in the ’833 patent. (See ’833
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`patent at col. 12 l. 64 – col. 13 l. 3.)
`
`For at least these reasons, and the reasons discussed above with respect to claims 1-3, claim
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`4 is invalid under 35 U.S.C. § 103 as obvious over WO ’421, NCT00696657, WO ’537 and/or
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`Lovshin 2009 in combination with one or more of WO ’537, WO ’530, the ’833 Patent, and WO
`
`’471, optionally in view of Madsbad 2011, in view of the knowledge of a person of ordinary skill
`
`in the art.
`
`3.
`
`Claim 5 is obvious over WO ’421, NCT00696657, WO ’537 and/or
`Lovshin 2009 in combination with one or more of WO ’530, the ’833
`Patent, and WO ’471, optionally in view of Madsbad 2011, in view of
`the knowledge of a person of ordinary skill in the art
`
`Claim 5 depends from claim 4 and adds the limitation “wherein the solution further
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`comprises propylene glycol and phenol.” (’462 patent at col. 35 ll. 53-54.)
`
`The ’833 patent claims “[a] pharmaceutical formulation comprising at least one GLP-1
`
`agonist, a disodium phosphate dihydrate buffer and propylene glycol, wherein said propylene
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`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 col. 22
`
`ll. 48-54 (claim 1).)
`
`The ’833 patent further discloses the use of propylene glycol as an isotonicity agent in
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`aqueous solutions containing GLP-1 agonists. (See id. at col. 24 ll. 7-14 (claim 23); see also id. at
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`col. 19 l. 44 (disclosing the use of propylene glycol as an isotonicity agent).) Semaglutide is a
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`GLP-1 agonist.
`
`The ’833 patent discloses that “[t]he use of a preservative in pharmaceutical compositions
`
`is well-known to the skilled person. (Id. at col. 11 ll. 6-7.)
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`
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`200
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`IPR2024-00009
`Page 00015
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`The ’833 patent further discloses the use of “phenol (5.0 or 5.5 mg/ml)” as a preservative.
`
`(Id. at col. 20 l. 13.) The ’833 patent also discloses that “[i]n a preferred embodiment of the
`
`invention the preservative is phenol or m-cresol.” (Id. at col. 10 ll. 65-67.)
`
`The ’833 patent discloses:
`
`[T]he present inventors have observed that mannitol causes
`problems during the production of peptide formulations as it
`crystallizes resulting in deposits in the production equipment and in
`the final product. . . . [T]he present inventors have observed that in
`peptide formulations to be administered by injection, the presence
`of mannitol results in clogging of injection devices.
`
`(Id. at col. 1 ll. 33-45.)
`
`The ’833 patent further discloses “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 col. 1 ll. 53-57; see also id. at col.
`
`13 ll. 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 discloses 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 col. 2 ll. 58-62.)
`
`WO ’537 (or US ’478 or the ’343 patent) discloses “[i]n a further embodiment of the
`
`invention the formulation further comprises a pharmaceutically acceptable preservative. In a
`
`further embodiment of the invention the preservative is selected from the group consisting of
`
`phenol . . . .” (WO ’537 at 25:11-13; US ’478 at [0150]; ’343 patent at col. 43 ll. 14-17.) WO
`
`’537 (or US ’478 or the ’343 patent) further discloses that