10 November 2011 (10.11.2011) (10) International Publication Number
`
`1111111111111111 IIIIII IIIII IIIII IIIII IIII I II Ill lllll lllll lllll lllll lllll 11111111111111111111111
`
`(51) International Patent Classification:
`International Patent Classification:
`(51)
`A61K 31/00 (2006.01)
`A61P 3/04 (2006.01)
`A61K 31/00 (2006.01)
`A61P 3/04 (2006.01)
`AG61K 31/522 (2006.01)
`A61P 3/10 (2006.01)
`A61K 31/522 (2006.01)
`A61P 3/10 (2006.01)
`AG1K 38/00 (2006.01)
`A61K 38/00 (2006.01)
`(21) International Application Number:
`(21) International Application Number:
`PCT/EP201 1/057256
`PCT/EP20l l/057256
`.
`eqs
`(22) International Filing Date:
`(22) International Filing Date:
`
`5 May 2011 (05.05.2011)
`5 May 201 l (05.05.2011)
`English
`English
`English
`English
`
`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`(19) World Intellectual Property Organization
`(19) World Intellectual Property Organization
`International Bureau
`International Bureau
`(10) International Publication Number
`(43) International Publication Date
`(43) International Publication Date
`WO 2011/138421 Al
`WO 2011/138421 Al
`10 November 2011 (10.11.2011)
`PCT
`
`(74) Agents: HAMMANN,et al, Heinz et al.; Boehringer In-
`(74) Agents: HAMMANN, et al, Heinz et al.; Boehringer In(cid:173)
`gelheim GmbH, Corporate Patents, Binger Str. 173,
`gelheim GmbH, Corporate Patents, Binger Str. 173,
`55216 Ingelheim Am Rhein (DE).
`55216 Ingelheim Am Rhein (DE).
`(81) Designated States (unless otherwise indicated, for every
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`kind of national protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
`AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
`CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO,
`CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO,
`DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM,GT,
`DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,
`HN, HR, HU,ID,IL,IN,IS, JP, KE, KG, KM, KN,KP,
`HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP,
`KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD,
`(25) Filing Language:
`KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD,
`(25) Filing Language:
`ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI
`ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI,
`NO, NZ, OM,PE, PG, PH, PL, PT, RO, RS, RU,SC, SD,
`(26) Publication Language:
`(26) Publication Language:
`NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD,
`SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR,
`(30) Priority Data:
`SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR,
`(30) Priority Data:
`TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
`EP
`5 May 2010 (05.05.2010)
`10162036.7
`TT, TZ, VA, VG, US, UZ, VC, VN, ZA, ZM, ZW.
`5 May 2010 (05.05.2010)
`10162036.7
`EP
`EP (84) Designated States (unless otherwise indicated, for every
`21 February 2011 (21.02.2011)
`11155154.5
`21 Febmary20ll (21.02.2011)
`l l 155154.5
`(84) Designated States (unless otherwise indicated, for every
`EP
`(for
`all designated States
`except US):
`kind of regional protection available): ARIPO (BW, GH,
`(71) Applicant
`kind of regional protection available): ARIPO (BW, GH,
`(71) Applicant
`(for all designated States except US):
`GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG,
`BOEHRINGER INGELHEIM INTERNATIONAL
`GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG,
`BOEHRINGER INGELHEIM
`INTERNATIONAL
`2M,ZW), Eurasian (AM, AZ, BY, KG, KZ, MD,RU,TJ,
`GMBH[DE/DE]; BingerStr. 173, 55216 Ingelheim Am
`ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ,
`GMBH [DE/DE]; Binger Str. 173, 55216 Ingelheim Am
`TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK,
`Rhein (DE).
`TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK,
`Rhein(DE).
`EE, ES, FI, FR, GB, GR, HR, HU,IE,IS, IT, LT, LU,
`EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU,
`LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SL, SK,
`Inventors; and
`Inventors; and
`LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK,
`SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
`Inventors/Applicants (for US only): KLEIN, Thomas
`Inventors/Applicants (for US only): KLEIN, Thomas
`SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
`[DE/DE]; Boehringer
`Ingelheim GmbH, Corporate
`GW,ML, MR, NE,SN, TD,TG).
`[DE/DE]; Boehringer
`Ingelheim GmbH, Corporate
`GW, ML, MR, NE, SN, TD, TG).
`Patents, Binger Str. 173, 55216 Ingelheim Am Rhein
`Declarations under Rule 4.17:
`Patents, Binger Str. 173, 55216 Ingelheim Am Rhein
`(DE). GREMPLER, Rolf [DE/DE]; Boehringer Ingel-
`Declarations under Rule 4.17:
`(DE). GREMPLER, Rolf [DE/DE]; Boehringer Ingel(cid:173)
`heim GmbH, Corporate Patents, Binger Str. 173, 55216
`as to applicant's entitlement to apply for and be granted
`heim GmbH, Corporate Patents, Binger Str. 173, 55216
`as to applicant's entitlement to apply for and be granted
`Ingelheim Am Rhein (DE). MARK, Michael [DE/DE];
`a patent (Rule 4.17(ii))
`Ingelheim Am Rhein (DE). MARK, Michael [DE/DE];
`a patent (Rule 4.17 (ii))
`Boehringer Ingelheim GmbH, Corporate Patents, Binger
`Published:
`Boehringer Ingelheim GmbH, Corporate Patents, Binger
`Str. 173, 55216 Ingelheim Am Rhein (DE).
`Published:
`Str. 173, 55216 Ingelheim Am Rhein (DE).
`with international search report (Art. 21(3))
`with international search report (Art. 21 (3))
`
`(72)
`(72)
`(75)
`(75)
`
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`M "" Q0
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`
`wo2011/138421At|IMDTIMNITINNININTTINNYAEAN (54) Title: COMBINATION THERAPY
`
`,-.-1
`
`~
`,-.-1
`.........
`,-.-1
`,-.-1
`0
`M
`(54) Title: COMBINATION THERAPY
`0
`(57) Abstract: The present invention relates to methods for treating and/or preventing metabolic diseases comprising the com-
`(57) Abstract: The present invention relates to methods for treating and/or preventing metabolic diseases comprising the com(cid:173)
`bined administration of a GLP-1 receptor agonist and a DPP-4 inhibitor.
`~
`bined administration of a GLP- l receptor agonist and a DPP-4 inhibitor.
`
`MPI EXHIBIT 1011 PAGE 1
`
`MPI EXHIBIT 1011 PAGE 1
`
`MPI EXHIBIT 1011 PAGE 1
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1011, p. 1 of 72
`
`

`

`WO 2011/138421
`
`PCT /EP2011/057256
`
`Combination therapy
`
`The present invention relates to methods for treating and/or preventing metabolic diseases,
`
`5
`
`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, to pharmaceutical
`
`compositions and combinations comprising such active components, and to certain
`
`therapeutic uses thereof.
`
`10
`
`Further, the present invention relates to a method for reducing and maintaining body weight
`
`and/or body fat in a patient in need thereof, such as e.g. in an overweight or obesity patient
`
`with or without diabetes (particularly type 2 diabetes patient being obese or overweight),
`
`comprising the combined (e.g. separate, simultaneous or sequential) administration of a
`
`GLP-1 receptor agonist (e.g. GLP-1 or GLP-1 analogue) and a certain DPP-4 inhibitor;
`
`15
`
`preferably said method comprising the sequential administration of a GLP-1 receptor agonist
`
`followed by a certain DPP-4 inhibitor.
`
`Furthermore, the present invention relates to a method for reducing and maintaining body
`
`weight and/or body fat in a patient in need thereof, such as e.g. in an overweight or obesity
`
`patient with or without diabetes (particularly type 2 diabetes patient being obese or
`
`20
`
`overweight), comprising i) inducing body weight loss (e.g. by administering an effective
`
`amount of a GLP-1 receptor agonist to the patient) and ii.) administering an effective amount
`
`of a certain DPP-4 inhibitor to the patient.
`
`Moreover, the present invention relates to a certain DPP-4 inhibitor for use in preventing of
`
`body weight and/or body fat gain or controlling, stabilizing or maintaining a reduced body
`
`25 weight and/or body fat followed discontinuation of weight reducing treatment (such as e.g.
`
`diet, exercise and/or treatment with an anti-obesity or body weight reducing agent),
`
`particularly after discontinuation of treatment with a GLP-1 receptor agonist.
`
`Further, the present invention relates to a certain DPP-4 inhibitor for use in delaying body
`
`weight and/or body fat gain and/or maintaining reduction in body weight and/or body fat in a
`
`30
`
`subject (particularly an obesity patient with or without diabetes), particularly subsequent to
`
`cessation of or withdrawn from body weight reducing and/or fat reducing treatment.
`
`Further, the present invention relates to a certain DPP-4 inhibitor for use in a method of
`
`delaying body weight and/or body fat gain and/or maintaining body weight and/or body fat
`
`loss induced by treatment with a GLP-1 receptor agonist in a subject, said method
`
`35
`
`comprising cessation of GLP-1 receptor agonist treatment and transferring the subject from
`
`GLP-1 receptor agonist to DPP-4 inhibitor treatment.
`
`MPI EXHIBIT 1011 PAGE 2
`
`MPI EXHIBIT 1011 PAGE 2
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1011, p. 2 of 72
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`

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`WO 2011/138421
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`PCT /EP2011/057256
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`- 2 -
`
`Furthermore, the present invention relates to a DPP-4 inhibitor for use in reducing,
`
`maintaining loss of or delaying increase of body weight and/or body fat in a subject actively
`
`putting on weight.
`
`Yet furthermore, the present invention relates to a DPP-4 inhibitor for use in reducing,
`
`5 maintaining loss of or delaying increase of body weight and/or body fat in a subject being in
`
`condition of actively putting on weight and/or increasing body weight through the deposition
`
`of fat, such as e.g. after withdrawing a weight loss treatment or under a treatment associated
`
`with weight gain (e.g. through the action of sulphonylureas, glinides, insulin and/or
`
`thiazolidinediones, the use of which is associated with weight gain).
`
`10
`
`Further, the present invention relates to a certain DPP-4 inhibitor for use in reducing intra(cid:173)
`
`myocellular fat and/or hepatic fat in a patient in need thereof, such as e.g. in an overweight
`
`or obesity patient with or without diabetes (particularly type 2 diabetes patient being obese or
`
`overweight).
`
`Further, the present invention relates to a DPP-4 inhibitor for use in achieving a reduction in
`
`15
`
`the dose of GLP-1 receptor agonist medication, e.g. required for effective therapy of
`
`metabolic diseases (such as e.g. type 2 diabetes mellitus, obesity and/or conditions related
`
`thereto (e.g. diabetic complications)), e.g. in an overweight or obesity patient with or without
`
`diabetes (particularly type 2 diabetes patient being obese or overweight).
`
`Moreover, the present invention relates to a certain DPP-4 inhibitor for use in treating,
`
`20
`
`preventing or reducing the risk of skin necrosis, particularly associated with or induced by
`
`infusions or injections, e.g. of a GLP-1 receptor agonist, insulin or insulin analogue or other
`
`drugs administered subcutaneously and/or via needle or syringe, typically pierced through
`
`the skin.
`
`Further, the present invention relates to the DPP-4 inhibitors and/or GLP-1 receptor agonists,
`
`25
`
`each as defined herein, for use in the combination therapies as described herein.
`
`Type 2 diabetes mellitus is a common chronic and progressive disease arising from a
`
`complex pathophysiology involving the dual endocrine effects of insulin resistance and
`
`impaired insulin secretion with the consequence not meeting the required demands to
`
`30 maintain plasma glucose levels in the normal range. This leads to chronic hyperglycaemia
`
`and its associated micro- and macrovascular complications or chronic damages, such as e.g.
`
`diabetic nephropathy, retinopathy or neuropathy, or macrovascular (e.g. cardio- or cerebro(cid:173)
`
`vascular) complications. The vascular disease component plays a significant role, but is not
`
`the only factor in the spectrum of diabetes associated disorders. The high frequency of
`
`35
`
`complications leads to a significant reduction of life expectancy. Diabetes is currently the
`
`MPI EXHIBIT 1011 PAGE 3
`
`MPI EXHIBIT 1011 PAGE 3
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1011, p. 3 of 72
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`WO 2011/138421
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`PCT /EP2011/057256
`
`- 3 -
`
`most frequent cause of adult-onset loss of vision, renal failure, and amputation in the
`
`Industrialised World because of diabetes induced complications and is associated with a two
`
`to five fold increase in cardiovascular disease risk.
`
`5
`
`Furthermore, diabetes (particularly type 2 diabetes) is often coexistent and interrelated with
`
`obesity and these two conditions together impose a particularly complex therapeutic
`
`challenge. Because of the effects of obesity on insulin resistance, weight loss and its
`
`maintainance is an important therapeutic objective in overweight or obese individuals with
`
`prediabetes, metabolic syndrome or diabetes. Studies have been demonstrated that weight
`
`10
`
`reduction in subjects with type 2 diabetes is associated with descreased insulin resistance,
`
`improved measures of glycemia and lipemia, and reduced blood pressure. Maintainance of
`
`weight reduction over longer term is considered to improve glycemic control and prevent
`
`diabetic complications (e.g. reduction of risk for cardiovascular diseases or events). Thus,
`
`weight loss is recommended for all overweight or obese indivuduals who have or are at risk
`
`15
`
`for diabetes. However, obese patients with type 2 diabetes have much greater difficulty
`
`losing weight and maintain the reduced weight than the general non-diabetic population.
`
`Overweight may be defined as the condition wherein the individual has a body mass index
`
`(BMI) greater than or 25 kg/m 2 and less than 30 kg/m 2
`
`. The terms "overweight" and "pre-
`
`20
`
`obese" are used interchangeably.
`
`Obesity may be defined as the condition wherein the individual has a BMI equal to or greater
`
`than 30 kg/m 2
`
`. According to a WHO definition the term obesity may be categorized as
`
`follows: class I obesity is the condition wherein the BMI is equal to or greater than 30 kg/m 2
`
`25
`
`but lower than 35 kg/m 2
`
`; class II obesity is the condition wherein the BMI is equal to or
`
`greater than 35 kg/m 2 but lower than 40 kg/m 2
`
`; class Ill obesity is the condition wherein the
`
`BMI is equal to or greater than 40 kg/m 2
`
`. Obesity may include e.g. visceral or abdominal
`
`obesity.
`
`30
`
`Visceral obesity may be defined as the condition wherein a waist-to-hip ratio of greater than
`
`or equal to 1.0 in men and 0.8 in women is measured. It defines the risk for insulin resistance
`
`and the development of pre-diabetes.
`
`Abdominal obesity may usually be defined as the condition wherein the waist circumference
`
`35
`
`is > 40 inches or 102 cm in men, and is > 35 inches or 94 cm in women. With regard to a
`
`MPI EXHIBIT 1011 PAGE 4
`
`MPI EXHIBIT 1011 PAGE 4
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1011, p. 4 of 72
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`WO 2011/138421
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`PCT /EP2011/057256
`
`- 4 -
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`Japanese ethnicity or Japanese patients abdominal obesity may be defined as waist
`
`circumference~ 85 cm in men and~ 90 cm in women (see e.g. investigating committee for
`
`the diagnosis of metabolic syndrome in Japan).
`
`5
`
`Diabetes patients within the meaning of this invention may include patients having obesity or
`
`overweight.
`
`Obesity patients within the meaning of this invention may include, in one embodiment,
`
`patients with diabetes (particularly having type 2 diabetes).
`
`10
`
`Obesity patients within the meaning of this invention may include, in another embodiment,
`
`patients without diabetes (particularly without type 1 or type 2 diabetes).
`
`The treatment of type 2 diabetes typically begins with diet and exercise, followed by oral
`
`15
`
`antidiabetic monotherapy, and although conventional monotherapy may initially control blood
`
`glucose in some patients, it is however associated with a high secondary failure rate. The
`
`limitations of single-agent therapy for maintaining glycemic control may be overcome, at least
`
`in some patients, and for a limited period of time by combining multiple drugs to achieve
`
`reductions in blood glucose that cannot be sustained during long-term therapy with single
`
`20
`
`agents. Available data support the conclusion that in most patients with type 2 diabetes
`
`current monotherapy will fail and treatment with multiple drugs will be required.
`
`But, because type 2 diabetes is a progressive disease, even patients with good initial
`
`responses to conventional combination therapy will eventually require an increase of the
`
`dosage or further treatment with insulin because the blood glucose level is very difficult to
`
`25 maintain stable for a long period of time. Although existing combination therapy has the
`
`potential to enhance glycemic control, it is not without limitations (especially with regard to
`
`long term efficacy). Further, traditional therapies may show an increased risk for side effects,
`
`such as hypoglycemia or weight gain, which may compromise their efficacy and
`
`acceptability.
`
`30
`
`Thus, for many patients, these existing drug therapies result in progressive deterioriation in
`
`metabolic control despite treatment and do not sufficiently control metabolic status especially
`
`over long-term and thus fail to achieve and to maintain glycemic control in advanced or late
`
`stage type 2 diabetes, including diabetes with inadequate glycemic control despite
`
`conventional oral or non-oral antidiabetic medication.
`
`35
`
`MPI EXHIBIT 1011 PAGE 5
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`MPI EXHIBIT 1011 PAGE 5
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`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1011, p. 5 of 72
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`WO 2011/138421
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`PCT /EP2011/057256
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`- 5 -
`
`Therefore, although intensive treatment of hyperglycemia can reduce the incidence of
`
`chronic damages, many patients with type 2 diabetes remain inadequately treated, partly
`
`because of limitations in long term efficacy, tolerability and dosing inconvenience of
`
`conventional antihyperglycemic therapies.
`
`5
`
`In addition, obesity, overweight or weight gain (e.g. as side or adverse effect of some
`
`conventional antidiabetic medications) further complicates the treatment of diabetes and its
`
`micorvascular or macrovascular complications.
`
`10
`
`This high incidence of therapeutic failure is a major contributor to the high rate of long-term
`
`hyperglycemia-associated complications or chronic damages (including micro- and
`
`makrovascular complications such as e.g. diabetic nephrophathy, retinopathy or neuropathy,
`
`or cardiovascular complications) in patients with type 2 diabetes.
`
`15 Oral antidiabetic drugs conventionally used in therapy (such as e.g. first- or second-line,
`
`and/or mono- or (initial or add-on) combination therapy) include, without being restricted
`
`thereto, metformin, sulphonylureas, thiazolidinediones, glinides and a-glucosidase inhibitors.
`
`Non-oral (typically injected) antidiabetic drugs conventionally used in therapy (such as e.g.
`
`20
`
`first- or second-line, and/or mono- or (initial or add-on) combination therapy) include, without
`
`being restricted thereto, GLP-1 or GLP-1 analogues, and insulin or insulin analogues.
`
`However, the use of these conventional antidiabetic or antihyperglycemic agents can be
`
`associated with various adverse effects. For example, metformin can be associated with
`
`25
`
`lactic acidosis or gastrointestinal side effects; sulfonylureas, glinides and insulin or insulin
`
`analogues can be associated with hypoglycemia and weight gain; thiazolidinediones can be
`
`associated with edema, bone fracture, weight gain and heart failure/cardiac effects; and
`
`alpha-glucosidase blockers and GLP-1 or GLP-1 analogues can be associated with
`
`gastrointestinal adverse effects (e.g. dyspepsia, flatulence or diarrhea, or nausea or
`
`30
`
`vomiting) and, most seriously (but rare), pancreatitis.
`
`Therefore, it remains a need in the art to provide efficacious, safe and tolerable antidiabetic
`
`therapies, particularly for obese or overweight diabetes patients.
`
`MPI EXHIBIT 1011 PAGE 6
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`MPI EXHIBIT 1011 PAGE 6
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`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1011, p. 6 of 72
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`WO 2011/138421
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`PCT /EP2011/057256
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`- 6 -
`
`Further, it remains a need in the art to provide efficacious, safe and tolerable therapies for
`
`obesity patients with or without diabetes, particularly for reducing body weight and
`
`maintaining reduced body weight as well as for preventing rebound of weight gain following
`
`cessation of weight loss treatment in such patients.
`
`Within the management of the dual epidemic of type 2 diabetes and obesity ("diabesity"), it is
`
`an objective to find therapies which are safe, tolerable and effective in the treatment or
`
`prevention of these conditions together, particularly in achieving long term weight reduction
`
`and improving glycemic control.
`
`Further, within the therapy of type 2 diabetes, obesity or both, it is a need for treating the
`
`condition effectively, avoiding the complications inherent to the condition, and delaying
`
`disease progression.
`
`5
`
`10
`
`15
`
`Furthermore, it remains a need that antidiabetic treatments not only prevent the long-term
`
`complications often found in advanced stages of diabetes disease, but also are a therapeutic
`
`option in those diabetes patients who have developed complications, such as renal
`
`impairment.
`
`20 Moreover, it remains a need to provide prevention or reduction of risk for adverse effects
`
`associated with conventional antidiabetic therapies.
`
`The enzyme DPP-4 (dipeptidyl peptidase IV) also known as CD26 is a serine protease
`
`known to lead to the cleavage of a dipeptide from the N-terminal end of a number of proteins
`
`25
`
`having at their N-terminal end a prolin or alanin residue. Due to this property DPP-4 inhibitors
`
`interfere with the plasma level of bioactive peptides including the peptide GLP-1 and are
`
`considered to be promising drugs for the treatment of diabetes mellitus.
`
`For example, DPP-4 inhibitors and their uses are disclosed in WO 2002/068420, WO
`
`30
`
`2004/018467, WO 2004/018468, WO 2004/018469, WO 2004/041820, WO 2004/046148,
`
`WO 2005/051950, WO 2005/082906, WO 2005/063750, WO 2005/085246, WO
`
`2006/027204, WO 2006/029769, WO2007/014886; WO 2004/050658, WO 2004/111051,
`
`WO 2005/058901, WO 2005/097798; WO 2006/068163, WO 2007/071738, WO
`
`2008/017670; WO 2007/128721, WO 2007/128724, WO 2007/128761, or WO 2009/121945.
`
`35
`
`MPI EXHIBIT 1011 PAGE 7
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`MPI EXHIBIT 1011 PAGE 7
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`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1011, p. 7 of 72
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`WO 2011/138421
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`PCT /EP2011/057256
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`
`Glucagon-like peptide-1 (GLP-1) is a hormon secreted from enteroendocrine L cells of the
`
`intestine in response to food. Exogenous GLP-1 administration at pharmacological doses
`
`results in effects that are beneficial for treating type 2 diabetes. However, native GLP-1 is
`
`subject to rapid enzymatic degradation. The action of GLP-1 is mediated through the GLP-1
`
`5
`
`receptor (GLP-1 R).
`
`In the monitoring of the treatment of diabetes mellitus the HbA 1 c value, the product of a non(cid:173)
`
`enzymatic glycation of the haemoglobin B chain, is of exceptional importance. As its
`
`formation depends essentially on the blood sugar level and the life time of the erythrocytes
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`10
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`the HbA 1 c in the sense of a "blood sugar memory" reflects the average blood sugar level of
`
`the preceding 4-12 weeks. Diabetic patients whose HbA1c level has been well controlled
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`over a long time by more intensive diabetes treatment (i.e. < 6.5 % of the total haemoglobin
`
`in the sample) are significantly better protected from diabetic microangiopathy. The available
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`treatments for diabetes can give the diabetic an average improvement in their HbA 1 c level of
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`15
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`the order of 1.0 - 1.5 %. This reduction in the HbA 1 C level is not sufficient in all diabetics to
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`bring them into the desired target range of< 7.0 %, preferably< 6.5 % and more preferably<
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`6 % HbA1c.
`
`Within the meaning of this invention, inadequate or insufficient glycemic control means in
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`20
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`particular a condition wherein patients show HbA1 c values above 6.5%, in particular above
`
`7.0%, even more preferably above 7.5%, especially above 8%. An embodiment of patients
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`with inadequate or insufficient glycemic control include, without being limited to, patients
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`having a HbA1 c value from 7.5 to 10% (or, in another embodiment, from 7.5 to 11 %). A
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`special sub-embodiment of inadequately controlled patients refers to patients with poor
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`25
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`glycemic control including, without being limited, patients having a HbA1c value~ 9%.
`
`Within glycemic control, in addition to improvement of the HbA 1 c level, other recommended
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`therapeutic goals for type 2 diabetes mellitus patients are improvement of fasting plasma
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`glucose (FPG) and of postprandial plasma glucose (PPG) levels to normal or as near normal
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`30
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`as possible. Recommended desired target ranges of preprandial (fasting) plasma glucose
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`are 70-130 mg/dl (or 90-130 mg/dl) or <110 mg/dl, and of two-hour postprandial plasma
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`glucose are <180 mg/dl or <140 mg/dl.
`
`In one embodiment, diabetes patients within the meaning of this invention may include
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`35
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`patients who have not previously been treated with an antidiabetic drug (drug-na"fve
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`MPI EXHIBIT 1011 PAGE 8
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`MPI EXHIBIT 1011 PAGE 8
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`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1011, p. 8 of 72
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`patients). Thus, in an embodiment, the therapies described herein may be used in na"fve
`
`patients. In another embodiment, diabetes patients within the meaning of this invention may
`
`include patients with advanced or late stage type 2 diabetes mellitus (including patients with
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`failure to conventional antidiabetic therapy), such as e.g. patients with inadequate glycemic
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`5
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`control on one, two or more conventional oral and/or non-oral antidiabetic drugs as defined
`
`herein, such as e.g. patients with insufficient glycemic control despite (mono-)therapy with
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`metformin, a thiazolidinedione (particularly pioglitazone), a sulphonylurea, a glinide, GLP-1 or
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`GLP-1 analogue, insulin or insulin analogue, or an a-glucosidase inhibitor, or despite dual
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`combination therapy with metformin/sulphonylurea, metformin/thiazolidinedione (particularly
`
`10
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`pioglitazone), metformin/insulin, pioglitazone/sulphonylurea, pioglitazone/insulin, or
`
`sulphonylurea/insulin. Thus, in an embodiment, the therapies described herein may be used
`
`in patients experienced with therapy, e.g. with conventional oral and/or non-oral antidiabetic
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`mono- or dual or triple combination medication as mentioned herein.
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`15
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`A further embodiment of diabetic patients within the meaning of this invention refers to
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`patients ineligible for metformin therapy including
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`- patients for whom metformin therapy is contraindicated, e.g. patients having one or more
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`contraindications against metformin therapy according to label, such as for example patients
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`with at least one contraindication selected from:
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`20
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`renal disease, renal impairment or renal dysfunction (e.g., as specified by product
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`information of locally approved metformin),
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`dehydration,
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`unstable or acute congestive heart failure,
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`acute or chronic metabolic acidosis, and
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`25
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`hereditary galactose intolerance;
`
`and
`
`- patients who suffer from one or more intolerable side effects attributed to metformin,
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`particularly gastrointestinal side effects associated with metformin, such as for example
`
`patients suffering from at least one gastrointestinal side effect selected from:
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`30
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`nausea,
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`vomiting,
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`diarrhoea,
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`intestinal gas, and
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`severe abdominal discomfort.
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`35
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`MPI EXHIBIT 1011 PAGE 9
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`MPI EXHIBIT 1011 PAGE 9
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`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
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`A further embodiment of the diabetes patients which may be amenable to the therapies of
`
`this invention may include, without being limited, those diabetes patients for whom normal
`
`metformin therapy is not appropriate, such as e.g. those diabetes patients who need reduced
`
`dose metformin therapy due to reduced tolerability, intolerability or contraindication against
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`5 metformin or due to (mildly) impaired/reduced renal function (including elderly patients, such
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`as e.g. ~ 60-65 years).
`
`A further embodiment of diabetic patients within the meaning of this invention refers to
`
`patients having renal disease, renal dysfunction, or insufficiency or impairment of renal
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`10
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`function (including mild, moderate and severe renal impairment), e.g. as suggested by
`
`elevated serum creatinine levels (e.g. serum creatinine levels above the upper limit of normal
`
`for their age, e.g. ~ 130 - 150 µmol/I, or~ 1.5 mg/di (~ 136 µmol/I) in men and ~ 1.4 mg/di (~
`
`124 µmol/I) in women) or abnormal creatinine clearance (e.g. glomerular filtration rate (GFR)
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`:5 30 - 60 ml/min).
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`15
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`In this context, for more detailed example, mild renal impairment may be e.g. suggested by a
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`creatinine clearance of 50-80 ml/min (approximately corresponding to serum creatine levels
`
`of :51.7 mg/dl in men and :51.5 mg/dl in women); moderate renal impairment may be e.g.
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`suggested by a creatinine clearance of 30-50 ml/min (approximately corresponding to serum
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`20
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`creatinine levels of >1.7 to :53.0 mg/dl in men and >1.5 to :52.5 mg/dl in women); and severe
`
`renal impairment may be e.g. suggested by a creatinine clearance of< 30 ml/min
`
`(approximately corresponding to serum creatinine levels of >3.0 mg/dl in men and >2.5
`
`mg/dl in women). Patients with end-stage renal disease require dialysis (e.g. hemodialysis or
`
`peritoneal dialysis).
`
`25
`
`For other more detailed example, patients with renal disease, renal dysfunction or renal
`
`impairment include patients with chronic renal insufficiency or impairment, which can be
`stratified according to glomerular filtration rate (GFR, ml/min/1.73m2
`stage 1 characterized by normal GFR ~ 90 plus either persistent albuminuria or known
`
`) into 5 disease stages:
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`30
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`structural or hereditary renal disease; stage 2 characterized by mild reduction of GFR (GFR
`
`60-89) describing mild renal impairment; stage 3 characterized by moderate reduction of
`
`GFR (GFR 30-59) describing moderate renal impairment; stage 4 characterized by severe
`
`reduction of GFR (GFR 15-30) describing severe renal impairment; and terminal stage 5
`
`characterized by requiring dialysis or GFR < 15 describing established kidney failure (end-
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`35
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`stage renal disease, ESRD).
`
`MPI EXHIBIT 1011 PAGE 10
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`MPI EXHIBIT 1011 PAGE 10
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`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1011, p. 10 of 72
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`Within the scope of the present invention it has now been found that certain DPP-4 inhibitors
`
`as defined herein as well as pharmaceutical combinations, compositions or combined uses
`
`according to this invention of these DPP-4 inhibitors and GLP-1 receptor agonists (e.g.
`
`5
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`exogenous GLP-1 or GLP-1 analogues) as defined herein have unexpected and particularly
`
`advantageous properties, which make them suitable for the purpose of this invention and/or
`
`for fulfilling one or more of above needs.
`
`The present invention thus relates to a combination comprising a certain DPP-4 inhibitor
`
`10
`
`(particularly Bl 1356) and a GLP-1 receptor agonist (e.g. exogenous GLP-1 or a GLP-1
`
`analogue), each as defined herein, particularly for simultaneous, separate or sequential use
`
`in the therapies described herein.
`
`The present invention further relates to a method for treating and/or preventing metabolic
`
`15
`
`diseases, especially type 2 diabetes mellitus, obesity and/or conditions related thereto (e.g.
`
`diabetic complications) comprising the combined (e.g. simultaneous, separate or sequential)
`
`administration of an effective amount of a GLP-1 receptor agonist (e.g. exogenous GLP-1 or
`
`a GLP-1 analogue) as defined herein and of an effective amount of a DPP-4 inhibitor as
`
`defined herein to the patient (particularly human patient) in need thereof, such as e.g a
`
`20
`
`patient as described herein.
`
`The present invention further relates to at least one of the following methods:
`
`- preventing, slowing the progression of, delaying or treating a metabolic disorder or
`
`disease, such as e.g. type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose
`
`25
`
`tolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia, postprandial
`
`hyperglycemia, overweigh