DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
This application is a national stage entry of PCT/EP2021/060548 filed on 04/22/2021. Acknowledgment is made of applicant's claim for foreign priority based on an application filed in the EUROPEAN PATENT OFFICE (EPO) on 11/23/2020 and 04/22/2020.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on June 4, 2026 has been entered.
Response to Amendment
By Applicant’s amendment filed on June 4, 2026, claim 59 is amended. Claims 1-35, 37, 38, 40, 47-49 were previously canceled. Claims 36, 39, 41-46 and 50-60 are currently pending and presented for examination.
Response to Arguments
Due to Applicant’s amendments to claim 59, the previous rejection of claim 59 under 35 U.S.C. 112(b) is hereby withdrawn.
Applicant's arguments filed June 4, 2026 with respect to the remaining rejections have been fully considered but they are not persuasive.
With respect to the rejection under 35 U.S.C.§102, Applicant argues that NCT075 does not anticipate the pending claims because it does not disclose, expressly or inherently, treating any patient having a BMI of greater than 30. Applicant argues that anticipation requires that a single prior-art reference disclose every claim limitation and any unstated limitation must be necessarily present-not merely possible or probable. Applicant argues that NCT075's trial eligibility criterion of BMI > 27 merely defines a broader pool of potential trial participants and that pool includes individuals with BMI values below 30 as well as individuals with BMI values higher than 30. Applicant argues that nothing in the reference states that any subject with greater than 30 was actually enrolled, treated, or necessarily would be enrolled or treated. Applicant argues that a teaching that a BMI of at least 27 are eligible is not the same as disclosure that a patient with BMI greater than 30 would actually be recruited or treated.
These arguments are found not persuasive since NCT075 specifically teaches treating patients having BMI ≥27 kg/m2 (where overweight is related to the HIO). Thus the patients treated have a BMI of greater than 27 kg/m2 which includes all patients having a BMI of greater than 27 kg/m2 including all patients as claimed having a BMI of greater than 30 kg/m². The subjects as claimed having a BMI of greater than 30 kg/m² are also patients as taught in the clinical study having a BMI greater than 27 kg/m². Thus the patient population as claimed having a BMI of greater than 30 kg/m² is the same patient population as taught in NCT075.
Thus the previous rejection under 35 USC 102 is hereby maintained and reproduced below.
With respect to the rejection under 35 USC 103, Applicant argues that Vath describes the unique nature of hypothalamic obesity (HO) and how its treatment is separate, distinct, and even more challenging than treating "obesity," generally. Applicant argues that HO weight gain "occurs from the disruption of the normal homeostatic functioning of the hypothalamic centers, with loss of control of satiety and hunger, inability to regulate energy balance, reduction of energy expenditure, and/or hyperinsulinemia." Vath at paragraph [0005]. "In contrast, 'simple' obesity seems to result from patient variability in environmental cues, psychological/emotional status, and/or weight-regulating mechanisms." Applicant argues that the Examiner believes that the person of ordinary skill in the art would have presumed that blocking hypothalamic synaptic reuptake of noradrenaline would predictably treat HO and concludes that treatment with any noradrenaline reuptake inhibitor, including tesofensine, would predictably lead to an HO patient with a BMI over 30 losing 2 kg over 6 months. Applicant argues that the Examiner cannot supply missing scientific or technical reasoning through conclusory statements or subjective belief, rather obviousness findings must be based on objective evidence of record and reasoned explanation. Applicant argues that the rejection relies on the Examiner's own scientific inference rather than on evidence in the prior art and the Office Action does not identify a prior-art teaching that tesofensine, or any other noradrenaline reuptake inhibitor, would be expected to treat HO specifically and merely draws an unsupported mechanistic conclusion from unrelated disclosures. Applicant argues that the cited art does not establish that tesofensine's results in obese patients without HO would reasonably predict success in patients whose obesity arises from hypothalamic dysfunction. Applicant argues that the cited references do not teach that efficacy of tesofensine in "simple" obesity would have provided a reasonable expectation of efficacy in hypothalamic obesity.
These arguments are found not persuasive since the rejection does not rely on the Examiner's own scientific inference rather the rejection does rely on evidence in the prior art. It is maintained that the Office Action identifies prior-art teachings that teach and suggest that tesofensine, would be expected to treat HO specifically based on mechanisms of tesofensine taught in the art. The Office does not presume that any treatment deemed reasonably effective in non-hypothalamic obesity would be similarly successful in hypothalamic obesity. The rejection of record does not state or even suggest that the rejection is based on the presumption that any treatment deemed reasonably effective in non-hypothalamic obesity would be similarly successful in hypothalamic obesity.
The rejection over Hansen in view of Vath is based on the following teachings: Hansen et al. teaches two distinct and important mechanisms of action of Tesofensine, namely the anti-obesity effects associated with b1 adrenoceptor stimulation wherein the b1 adrenoceptor effect of Tesofensine is suggested to be secondary to a blockade of hypothalamic synaptic noradrenaline reuptake leading to inhibition of intrahypothalamic appetite signaling circuits to evoke satiety responses [0093]. Vath teaches that weight gain due to hypothalamic obesity occurs from the disruption of the normal homeostatic functioning of the hypothalamic centers, with loss of control of satiety and hunger, inability to regulate energy balance, reduction of energy expenditure, and/or hyperinsulinemia and frequent progression to diabetes [0005].
Accordingly, prior to the effective filing date of the claimed invention it would have been obvious to a person of ordinary skill in the art to treat hypothalamic obesity according to the teachings of Hansen et al. since Vath teaches that weight gain associated with hypothalamic obesity occurs from the disruption of the normal homeostatic functioning of the hypothalamic centers, with loss of control of satiety and hunger, inability to regulate energy balance, reduction of energy expenditure, and/or hyperinsulinemia [0005] and Hansen et al. specifically teaches an important mechanism of action of Tesofensine is a blockade of hypothalamic synaptic noradrenaline reuptake leading to inhibition of intrahypothalamic appetite signaling circuits to evoke satiety responses [0093]. Thus since Hansen et al. teaches that tesofensine has hypothalamic activity leading to satiety and hypothalamic obesity occurs from the disruption of the normal homeostatic functioning of the hypothalamic centers, with loss of control of satiety and hunger, a person of ordinary skill in the art would have been motivated to use tesofensine to restore normal homeostatic functioning of the hypothalamic centers to evoke satiety responses leading to the treatment or improvement in hypothalamic obesity. Thus in view of the cited prior art teachings, a prima facie case of obviousness in the treatment of hypothalamic obesity comprising the administration of tesofensine has been established.
Obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g., In re O ’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988). Par Pharm., Inc. v. TWi Pharms., Inc., 773 F.3d 1186, 1198 (Fed. Cir. 2014). Proof sufficient “to obtain approval” for a drug by a regulatory agency, such as by a randomized, placebo-controlled, double-blinded design is not necessary to establish obviousness. Hoffmann—La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014) (“[c]onclusive proof of efficacy is not necessary to show obviousness.”). “Scientific confirmation of what was already believed to be true may be a valuable contribution, but it does not give rise to a patentable invention.” PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1363-64 (Fed. Cir. 2007).
In the instant case, because of the prior art cited, a reasonable expectation of success exists since Vath teaches that weight gain due to hypothalamic obesity occurs from the disruption of the normal homeostatic functioning of the hypothalamic centers, with loss of control of satiety and hunger, inability to regulate energy balance, reduction of energy expenditure, and/or hyperinsulinemia and frequent progression to diabetes [0005], and Hansen et al. teaches two distinct and important mechanisms of action of Tesofensine, namely the anti-obesity effects associated with b1 adrenoceptor stimulation wherein the b1 adrenoceptor effect of Tesofensine is suggested to be secondary to a blockade of hypothalamic synaptic noradrenaline reuptake leading to inhibition of intrahypothalamic appetite signaling circuits to evoke satiety responses [0093]. Thus, due to the mechanism of tesofensine as taught in the prior art, an ordinary skilled artisan would reasonably expect tesofensine to be useful in the treatment of hypothalamic obesity.
Applicant further argues that the Examiner alleges that claims 36, 39, 41-46 and 50-60 would have been obvious over Edsberg in view of Vath and the Office Action relies on Edsberg's reference to Prader Willi syndrome, which "is a genetic disorder due to loss of function of specific genes on chromosome 15." Applicant argues that similar to Hansen, Edsberg does not provide the scientific rationale or reasonable expectation of success that tesofensine treatment will result in a fat mass reduction of at least 2 kg after 6 months of treatment in an HO patient with a BMI greater than 30.
These arguments are found not persuasive since the rejection over Edsberg in view of Vath is based on the following teachings:
Edsberg et al. teaches the treatment of obesity and in one embodiment, the subject is suffering from Prader Willi syndrome [0107]. Prader-Willi syndrome (PWS) is a genetic disorder due to loss of function of specific genes on chromosome 15, wherein in childhood the person becomes constantly hungry which often leads to obesity and type 2 diabetes [0107].
Vath teaches that Prader-Willi syndrome, caused by deletion of paternally imprinted genes on chromosome 15q11-q13 and BBS (Bradet-Biedl syndrome) can also cause hypothalamic obesity [0004].
Accordingly, since Edsberg et al. teaches treating a subject suffering from an obesity-associated disorder or condition, such as Prader-Willi Syndrome, and Vath teaches that Prader-Willi syndrome causes hypothalamic obesity, Edsberg et al. teaches that tesofensine administration is useful for the treatment of obesity associated with Prader-Willi syndrome which is a form of hypothalamic obesity. Thus Edsberg et al. teaches the treatment of hypothalamic obesity since Edsberg et al. teaches the treatment of Prader-Will syndrome which is a form of hypothalamic obesity.
Thus since obesity associated with Prader-Willi syndrome is due to hypothalamic dysregulation and Edsberg et al. specifically teaches treating obesity due to Prader-Willi syndrome, Edsberg et al. necessarily teaches the treatment of hypothalamic obesity comprising the administration of tesofensine. Thus in view of the cited prior art teachings, a prima facie case of obviousness in the treatment of hypothalamic obesity comprising the administration of tesofensine has been established.
Thus, Applicant’s arguments are found not persuasive and therefore the previous rejections under 35 USC 103 are hereby maintained and reproduced below.
With respect to the Double Patenting Rejections, Applicant argues that they will consider these rejections once allowable subject is indicated. Accordingly, the previous double patenting rejections are hereby maintained and reproduced below.
This action is FINAL.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 36, 39, 41-46, 50-55 and 57-59 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 12,178,810 B2 in view of Vath U.S. Publication No. 2015/0150840 A1. Although the claims at issue are not identical, they are not patentably distinct from each other because the cited claims of the instant application and the cited claims of the patent are substantially overlapping in scope and mutually obvious.
Claims 36, 39, 41-46, 50-55 and 57-59 of the instant application claim a method for treating hypothalamic obesity in a subject in need thereof comprising administering to the subject one time daily a pharmaceutical composition comprising 0.01 to 1.5 mg tesofensine, or a pharmaceutically acceptable salt thereof; wherein the subject has a body mass index (BMI) of greater than 30 kg/m2 prior to the treatment and wherein the fat mass of the subject is reduced by at least 2 kg after 6 months of the treatment.
Claims 1-12 of the patent claims a method for treating hyperphagia in a subject having Prader Willi Syndrome comprising orally administering to the subject 0.1 mg to 1 mg of tesofensine or a pharmaceutically acceptable salt thereof; and 10 mg to 200 mg of metoprolol or a pharmaceutically acceptable salt thereof; wherein the subject has a BMI of greater than 25 kg/m2.
The patent does not specifically claim the treatment of hypothalamic obesity or reducing serum HbA1c.
Vath teaches that hypothalamic obesity occurs subsequent to or in association with a pathological process injuring the hypothalamus and this syndrome is characterized by rapid, unrelenting weight gain that may be accompanied by severe hyperphagia [0002]. Vath teaches that hypothalamic obesity can occur with any damage to or defect of the energy controlling centers of the hypothalamus, in particular, hypothalamic obesity is an unfortunate complication in some survivors of brain tumors, especially those diagnosed in childhood [0003]. Vath further teaches that hypothalamic obesity can also occur with genetic syndromes, such as in patients having mutations in leptin or leptin receptor, CART (cocaine and amphetamine-related transcript), POMC (proopiomelanocorgin), prophormone convertase, MC4R (melanocortin-4 receptor), singleminded 1 (a transcription factor essential for formation of the supraoptic and PVN nuclei in the hypothalamus), and TrkB [0004]. Vath teaches that Prader-Willi syndrome, caused by deletion of paternally imprinted genes on chromosome 15q11-q13 and BBS (Bradet-Biedl syndrome) can also cause hypothalamic obesity [0004].
Thus Vath teaches that obesity associated with Prader-Willi syndrome is a form of hypothalamic obesity.
Accordingly, since the patent claims treating a subject having Prader-Willi Syndrome, and Vath teaches that Prader-Willi syndrome causes hypothalamic obesity, the patent claims that tesofensine administration is useful for the treatment of obesity associated with Prader-Willi syndrome which is a form of hypothalamic obesity. Thus the patent claims the treatment of hypothalamic obesity since the patent claims the treatment of a subject with Prader-Will syndrome which is a form of hypothalamic obesity.
Although the patent does not specifically claim that treatment will reduce serum HbA1c levels, the patent specifically claims administration of the same compound in the same amount to the same patient population having a form of hypothalamic obesity. Thus administration to the same patient population with the same compound will necessarily result in the same effect as claimed which is reducing serum HbA1c levels.
Thus, since the patent claims treating a subject with a form of hypothalamic obesity comprising administering to the subject a pharmaceutical composition comprising tesofensine, or a pharmaceutically acceptable salt thereof, the effects as claimed such as wherein the fat mass of the subject is reduced by at least 2 kg after 6 months of the treatment, and those effects as claimed in claims 41-44, 52, 54 and 55 are also rendered obvious since administration of the same compound to the same patient population for the same purpose will necessarily have the same effects. It is not necessary that the prior art suggests the same advantage or result discovered by Applicant when the steps of the claim are the same as those described or suggested by the prior art. See, e.g., In re Kahn, 441 F.3d 977, 987 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323 (Fed. Cir. 2005) (“One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings.”); In re Lintner, 458 F.2d 1013 (CCPA 1972); In re Dillon, 919 F.2d 688 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991).
With respect to new claims 57-59 which claim the characteristics of an obese subject including the waist circumference of at least 102 cm, a BMI of at least 35 kg/m2 and a fat mass of at least 31.46 kg, said claims are rendered obvious since the patent claims treating a subject having a BMI of greater than 25 kg/m2. Thus, it would have been obvious to a person of ordinary skill in the art to treat the subjects as claimed in claims 57-59 according to the treatment of the patent since a subject having a BMI of greater than 25 kg/m2 as claimed in the patent is inclusive of those subjects as claimed in claims 57-59.
Thus the cited claims of the instant application are not patentably distinct from the cited claims of the patent.
Claims 36, 39, 41-46, 50-55 and 57-59 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 9,211,271 in view of Vath U.S. Publication No. 2015/0150840 A1. Although the claims at issue are not identical, they are not patentably distinct from each other because the cited claims of the instant application and the cited claims of the patent are substantially overlapping in scope and mutually obvious.
Claims 36, 39, 41-46, 50-55 and 57-59 of the instant application claim a method for treating hypothalamic obesity in a subject in need thereof comprising administering to the subject one time daily a pharmaceutical composition comprising 0.01 to 1.5 mg tesofensine, or a pharmaceutically acceptable salt thereof; wherein the subject has a body mass index (BMI) of greater than 30 kg/m2 prior to the treatment and wherein the fat mass of the subject is reduced by at least 2 kg after 6 months of the treatment.
The cited claims of the patent claim a method of treating obesity in a human comprising administering to the human, an amount of Tesofensine, or a pharmaceutically acceptable salt thereof; effective to decrease the body mass index of the human, in combination with an amount of Metoprolol, or a pharmaceutically acceptable salt thereof, effective to treat the cardiovascular side effects of Tesofensine; wherein the combination is effective in decreasing the body mass index of the human; and wherein the subject has a body mass index (BMI) of greater than 30 kg/m2.
The patent does not specifically claim the treatment of hypothalamic obesity or reducing serum HbA1c.
However, the cited claims of the patent claims treating obesity and as such all forms of obesity are contemplated.
Vath teaches that hypothalamic obesity occurs subsequent to or in association with a pathological process injuring the hypothalamus and this syndrome is characterized by rapid, unrelenting weight gain that may be accompanied by severe hyperphagia [0002]. Vath teaches that hypothalamic obesity can occur with any damage to or defect of the energy controlling centers of the hypothalamus, in particular, hypothalamic obesity is an unfortunate complication in some survivors of brain tumors, especially those diagnosed in childhood [0003]. Vath further teaches that hypothalamic obesity can also occur with genetic syndromes, such as in patients having mutations in leptin or leptin receptor, CART (cocaine and amphetamine-related transcript), POMC (proopiomelanocorgin), prophormone convertase, MC4R (melanocortin-4 receptor), singleminded 1 (a transcription factor essential for formation of the supraoptic and PVN nuclei in the hypothalamus), and TrkB [0004]. Vath teaches that Prader-Willi syndrome, caused by deletion of paternally imprinted genes on chromosome 15q11-q13 and BBS (Bradet-Biedl syndrome) can also cause hypothalamic obesity [0004].
Vath teaches that the hypothalamus regulates body weight by precisely balancing the intake of food, energy expenditure and amount of body fat tissue, and the main hypothalamic areas involved in energy regulation (that when damaged cause hypothalamic obesity) include the ventromedial hypothalamus, paraventricular nuclei, arcuate nucleus and the lateral hypothalamic area [0005]. Vath teaches that disorders involving any of these type signals interaction with the hypothalamus, or damage to the hypothalamus, can lead to morbid, hypothalamic obesity [0005]. Weight gain occurs from the disruption of the normal homeostatic functioning of the hypothalamic centers, with loss of control of satiety and hunger, inability to regulate energy balance, reduction of energy expenditure, and/or hyperinsulinemia and frequent progression to diabetes [0005].
Thus since hypothalamic obesity is a form of obesity and the claims of the patent claims treating obesity in general, it would have been obvious to a person of ordinary skill in the art to treat hypothalamic obesity which is a form of obesity causing weight gain according to the methods as claimed in the patent with a reasonable expectation that the administration of the tesofensine would decrease the body mass index of the patient with hypothalamic obesity as claimed in the patent.
Thus, since a method for treating hypothalamic obesity comprising administering to the subject a pharmaceutical composition comprising tesofensine, or a pharmaceutically acceptable salt thereof, is rendered obvious over the patent claims, the effects as claimed such as wherein the fat mass of the subject is reduced by at least 2 kg after 6 months of the treatment, reducing serum HbA1c levels, and those effects as claimed in claims 41-44, 52, 54 and 55 are also rendered obvious since administration of the same compound to the same patient population for the same purpose will necessarily have the same effects. It is not necessary that the prior art suggests the same advantage or result discovered by Applicant when the steps of the claim are the same as those described or suggested by the prior art. See, e.g., In re Kahn, 441 F.3d 977, 987 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323 (Fed. Cir. 2005) (“One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings.”); In re Lintner, 458 F.2d 1013 (CCPA 1972); In re Dillon, 919 F.2d 688 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991).
With respect to new claims 57-59 which claim the characteristics of an obese subject including the waist circumference of at least 102 cm, a BMI of at least 35 kg/m2 and a fat mass of at least 31.46 kg, said claims are rendered obvious since the patent claims treating a subject having a BMI of greater than 30 kg/m2. Thus, it would have been obvious to a person of ordinary skill in the art to treat the subjects as claimed in claims 57-59 according to the treatment of the patent since a subject having a BMI of greater than 30 kg/m2 as claimed in the patent is inclusive of those subjects as claimed in claims 57-59 of the instant application.
Thus the cited claims of the instant application are rendered obvious over the cited patent claims and thus are not patentably distinct from the cited claims of the patent.
Claims 36, 39, 41-46 and 50-60 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 9,387,184 B2 in view of Vath U.S. Publication No. 2015/0150840 A1. Although the claims at issue are not identical, they are not patentably distinct from each other because the cited claims of the instant application and the cited claims of the patent are substantially overlapping in scope and mutually obvious.
Claims 36, 39, 41-46 and 50-60 of the instant application claim a method for treating hypothalamic obesity in a subject in need thereof comprising administering to the subject one time daily a pharmaceutical composition comprising 0.01 to 1.5 mg tesofensine, or a pharmaceutically acceptable salt thereof; wherein the subject has a body mass index (BMI) of greater than 30 kg/m2 prior to the treatment and wherein the fat mass of the subject is reduced by at least 2 kg after 6 months of the treatment.
The cited claims of the patent claim a method of reducing food intake by a human and method of reducing body weight of a human comprising: administering to the human, 0.1 mg to 1 mg of Tesofensine, or a pharmaceutically acceptable salt thereof, daily in combination with 0.25 mg to 200 mg of Metoprolol, or a pharmaceutically acceptable salt thereof, daily wherein the combination is effective in reducing the food intake by the human, reducing the body weight of the human and wherein the combination is effective in preventing or alleviating drug-induced cardiovascular side-effects, wherein the human is a pre-obese human, an obese human, or a morbid obese human, and wherein the human suffers from a condition selected from the group consisting of over-eating disorders, bulimia nervosa, binge eating disorder, compulsive over-eating, impaired appetite regulation, metabolic syndrome, type 2 diabetes, dyslipidemia, atherosclerosis, and drug-induced obesity.
The patent does not specifically claim the treatment of hypothalamic obesity or reducing serum HbA1c.
However, the cited claims of the patent claims reducing food intake as well as reducing body weight of a pre-obese human, an obese human, or a morbid obese human, and wherein the human suffers from a condition such as over-eating disorders, or compulsive over-eating and type 2 diabetes.
Vath teaches that hypothalamic obesity occurs subsequent to or in association with a pathological process injuring the hypothalamus and this syndrome is characterized by rapid, unrelenting weight gain that may be accompanied by severe hyperphagia [0002]. Vath teaches that hypothalamic obesity can occur with any damage to or defect of the energy controlling centers of the hypothalamus, in particular, hypothalamic obesity is an unfortunate complication in some survivors of brain tumors, especially those diagnosed in childhood [0003]. Vath further teaches that hypothalamic obesity can also occur with genetic syndromes, such as in patients having mutations in leptin or leptin receptor, CART (cocaine and amphetamine-related transcript), POMC (proopiomelanocorgin), prophormone convertase, MC4R (melanocortin-4 receptor), singleminded 1 (a transcription factor essential for formation of the supraoptic and PVN nuclei in the hypothalamus), and TrkB [0004]. Vath teaches that Prader-Willi syndrome, caused by deletion of paternally imprinted genes on chromosome 15q11-q13 and BBS (Bradet-Biedl syndrome) can also cause hypothalamic obesity [0004].
Vath teaches that the hypothalamus regulates body weight by precisely balancing the intake of food, energy expenditure and amount of body fat tissue, and the main hypothalamic areas involved in energy regulation (that when damaged cause hypothalamic obesity) include the ventromedial hypothalamus, paraventricular nuclei, arcuate nucleus and the lateral hypothalamic area [0005]. Vath teaches that disorders involving any of these type signals interaction with the hypothalamus, or damage to the hypothalamus, can lead to morbid, hypothalamic obesity [0005]. Weight gain occurs from the disruption of the normal homeostatic functioning of the hypothalamic centers, with loss of control of satiety and hunger, inability to regulate energy balance, reduction of energy expenditure, and/or hyperinsulinemia and frequent progression to diabetes [0005].
Thus since hypothalamic obesity leads to an obese human, or a morbid obese human, and is an over-eating disorder, or a condition resulting in compulsive over-eating, it would have been obvious to a person of ordinary skill in the art to treat hypothalamic obesity according to the methods as claimed in the patent with a reasonable expectation that the administration of the tesofensine would reduce food intake and reduce body weight of the patient as claimed in the patent.
Thus, since a method for treating hypothalamic obesity comprising administering to the subject a pharmaceutical composition comprising tesofensine, or a pharmaceutically acceptable salt thereof, is rendered obvious over the patent claims, the effects as claimed such as wherein the fat mass of the subject is reduced by at least 2 kg after 6 months of the treatment, reducing serum HbA1c levels, and those effects as claimed in claims 41-44, 52, 54 and 55 are also rendered obvious since administration of the same compound to the same patient population for the same purpose will necessarily have the same effects. It is not necessary that the prior art suggests the same advantage or result discovered by Applicant when the steps of the claim are the same as those described or suggested by the prior art. See, e.g., In re Kahn, 441 F.3d 977, 987 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323 (Fed. Cir. 2005) (“One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings.”); In re Lintner, 458 F.2d 1013 (CCPA 1972); In re Dillon, 919 F.2d 688 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991).
With respect to new claims 56-60 which claim the characteristics of an obese subject including the waist circumference of at least 102 cm, a BMI of at least 35 kg/m2 and a fat mass of at least 31.46 kg, and the characteristics of a subject having type 2 diabetes with an HbA1c of at least 29 mmol/mol which is inclusive of HbA1c levels far above 29 mmol/mol, said claims are rendered obvious since the patent claims treating a subject that is obese, morbid obese and having type 2 diabetes Thus, it would have been obvious to a person of ordinary skill in the art to treat the subjects as claimed in claims 56-60 according to the treatment of the patent since an obese, morbid obese or type 2 diabetic subject as claimed in the patent is inclusive of those subjects as claimed in claims 56-60 of the instant application.
Thus the cited claims of the instant application are rendered obvious over the cited claims of the patent and thus are not patentably distinct from the cited claims of the patent.
Claims 36, 39, 41-46, 50-55 and 57-59 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Application No. 18/959,912 (U.S. Publication No. 2025/0082626 A1) in view of Vath U.S. Publication No. 2015/0150840 A1. Although the claims at issue are not identical, they are not patentably distinct from each other because the cited claims of the instant application and the cited claims of copending ‘912 are substantially overlapping in scope and mutually obvious.
Claims 36, 39, 41-46, 50-55 and 57-59 of the instant application claim a method for treating hypothalamic obesity in a subject in need thereof comprising administering to the subject one time daily a pharmaceutical composition comprising 0.01 to 1.5 mg tesofensine, or a pharmaceutically acceptable salt thereof; wherein the subject has a body mass index (BMI) of greater than 30 kg/m2 prior to the treatment and wherein the fat mass of the subject is reduced by at least 2 kg after 6 months of the treatment.
Claims 1-13 of copending ‘912 claims a method for treating hyperphagia in a subject having Prader Willi Syndrome comprising orally administering to the subject 0.1 mg to 1 mg of tesofensine or a pharmaceutically acceptable salt thereof; wherein the subject has a body mass index (BMI) of greater than 25 kg/m2.
Copending ‘912 does not specifically claim the treatment of hypothalamic obesity or reducing serum HbA1c.
Vath teaches that hypothalamic obesity occurs subsequent to or in association with a pathological process injuring the hypothalamus and this syndrome is characterized by rapid, unrelenting weight gain that may be accompanied by severe hyperphagia [0002]. Vath teaches that hypothalamic obesity can occur with any damage to or defect of the energy controlling centers of the hypothalamus, in particular, hypothalamic obesity is an unfortunate complication in some survivors of brain tumors, especially those diagnosed in childhood [0003]. Vath further teaches that hypothalamic obesity can also occur with genetic syndromes, such as in patients having mutations in leptin or leptin receptor, CART (cocaine and amphetamine-related transcript), POMC (proopiomelanocorgin), prophormone convertase, MC4R (melanocortin-4 receptor), singleminded 1 (a transcription factor essential for formation of the supraoptic and PVN nuclei in the hypothalamus), and TrkB [0004]. Vath teaches that Prader-Willi syndrome, caused by deletion of paternally imprinted genes on chromosome 15q11-q13 and BBS (Bradet-Biedl syndrome) can also cause hypothalamic obesity [0004].
Thus Vath teaches that obesity associated with Prader-Willi syndrome is a form of hypothalamic obesity.
Accordingly, since copending ‘912 claims treating a subject having Prader-Willi Syndrome, and Vath teaches that Prader-Willi syndrome causes hypothalamic obesity, copending ‘912 claims that tesofensine administration is useful for the treatment of obesity associated with Prader-Willi syndrome which is a form of hypothalamic obesity. Thus copending ‘912 claims the treatment of hypothalamic obesity since copending ‘912 claims the treatment of a subject with Prader-Will syndrome which is a form of hypothalamic obesity.
Although copending ‘912 does not specifically claim that treatment will reduce serum HbA1c levels, copending ‘912 specifically claims administration of the same compound in the same amount to the same patient population having a form of hypothalamic obesity. Thus administration to the same patient population with the same compound will necessarily result in the same effect as claimed which is reducing serum HbA1c levels.
Thus, since copending ‘912 claims treating a subject with a form of hypothalamic obesity comprising administering to the subject a pharmaceutical composition comprising tesofensine, or a pharmaceutically acceptable salt thereof, the effects as claimed such as wherein the fat mass of the subject is reduced by at least 2 kg after 6 months of the treatment, and those effects as claimed in claims 41-44, 52, 54 and 55 are also rendered obvious since administration of the same compound to the same patient population for the same purpose will necessarily have the same effects. It is not necessary that the prior art suggests the same advantage or result discovered by Applicant when the steps of the claim are the same as those described or suggested by the prior art. See, e.g., In re Kahn, 441 F.3d 977, 987 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323 (Fed. Cir. 2005) (“One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings.”); In re Lintner, 458 F.2d 1013 (CCPA 1972); In re Dillon, 919 F.2d 688 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991).
With respect to new claims 57-59 which claim the characteristics of an obese subject including the waist circumference of at least 102 cm, a BMI of at least 35 kg/m2 and a fat mass of at least 31.46 kg, said claims are rendered obvious since copending ‘912 claims treating a subject having a BMI of greater than 25 kg/m2. Thus, it would have been obvious to a person of ordinary skill in the art to treat the subjects as claimed in claims 57-59 according to the treatment of copending ‘912 since a subject having a BMI of greater than 25 kg/m2 as claimed in copending ‘912 is inclusive of those subjects as claimed in claims 57-59 of the instant application.
Thus the cited claims of the instant application are not patentably distinct from the cited claims of copending ‘912.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 36, 39, 41-46 and 50-55 and 58 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by ClinicalTrials.gov ID NCT03845075 (first posted on 02-18-2019 Provided on IDS) herein referred to as NCT075.
Claims 36, 39, 41-46 and 50-55 and 58 of the instant application claim a method for treating hypothalamic obesity in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising 0.01 to 1.5 mg tesofensine, or a pharmaceutically acceptable salt thereof; wherein the fat mass of the subject is reduced by at least 2 kg after 6 months of the treatment.
NCT075 is a Study to Evaluate Overall Safety and Tolerability of Co-administration of Tesofensine and Metoprolol in Subjects With Hypothalamic Injury-induced Obesity (HIO) (Title). Participants will be given co-administration of 0.5 mg tesofensine/50 mg metoprolol daily for 24 weeks for the treatment of Hypothalamic Injury-induced Obesity (HIO) (detailed description). Eligible participants include those with a BMI ≥27 kg/m2 (where overweight is related to the HIO) (eligibility).
Thus the cited claims of the instant application are anticipated since NCT075 specifically discloses a method for treating hypothalamic obesity in a subject in need thereof comprising daily administering to the subject a pharmaceutical composition comprising 0.5 mg tesofensine and as such said method will inherently have the same effects as claimed including the fat mass of the subject is reduced by at least 2 kg after 6 months of the treatment; as well as the effects as claimed in claims 41-44.
In addition, the claims are anticipated since the patients of NCT075 have a BMI ≥27 kg/m2 which inherently includes the subjects as claimed having a BMI of greater than 30 kg/m2 since a subject having a BMI of more than 30 kg/m2 or at least 35 kg/m2 as claimed are included in the patient population of more than 27 kg/m2 as taught in NCT075.
Furthermore, since NCT075 specifically teaches treating the same patient population who is overweight due to Hypothalamic Obesity, with the same composition comprising 0.5 mg tesofensine, said treatment will inherently reduce serum HbA1c levels and to the same degree as claimed in claims 51-52. Likewise, since NCT075 specifically teaches treating the same patient population who is overweight due to Hypothalamic Obesity, with the same composition comprising 0.5 mg tesofensine, said treatment will inherently reduce body weight and the fat mass of the subject to the same degree as claimed in claims 53-55. It is not necessary that the prior art suggests the same advantage or result discovered by Applicant when the steps of the claim are the same as those described or suggested by the prior art. See, e.g., In re Kahn, 441 F.3d 977, 987 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323 (Fed. Cir. 2005) (“One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings.”); In re Lintner, 458 F.2d 1013 (CCPA 1972); In re Dillon, 919 F.2d 688 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991).
Thus the cited claims of the instant application are rejected.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 36, 39, 41-46 and 50-60 are rejected under 35 U.S.C. 103 as being unpatentable over Hansen et al. U.S. Publication No. 2015/0025107 A1 in view of Vath U.S. Publication No. 2015/0150840 A1.
Claims 36, 39, 41-46 and 50-60 of the instant application claim a method for treating hypothalamic obesity in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising 0.01 to 1.5 mg tesofensine, or a pharmaceutically acceptable salt thereof; wherein the fat mass of the subject is reduced by at least 2 kg after 6 months of the treatment.
Hansen et al. teaches a method of treatment, prevention or alleviation of obesity, or an obesity associated disorder, and for treatment, prevention or alleviation of the cardiovascular side effects of Tesofensine, in a living animal body, including a human, which method comprises the step of administering to such a living animal body in need thereof, a therapeutically effective amount of Tesofensine, or a pharmaceutically acceptable salt thereof; in a combination therapy with Metoprolol, or a pharmaceutically acceptable salt thereof [0011].
Hansen et al. teaches that tesofensine is a centrally acting triple monoamine reuptake inhibitor (MRI) with intrinsic inhibitory activity on noradrenaline, serotonin and dopamine transporter function, wherein long-term Tesofensine treatment produces a weight loss of about 10% in obese patients, which is twice as much as that achieved by currently marketed anti-obesity drugs [0020]. Hansen et al. teaches that the anti-obesity effect of Tesofensine is likely explained by dose-dependent hypophagia due to stimulation of satiety, suggesting that Tesofensine acts as an appetite suppressant to produce a negative energy balance [0021]. Tesofensine is also demonstrated to increase nocturnal energy expenditure in human subjects [0021].
Hansen et al. teaches that obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems [0027] . Hansen et al. teaches the treatment of pre-obese subjects, i.e. having a BMI between 25 and 30 kg/m2; the treatment of obese subjects, i.e. having a BMI of above 30 kg/m2; and the treatment of morbid obese subjects, i.e. having a BMI of above 35 kg/m2 [0028]-[0030].
Hansen et al. teaches an obesity associated disorder is a disorder or condition selected from the group consisting of over-eating disorders, bulimia nervosa, binge eating disorder, compulsive over-eating, impaired appetite regulation, metabolic syndrome, type 2 diabetes, dyslipidemia, atherosclerosis and drug-induced obesity, e.g. following therapy with antidepressive or antipsychotic drugs [0031].
Hansen et al. teaches that a daily dosage of Tesofensine in the range of from about 0.1 to about 1 mg active ingredient, preferably of from about 0.1 to about 0.5 mg active ingredient, is suitable for therapeutic treatments and the daily dosage of Tesofensine may be administered in one or several doses, such as two, per day, wherein in one embodiment, the daily dosage is administered in one dose [0046] and [0058].
Hansen et al. teaches methods of treatment, prevention or alleviation of obesity or an obesity associated disease of a living animal body, including a human, which method comprises the step of administering to such a living animal body in need thereof, a therapeutically effective amount of a combination of Tesofensine, or a pharmaceutically acceptable salt thereof, and Metoprolol, a pharmaceutically acceptable salt thereof [0056]. In a preferred embodiment the obesity associated disorder is a disorder or condition selected from the group consisting of over-eating disorders, bulimia nervosa, binge eating disorder, compulsive over-eating, impaired appetite regulation, metabolic syndrome, type 2 diabetes, dyslipidemia, atherosclerosis and drug-induced obesity [0057].
Hansen et al. teaches two distinct and important mechanisms of action of Tesofensine, namely the anti-obesity effects associated with b1 adrenoceptor stimulation wherein the b1 adrenoceptor effect of Tesofensine is suggested to be secondary to a blockade of hypothalamic synaptic noradrenaline reuptake leading to inhibition of intrahypothalamic appetite signaling circuits to evoke satiety responses [0093].
Claims 1-5 of Hansen et al. claim a method of treatment, prevention or alleviation of obesity, or an obesity associated disorder, and for treatment, prevention or alleviation of the cardiovascular side effects of Tesofensine, in a living animal body, including a human, which method comprises the step of administering to such a living animal body in need thereof, a therapeutically effective amount of Tesofensine, or a pharmaceutically acceptable salt thereof; in a combination therapy with Metoprolol, or a pharmaceutically acceptable salt thereof, wherein the obesity associated disorder is a disorder or condition selected from the group consisting of over-eating disorders, bulimia nervosa, binge eating disorder, compulsive over-eating, impaired appetite regulation, metabolic syndrome, type 2 diabetes, dyslipidemia, atherosclerosis and drug-induced obesity, wherein Tesofensine is dosed in a range of from about 0.1 to about 1 mg API daily, and the living animal body is a subject having a BMI of above 30 kg/m2.
Hansen et al. does not specifically teach treatment of hypothalamic obesity. Hansen et al. does not specifically teach reducing serum HbA1c. Hansen et al. does not specifically teach the effects as claimed including the fat mass of the subject is reduced by at least 2 kg after 6 months of the treatment, and those effects as claimed in claims 41-44, 52, 54 and 55. Hansen et al. does not specifically teach treating the subjects as claimed in claims 57, 59 and 60.
Vath teaches that hypothalamic obesity occurs subsequent to or in association with a pathological process injuring the hypothalamus and this syndrome is characterized by rapid, unrelenting weight gain that may be accompanied by severe hyperphagia [0002]. Vath teaches that hypothalamic obesity can occur with any damage to or defect of the energy controlling centers of the hypothalamus, in particular, hypothalamic obesity is an unfortunate complication in some survivors of brain tumors, especially those diagnosed in childhood [0003]. Vath further teaches that hypothalamic obesity can also occur with genetic syndromes, such as in patients having mutations in leptin or leptin receptor, CART (cocaine and amphetamine-related transcript), POMC (proopiomelanocorgin), prophormone convertase, MC4R (melanocortin-4 receptor), singleminded 1 (a transcription factor essential for formation of the supraoptic and PVN nuclei in the hypothalamus), and TrkB [0004]. Vath teaches that Prader-Willi syndrome, caused by deletion of paternally imprinted genes on chromosome 15q11-q13 and BBS (Bradet-Biedl syndrome) can also cause hypothalamic obesity [0004].
Vath teaches that the hypothalamus regulates body weight by precisely balancing the intake of food, energy expenditure and amount of body fat tissue, and the main hypothalamic areas involved in energy regulation (that when damaged cause hypothalamic obesity) include the ventromedial hypothalamus, paraventricular nuclei, arcuate nucleus and the lateral hypothalamic area [0005]. Vath teaches that disorders involving any of these type signals interaction with the hypothalamus, or damage to the hypothalamus, can lead to morbid, hypothalamic obesity [0005]. Weight gain occurs from the disruption of the normal homeostatic functioning of the hypothalamic centers, with loss of control of satiety and hunger, inability to regulate energy balance, reduction of energy expenditure, and/or hyperinsulinemia and frequent progression to diabetes [0005].
Accordingly, prior to the effective filing date of the claimed invention it would have been obvious to a person of ordinary skill in the art to treat hypothalamic obesity according to the teachings of Hansen et al. since Vath teaches that weight gain associated with hypothalamic obesity occurs from the disruption of the normal homeostatic functioning of the hypothalamic centers, with loss of control of satiety and hunger, inability to regulate energy balance, reduction of energy expenditure, and/or hyperinsulinemia [0005] and Hansen et al. specifically teaches an important mechanism of action of Tesofensine is a blockade of hypothalamic synaptic noradrenaline reuptake leading to inhibition of intrahypothalamic appetite signaling circuits to evoke satiety responses [0093]. Thus since Hansen et al. teaches that tesofensine has hypothalamic activity leading to satiety and hypothalamic obesity occurs from the disruption of the normal homeostatic functioning of the hypothalamic centers, with loss of control of satiety and hunger, a person of ordinary skill in the art would have been motivated to use tesofensine to restore normal homeostatic functioning of the hypothalamic centers to evoke satiety responses leading to the treatment or improvement in hypothalamic obesity. Thus the treatment of hypothalamic obesity comprising the administration of tesofensine is rendered obvious in view of the cited prior art teachings.
Although Hansen et al. does not specifically teach that treatment will reduce serum HbA1c levels, Hansen et al. specifically teaches treating a subject with type 2 diabetes. Thus administration to the same patient population with the same compound will necessarily result in the same effect as claimed which is reducing serum HbA1c levels.
Thus, since the prior art renders obvious a method for treating hypothalamic obesity in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising 0.01 to 1.5 mg tesofensine, or a pharmaceutically acceptable salt thereof, the effects as claimed such as wherein the fat mass of the subject is reduced by at least 2 kg after 6 months of the treatment, and those effects as claimed in claims 41-44, 52, 54 and 55 are also rendered obvious since administration of the same compound to the same patient population for the same purpose will necessarily have the same effects. It is not necessary that the prior art suggests the same advantage or result discovered by Applicant when the steps of the claim are the same as those described or suggested by the prior art. See, e.g., In re Kahn, 441 F.3d 977, 987 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323 (Fed. Cir. 2005) (“One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings.”); In re Lintner, 458 F.2d 1013 (CCPA 1972); In re Dillon, 919 F.2d 688 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991).
With respect to new claims 56-60 which claim the characteristics of an obese subject including the waist circumference of at least 102 cm, a BMI of at least 35 kg/m2 and a fat mass of at least 31.46 kg, and the characteristics of a subject having type 2 diabetes with an HbA1c of at least 29 mmol/mol which is inclusive of HbA1c levels far above 29 mmol/mol, said claims are rendered obvious since Hansen et al. teaches the treatment of obese subjects, i.e. having a BMI of above 30 kg/m2; and the treatment of morbid obese subjects, i.e. having a BMI of above 35 kg/m2; as well as subjects having type 2 diabetes. Thus, it would have been obvious to a person of ordinary skill in the art to treat the subjects as claimed in claims 56-60 according to the treatment of Hansen et al. since an obese, morbid obese or type 2 diabetic subject as claimed in Hansen et al. is inclusive of those subjects as claimed in claims 56-60 of the instant application.
Thus the cited claims of the instant application are rendered obvious in view of cited prior art teachings.
Claims 36, 39, 41-46 and 50-60 are rejected under 35 U.S.C. 103 as being unpatentable over Edsberg et al. U.S. Publication No. 2019/0060301 A1 in view of Vath U.S. Publication No. 2015/0150840 A1.
Claims 36, 39, 41-46 and 50-60 of the instant application claim a method for treating hypothalamic obesity in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising 0.01 to 1.5 mg tesofensine, or a pharmaceutically acceptable salt thereof; wherein the fat mass of the subject is reduced by at least 2 kg after 6 months of the treatment.
Edsberg et al. teaches co-treatment with tesofensine and metoprolol is capable of reducing both weight and blood pressure in a subject [0021]. Edsberg et al. teaches a method for treatment of hypertension and obesity in a subject in need thereof, the method comprising administering to said subject: i) a therapeutically effective amount of tesofensine or a pharmaceutically acceptable salt thereof; and ii) a therapeutically effective amount of metoprolol or a pharmaceutically acceptable salt thereof, thereby reducing blood pressure and body weight of said subject [0021]- [0023]. Edsberg et al. teaches that the composition comprising tesofensine and metoprolol is particularly well suited for use in the treatment of hypertensive obese and/or diabetic subjects [0024].
Edsberg et al. teaches that the data confirms that tesofensine and metoprolol co-administration effectively reduces weight and blood pressure, and thus the combined use is for the treatment of hypertension and obesity or an obesity related disorder [0028]. Edsberg et al. teaches the treatment of obese patients, with a BMI of above 25 kg/m2, such as above 30 kg/m2, for example above 35 kg/m2, such as above 40 kg/m2 [0085]-[0089].
Edsberg et al. teaches that tesofensine is selected from the free base, the citrate salt and the tartrate salt [0037]. The tesofensine or pharmaceutically acceptable salt thereof is usually administered orally [0038]. Tesofensine is normally administered at a daily dose of about 0.25-2 mg [0039]. Edsberg et al. teaches in one embodiment tesofensine or pharmaceutical salt thereof is administered at about 0.25 mg or about 0.5 mg API per day, such as at about 0.2 mg to about 0.3 mg or about 0.45 to about 0.55 mg API per day [0040]-[0051]. Edsberg et al. teaches that the daily dosage of tesofensine may be administered in one or several doses, such as two, per day, and in one embodiment, the daily dosage is administered in one dose [0051].
Edsberg et al. teaches the subject benefitting from co-treatment of tesofensine and metoprolol according to the methods of the present invention may also be a subject suffering from an obesity-associated disorder or condition, such as one selected from the group consisting of metabolic syndrome, dyslipidemia, atherosclerosis, drug-induced obesity, overeating disorders, bulimia nervosa, binge eating disorder, compulsive over-eating, impaired appetite regulation, Prader-Willi Syndrome, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) [0105]-[0106].
Edsberg et al. teaches in one embodiment, the subject is suffering from Prader Willi syndrome [0107]. Prader-Willi syndrome (PWS) is a genetic disorder due to loss of function of specific genes on chromosome 15, wherein in childhood the person becomes constantly hungry which often leads to obesity and type 2 diabetes [0107].
Edsberg et al. specifically demonstrates safety, and efficacy of co-administration of Tesofensin/Metoprolol (Tesomet) in subjects with type 2 diabetes mellitus (HbA1c≥7.0%) in 60 patients with a mean BMI of 32.59 administered 0.5 mg tesofensine (tablets)+100 mg metoprolol once a day (Tesomet) for 90 days [0166]-[0167]. The study demonstrated a statistically significant reduction in bodyweight during the course of the study (day 0 to day 90) of 3.50 kg (3.54%) in the treatment group compared to a reduction of 0.29 kg (0.31%) in the placebo group (p<0.0001). The reduction in body weight correlated with a decrease in waist circumference of 2.29 cm in the Tesomet treatment group compared to a reduction of 0.03 cm for patients receiving placebo (p<0.007) [0169].
Thus Edsberg et al. specifically teaches treating obesity and reducing body weight in a subject in need thereof such as a subject with Prader Willi syndrome. Edsberg et al. specifically teaches treating a subject that is diabetic prior to treatment and having an HbA1c of at least 29 mmol/mol prior to treatment.
Edsberg et al. does not specifically teach treatment of hypothalamic obesity. Edsberg et al. does not specifically teach reducing serum HbA1c. Edsberg et al. does not teach the subjects as claimed in claims 57 and 59.
Vath teaches that hypothalamic obesity occurs subsequent to or in association with a pathological process injuring the hypothalamus and this syndrome is characterized by rapid, unrelenting weight gain that may be accompanied by severe hyperphagia [0002]. Vath teaches that hypothalamic obesity can occur with any damage to or defect of the energy controlling centers of the hypothalamus, in particular, hypothalamic obesity is an unfortunate complication in some survivors of brain tumors, especially those diagnosed in childhood [0003]. Vath further teaches that hypothalamic obesity can also occur with genetic syndromes, such as in patients having mutations in leptin or leptin receptor, CART (cocaine and amphetamine-related transcript), POMC (proopiomelanocorgin), prophormone convertase, MC4R (melanocortin-4 receptor), singleminded 1 (a transcription factor essential for formation of the supraoptic and PVN nuclei in the hypothalamus), and TrkB [0004]. Vath teaches that Prader-Willi syndrome, caused by deletion of paternally imprinted genes on chromosome 15q11-q13 and BBS (Bradet-Biedl syndrome) can also cause hypothalamic obesity [0004].
Vath teaches that the hypothalamus regulates body weight by precisely balancing the intake of food, energy expenditure and amount of body fat tissue, and the main hypothalamic areas involved in energy regulation (that when damaged cause hypothalamic obesity) include the ventromedial hypothalamus, paraventricular nuclei, arcuate nucleus and the lateral hypothalamic area [0005]. Vath teaches that disorders involving any of these type signals interaction with the hypothalamus, or damage to the hypothalamus, can lead to morbid, hypothalamic obesity [0005]. Weight gain occurs from the disruption of the normal homeostatic functioning of the hypothalamic centers, with loss of control of satiety and hunger, inability to regulate energy balance, reduction of energy expenditure, and/or hyperinsulinemia and frequent progression to diabetes [0005].
Thus Vath teaches that obesity associated with Prader-Willi syndrome is a form of hypothalamic obesity.
Accordingly, since Edsberg et al. teaches treating a subject suffering from an obesity-associated disorder or condition, such as Prader-Willi Syndrome, and Vath teaches that Prader-Willi syndrome causes hypothalamic obesity, Edsberg et al. teaches that tesofensine administration is useful for the treatment of obesity associated with Prader-Willi syndrome which is a form of hypothalamic obesity. Thus Edsberg et al. teaches the treatment of hypothalamic obesity since Edsberg et al. teaches the treatment of Prader-Will syndrome which is a form of hypothalamic obesity.
Although Edsberg et al. does not specifically teach that treatment will reduce serum HbA1c levels, Edsberg et al. specifically teaches treating a subject with type 2 diabetes and having elevated serum HbA1c levels. Thus administration of the same patient population with the same compound will necessarily result in the same effect as claimed which is reducing serum HbA1c levels.
Thus, since the prior art renders obvious a method for treating hypothalamic obesity in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising 0.01 to 1.5 mg tesofensine, or a pharmaceutically acceptable salt thereof, the effects as claimed such as wherein the fat mass of the subject is reduced by at least 2 kg after 6 months of the treatment, and those effects as claimed in claims 41-44, 52, 54 and 55 are also rendered obvious since administration of the same compound to the same patient population for the same purpose will necessarily have the same effects. It is not necessary that the prior art suggests the same advantage or result discovered by Applicant when the steps of the claim are the same as those described or suggested by the prior art. See, e.g., In re Kahn, 441 F.3d 977, 987 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323 (Fed. Cir. 2005) (“One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings.”); In re Lintner, 458 F.2d 1013 (CCPA 1972); In re Dillon, 919 F.2d 688 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991).
With respect to new claims 56-60 which claim the characteristics of an obese subject including the waist circumference of at least 102 cm, a BMI of at least 35 kg/m2 and a fat mass of at least 31.46 kg, and the characteristics of a subject having type 2 diabetes with an HbA1c of at least 29 mmol/mol which is inclusive of HbA1c levels far above 29 mmol/mol, said claims are rendered obvious since Edsberg et al. teaches the treatment of obese subjects, i.e. having a BMI of above 30 kg/m2; and the treatment of morbid obese subjects, i.e. having a BMI of above 35 kg/m2; as well as subjects having type 2 diabetes. Thus, it would have been obvious to a person of ordinary skill in the art to treat the subjects as claimed in claims 56-60 according to the treatment of Edsberg et al. since an obese, morbid obese or type 2 diabetic subject as taught in Edsberg et al. is inclusive of those subjects as claimed in claims 56-60 of the instant application.
Thus the cited claims of the instant application are rendered obvious in view of cited prior art teachings.
Conclusion
Claims 1-35, 37-38, 40 and 47-49 are canceled. Claims 36, 39, 41-46 and 50-60 are rejected. No claims are allowed.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KARA R. MCMILLIAN whose telephone number is (571)270-5236. The examiner can normally be reached Tuesday-Friday 12:00 PM-6:00 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam C. Milligan can be reached at (571)270-7674. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KARA R. MCMILLIAN/Primary Examiner, Art Unit 1623
KRM
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