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.
Response to Amendment
Applicant’s amendment filed on November 11, 2025 amending claims 36, 39, 41-46, 50, 51, 53 and 55; canceling claims 37, 38, 40, 47-49; and adding new claims 56-60 has been entered. Claims 1-35 were previously canceled. Claims 36, 39, 41-46, 50-60 are currently pending and presented for examination.
Response to Arguments
Applicant's arguments filed November 11, 2025 have been fully considered but they are not persuasive.
With respect to the rejection under 35 U.S.C.§102, Applicant argues that the independent claims have been amended to recite that the administration is one time daily and that the subject's body mass index (BMI) is greater than 30 kg/m2 prior to the treatment. Applicant argues that NCT075 states that administration is "daily," but does not expressly state that administration is one time daily. Applicant also argues that it is common knowledge that a BMI < 30 kg/m2 is "obese" and that a BMI of 25-30 kg/m2 is "overweight."
These arguments are found not persuasive since Applicant’s amendments to the claims do not overcome the anticipation rejection. NCT075 specifically teaches in the Arms and interventions section that the active medication arm will be given co-administration of 0.5 mg tesofensine/50 mg metoprolol daily for 24 weeks. There is no indication that this treatment is given any other than one time a day. Co-administration of 0.5 mg tesofensine/50 mg metoprolol daily specifically means administration one time a day. There is no teaching stating that the treatment is administered multiple times a day or that the dosage is divided up and administered multiple times a day. Moreover, the claims of the instant application recite wherein the subject has a body mass index (BMI) of greater than 30 kg/m² prior to the treatment. NCT075 specifically teaches treating patients having BMI ≥27 kg/m2 (where overweight is related to the HIO). The subjects as claimed having a BMI of greater than 30 kg/m² is also a patient as taught in the clinical study having a BMI greater than 30 kg/m². Thus the patient population as claimed is the same patient population as taught in NCT075.
Thus the previous rejection under 35 USC 102 is hereby maintained and detailed below with modifications necessary to address Applicant’s amendments to the claims.
With respect to the rejection under 35 USC 103, Applicant argues that the Office acknowledges that neither Hansen nor Edsberg describe or suggest any treatments for hypothalamic obesity. Nevertheless, the Office presumes that any treatment deemed reasonably effective in non-hypothalamic obesity would be similarly successful in hypothalamic obesity. Applicant argues that the art recognizes that hypothalamic obesity cannot be successfully treated using methods successful in treating non-hypothalamic obesity. Applicant argues that treatment for non-hypothalamic obesity is different from treatment for hypothalamic obesity and treatments for non-hypothalamic obesity will not treat nonhypothalamic obesity.
Applicant further argues that Vath does not cure the deficiencies of either Hansen or Edsberg since Vath is merely cited for its general description of possible genetic mutations that can lead to hypothalamic obesity. Applicant argues that Vath suggests that hypothalamic obesity may be treated by administering methionine aminopeptidase 2 (MetAP-2) inhibitors, and nothing in the cited art suggests that Tesofensine is a MetAP-2 inhibitor. Applicant argues that given the mechanistic differences between Tesofensine and Vath's MetAP- 2 compounds, one would have had no reason to turn to the teachings of Vath for alternate uses for Tesofensine.
Applicant also argues that despite the well-known challenges associated with treating patients with hypothalamic obesity, the claimed methods surprisingly result in statistically significant reductions in bodyweight and fat mass in hypothalamic obesity subjects, while increasing lean tissue mass and Applicant received FDA Orphan Drug Designation for using tesofensine to treat hypothalamic obesity. Applicant argues that there are currently no FDA-approved medicines for hypothalamic obesity and Applicant's designation is the first and only investigational treatment for hypothalamic obesity to receive Orphan Drug Designation.
These arguments are found not persuasive since 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.
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.
With regard to Applicant’s arguments of surprising results, based on the prior art references cited above, it would not have been surprising or unexpected to treat hypothalamic obesity comprising the administration of tesofensine as claimed since as detailed above, Edsberg et al. teaches the treatment of obesity and in one embodiment, the subject is suffering from Prader Willi syndrome and obesity associated with Prader-Willi syndrome is due to hypothalamic dysregulation; and 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; and thus a person of ordinary skill in the art would expect tesofensine to restore normal homeostatic functioning of the hypothalamic centers to evoke satiety responses leading to the treatment or improvement in hypothalamic obesity.
It is Applicant’s burden to demonstrate unexpected results over the prior art. See MPEP 716.02, also 716.02 (a)-(g). Furthermore, the unexpected results should be demonstrated with evidence that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance. Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992). “Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof.” In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967) (resultant decrease of dental enamel solubility accomplished by adding an acidic buffering agent to a fluoride containing dentifrice was expected based on the teaching of the prior art); Ex parte Blanc, 13 USPQ2d 1383 (Bd. Pat. App. & Inter. 1989) (Claims at issue were directed to a process of sterilizing a polyolefinic composition which contains an antioxidant with high-energy radiation. Although evidence was presented in appellant’s specification showing that particular antioxidants are effective, the Board concluded that these beneficial results would have been expected because one of the references taught a claimed antioxidant is very efficient and provides better results compared with other prior art antioxidants.).
Thus, Applicant’s arguments are found not persuasive and therefore the previous rejections under 35 USC 103 are hereby maintained and detailed below with modifications necessary to address Applicant’s amendments to the claims.
With respect to the Double Patenting Rejections, Applicant argues that they have demonstrated that treatments for hypothalamic obesity cannot be predictably derived from treatments for non-hypothalamic obesity and Vath requires administering a MetAP-2 inhibitor, which Tesofensine is not. Thus Applicant argues that the claims are patentably distinct over each of the cited patents/application.
These arguments are found not persuasive for the same reasons as detailed above. Specifically claims 1-12 of patent No. 12,178,810 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. 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 patent No. 12,178,810 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.
The cited claims of patent No. 9,211,271 claim a method of treating obesity in general 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. Thus the claims of patent No. 9,211,271 claim treating all forms of obesity and do not claim treating only non-hypothalamic obesity as argued by Applicant.
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]. Thus since hypothalamic obesity is a form of obesity and the claims of the patent claim 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.
The claims of patent No. 9,387,184 B2 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.
Thus the claims of patent No. 9,387,184 B2 claim treating any obese human suffering an over-eating disorder, compulsive over-eating, or impaired appetite regulation, which necessarily includes a patient with hypothalamic obesity as taught by Vath (see teachings as described above). The claims of the patent do not claim treating only non-hypothalamic obesity as argued by Applicant.
Claims 1-13 of copending ‘912 claim 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. 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 hyperphagia associated with Prader-Willi syndrome is due to 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 overeating 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.
Thus Applicant’s argument that each of the patents or copending applications claim treating non-hypothalamic obesity is found not persuasive for these reasons.
Accordingly, the previous double patenting rejections are hereby maintained and detailed below with modifications necessary to address Applicant’s amendments to the claims.
New claims 56-60 are also being rejected on the same grounds. In addition, a new rejection under 35 USC 112(b) necessitated by Applicant’s amendments to the claims is detailed below
This action is made FINAL.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 59 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 59 of the instant application claims treating a subject wherein the subject has a fat mass of at least 3146 kg prior to treatment.
This claim is indefinite since it is unclear how any subject having hypothalamic obesity, presumably a human subject, can have a fat mass of at least 3146 kg since 3146 kg is equivalent to 6,921.2 pounds.
For the sake of compact prosecution, claim 59 is being interpreted as treating a subject wherein the subject has a fat mass of at least 31.46 kg (as taught on Table 8 on page 49 of the instant specification) prior to treatment and examined herewith.
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.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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/KARA R. MCMILLIAN/Primary Examiner, Art Unit 1623
KRM