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 .
Claim Rejections - 35 USC § 103
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 1, 36, 45, 75, 81, 82, 83, 84, 85, 86, 87, 88, 89, 91, 95, and 96 are rejected under 35 U.S.C. 103 as being unpatentable over Shang et al. (US20090068110A1, of record) hereinafter Shang, in view of Navaratnarajah et al (Navaratnarajah, Arunraj, and Stephen HD Jackson. "The physiology of ageing." Medicine 45.1 (2017): 6-10), hereinafter Navaratnarajah, Mendonca et al (Mendonca, Goncalo V., et al. "Impact of aging on endurance and neuromuscular physical performance: the role of vascular senescence." Sports medicine 47 (2017): 583-598.), hereinafter Mendonca, White et al (White, Mary C et al. “Age and cancer risk: a potentially modifiable relationship.” American journal of preventive medicine vol. 46,3 Suppl 1 (2014): S7-15. doi:10.1016/j.amepre.2013.10.029), hereinafter White, Purves et al (Purves D, Augustine GJ, Fitzpatrick D, et al., editors. Neuroscience. 2nd edition. Sunderland (MA): Sinauer Associates; 2001. Chapter 16, Lower Motor Neuron Circuits and Motor Control), hereinafter Purves, and Luratin (Lurati, Ann R. “Menopause and Exercise Intolerance.” Nursing for women's health vol. 21,2 (2017): 130-136. doi:10.1016/j.nwh.2017.02.002, of record), and Calzone et al, (US20150274829A1, of record), hereinafter Calzone.
Shang discloses a method for treating or preventing cancer, aging, or age-related disorders in a subject comprising administering an anti-IGF1R antibody that specifically binds to human IGF-1R and blocks the interaction of an insulin-like growth factor (IGF, including IGF-I and IGF-II) with IGF-1R and thus reduce IGF-1R signaling (Abstract, Para. 0069, Para. 0166, Para. 0255, and Para. 0584). Pharmaceutical compositions comprising the anti-IGF-1R antibodies and a pharmaceutically acceptable carrier, diluent, or excipient are also disclosed (Para. 0098 , 0099, 0101, 0108, and 0562). A second therapeutic agent can also be provided in combination with the anti-IGF-1R antibody (Para. 0091) such as the mTOR inhibitor rapamycin (Para. 104)The term “treatment” refers to clinical intervention designed to alter the natural course of the individual or cell being treated, and can be performed either for prophylaxis or during the course of clinical pathology (Para. 0255). Preferably, the anti-IGF-1R antibodies inhibit aging for at least a subpopulation of mature (post-puberty) adult subjects defined by sex (i.e. male or female) and/or age, wherein the mature adult subject can be at least 40 years of age in particular (Para. 0241-246). The subject to be treated is preferably human (Para. 0113). The subject in which aging is to be treated or prevented thus includes human female subjects that are at least 45 years of age per instant claim 97. The antibodies can be administered by intravenous or subcutaneous routes (Routes of Administration: Para. 0590). The antibodies can also be administered at a dosage and frequency that is within the skill and judgment of the practicing physician, depending on various factors. This frequency includes twice a week, three times a week, once a week, bi-weekly, or once a month. In a preferred aspect of this method, the antibody is administered no more than about once every other week, more preferably about once a month. The anti-IGF-1R-binding antibodies of the invention can be administered to the patient chronically or intermittently. For repeated administrations over several days or longer, depending on the condition, the treatment is sustained until a desired suppression of disease symptoms occurs (Dosage: Para. 0584-0589). A subject is successfully “treated” for aging, for example, if after receiving a therapeutic amount of an antibody of the invention, the subject shows observable and/or measurable reduction in or absence of one or more signs and symptoms of the particular disease (Para. 0255). The method of treating aging thus encompasses reducing one or more symptoms of aging.
Shang does not teach that the method of treating or preventing one or more symptoms of aging in an adult subject at least 40 years of age comprising administering an inhibitory anti-IGF-1R antibody or antigen-binding fragment specifically includes treatment or prevention of a physiological decline in cardiac function, motor function, muscle strength, exercise endurance and/or freedom from malignancy nor that the adult subject that is at least 40 years of age is a menopausal or postmenopausal female. Further, it is not taught that the inhibitory anti-IGF-1R antibody or antigen-binding fragment comprises the CDRs of SEQ ID NOs: 322-327 recited in the instant claims.
However, Navaratnarajah teaches that aging results in a progressive decline in cardiac function (attenuation in mechanical and contractile efficiency), muscle strength (sarcopenia), as well as reduction in the maximum amount of oxygen consumed per kg per minute and force of muscle contraction (see Abstract, Introduction, “The Cardiovascular System” section, and “The musculoskeletal system” section); and Purves teaches that motor neurons initiate muscle contraction (Overview). Per the instant specification, motor function is any activity or movement completed due to the use of motor neurons (Para. 0044). Thus, muscle contraction involves motor function; and an age-related decline in the force of muscle contraction can be considered a decline in motor function. Thus, aging is associated with a deterioration in muscle strength and motor function.
Mendonca further teaches that there is an age-related decline in exercise endurance (Abstract). Thus, aging is associated with a deterioration of exercise endurance
White further teaches that aging is associated with an increased risk of cancer especially beginning midlife when the prevalence of multiple cancer risk factors is high and incidence rates begin to increase for many types of cancer (Abstract). Thus, aging is associated with a deterioration in a freedom from malignancy.
Lurati further teaches that menopause typically begins in human females in their 40s ( see “Menopause” section). Thus, a female subject that is at least 40 years of age as taught by Shang includes menopausal/postmenopausal females.
Calzone further teaches an anti-IGF-1R antibody that binds to human IGF-1R and inhibits binding of IGF-1 and/or IGF-2 to said human IGF-1R having a variable light chain of SEQ ID NO: 104 (corresponding to SEQ ID NO: 304, which fully comprises the CDRs of SEQ ID NO: 322-324 of the instant claims) and a variable heavy chain of SEQ ID NO: 208 (corresponding to SEQ ID NO: 305, which fully comprises the CDRs of SEQ ID NOs: 325-327 of the instant claims) (Abstract, Figures 2B and 3B).
It would have been obvious to one of ordinary skill in the art to modify the method of treating one or more symptoms of aging in a female subject at least 40 years of age comprising administering an anti-IgF-1R antibody disclosed by Shang such that the one or more symptoms of aging includes a decline or deterioration of cardiac function, motor function, muscle strength, exercise endurance, freedom from malignancy, and/or elevated inflammatory markers; and the female subject at least 40 years of age is menopausal/postmenopausal. One of ordinary skill in the art would have been motivated to do so since a decline or deterioration in cardiac function, motor function, muscle strength, and exercise endurance as well as an increase in freedom from malignancy are symptoms of aging as taught by Navaratnarajah, Mendonca and White; and the anti-IGF-1R antibodies of Shang can be used to treat one or more symptoms of aging. Further, it would have been obvious to substitute the anti-IGF-1R antibody of Shang with that disclosed by Calzone. One of ordinary skill in the art would have since they have the same function and can be used for the same purpose. An express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213USPQ 532 (CCPA 1982). Therefore, one of ordinary skill in the art would expect that the anti-IGF-1R antibodies disclosed by Calzone can be used to effectively inhibit deterioration of the recited healthspan parameters and the healthspan in a menopausal/postmenopausal human female that is at least 40 years of age.
Claims 20 and 85 are rejected under 35 U.S.C. 103 as being unpatentable over Shang in view of Navaratnarajah, Purves, White, Lurati, and Calzone, as applied to claims 1, 36, 45, 75, 81, 82, 83, 84, 86, 87, 88, 89, 91, 95, and 96 above, and further in view of Singh et al (Singh, Tushar, and Anne B Newman. “Inflammatory markers in population studies of aging.” Ageing research reviews vol. 10,3 (2011): 319-29. doi:10.1016/j.arr.2010.11.002), hereinafter Singh.
The teachings of Shang in view Navaratnarajah, Purves, White, Lurati, and Calzone have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that in the method of treating or preventing one or more symptoms of aging that one or more symptoms includes elevated inflammatory mediators such as CRP.
However, Singh further teaches that aging and a decline in sex hormones are associated with elevated levels of IL-6, TNF-alpha and CRP (Abstract).
It would have been obvious to one of ordinary skill in the art to modify the method of treating one or more symptoms of aging in a female subject at least 40 years of age comprising administering an anti-IgF-1R antibody disclosed by Shang such that the one or more symptoms of aging includes an elevation in inflammatory markers such as IL-6, TNF-alpha, and CRP; and the female subject at least 40 years of age is menopausal/postmenopausal. One of ordinary skill in the art would have been motivated to do so since an elevation in inflammatory markers such as IL-6, TNF-alpha, and CRP as taught by Singh is a symptom of aging; and the anti-IGF-1R antibodies of Shang can be used to treat one or more symptoms of aging, wherein treatment includes reducing said symptoms. Further, it would have been obvious to substitute the anti-IGF-1R antibody of Shang with that disclosed by Calzone. One of ordinary skill in the art would have since they have the same function and can be used for the same purpose. An express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213USPQ 532 (CCPA 1982). Therefore, one of ordinary skill in the art would expect that the anti-IGF-1R antibodies disclosed by Calzone can be used to reduce an elevation in inflammatory markers such as IL-6, TNF-alpha, and CRP in a menopausal/postmenopausal human female that is at least 40 years of age.
Claims 37 and 38 are rejected under 35 U.S.C. 103 as being unpatentable over Shang in view of Navaratnarajah, Purves, White, Lurati, and Calzone, as applied to claims 1, 36, 45, 75, 81, 82, 83, 84, 86, 87, 88, 89, 91, 95, and 96 above, and further in view of Hoffman et al (Hoffman, Andrew R., et al. "Functional consequences of the somatopause and its treatment." Endocrine 7 (1997): 73-76), hereinafter Hoffman.
The teachings of Shang in view of Navaratnarajah, Purves, White, Lurati, and Calzone have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the human menopausal/postmenopausal female subject is experiencing an age-related decline in growth hormone or somatopause.
However, Hoffman teaches that the age-related decline in the function of the growth hormone-releasing hormone, growth hormone, insulin-like growth factor (GHRH-GH-IGF) axis has been termed the somatopause; and many of the catabolic sequelae seen in normal aging has been attributed to this decrease in circulating GH and IGF-I (Abstract).
It would have been obvious to one of ordinary skill in the art to modify the method of treating or preventing one or more symptoms of aging in a menopausal/postmenopausal female subject taught by Shang in view of Navaratnarajah, Singh, White, and Calzone such that the subject is also experiencing an age-related decline in growth hormone or somatopause. One of ordinary skill in the art would have been motivated to do so since a decline in growth hormone or somatopause is a symptom of aging; and the anti-IGF-1R antibodies can be used to treat symptoms of aging as taught by Shang. Therefore, one of ordinary skill in the art would reasonably expect that the method of treating or preventing one or more symptoms of aging in a menopausal/postmenopausal female subject taught by Shang in view of Navaratnarajah, Singh, White, and Calzone can also be applied to those menopausal/postmenopausal women experiencing an age-related decline in growth hormone or somatopause.
Claim 77 is rejected under 35 U.S.C. 103 as being unpatentable over Shang in view of Navaratnarajah, Purves, Singh, White, Lurati, and Calzone, as applied to claims 1, 36, 45, 75, 81, 82, 83, 84, 86, 87, 88, 89, 91, 95, and 96 above, and further in view of Lobo (Lobo, R A. “Benefits and risks of estrogen replacement therapy.” American journal of obstetrics and gynecology vol. 173,3 Pt 2 (1995): 982-9. doi:10.1016/0002-9378(95)90247-3)
The teachings of Shang in view of Navaratnarajah, Singh, White, and Calzone have been discussed above and differ from the instantly claimed invention in that further administration of estrogen replacement therapy is not specifically taught.
However, Lobo teaches that estrogen replacement therapy (ERT) can reduce the risk of cardiovascular disease and osteoporosis in postmenopausal women and provide relief for changes associated with menopause such as hot flashes. Further, ERT reduces overall morbidity and mortality (Abstract, “Benefits of Estrogen”, and “Where we are today” sections).
It would have been obvious to one of ordinary skill in the art to modify the method of treating or preventing one or more symptoms of aging in a menopausal/postmenopausal female subject taught by Shang in view of Navaratnarajah, Singh, White, and Calzone such that the subject further receives estrogen replacement therapy (ERT). One of ordinary skill in the art would have been motivated to do so since ERT can reduce the risk of cardiovascular disease and osteoporosis in postmenopausal women, provide relief for changes associated with menopause such as hot flashes, and reduce overall morbidity and mortality. Therefore, one of ordinary skill in the art would reasonably expect that further administration of ERT can help treat or prevent one or more symptoms of aging in a menopausal/postmenopausal female subject.
Claim 92 is rejected under 35 U.S.C. 103 as being unpatentable over Shang in view of Navaratnarajah, Singh, White, and Calzone, as applied to claims 1, 36, 45, 75, 81, 82, 83, 84, 86, 87, 88, 89, 91, 95, and 96 above, and further in view of Goldman et al (Goldman, Jonathan W et al. “Hyperglycemia Associated With Targeted Oncologic Treatment: Mechanisms and Management.” The oncologist vol. 21,11 (2016): 1326-1336. doi:10.1634/theoncologist.2015-0519, of record), hereinafter Goldman.
The teachings of the Shang in view of Navaratnarajah, Singh, White, and Calzone, have been discussed above and differ from the instantly claimed invention in that administering IGF-1R antibody at a dose that does not elevate blood glucose more than 10% is not specifically taught.
However, Goldman teaches that IGF-1R inhibitors/antibodies can increase the incidence of hyperglycemia in a dose-dependent manner. Indeed, the incidence of hyperglycemia for anti-IGF-1R antibody ranged from 10% to 100% (any grade) and from 0% to 46% (grade 3). As such, during treatment with anti-IGF-1R inhibitors patients can be monitored for hyperglycemia (with fasting and/or postprandial blood-glucose levels and periodic hemoglobin A1c testing) and for insulin resistance (with insulin levels). Mild treatment-related hyperglycemia may be sufficiently managed through modifications in diet and exercise. Management of grade 3 and 4 hyperglycemia may involve dose reductions and/or the use of oral antihyperglycemic agents. In many studies, dose reductions and use of antihyperglycemic agents were sufficient to manage hyperglycemia (see Abstract, “IGF-1R specific monoclonal antibodies” and “Screening, Monitoring, and Management” sections).
It would have been obvious to one of ordinary skill in the art to modify the dose of anti-IGF-1R antibodies administered to a menopausal/post-menopausal female to ensure that blood glucose levels do not elevate more than 10%. One of ordinary skill in the art would have been motivated to do so since IGF-1R inhibitors/antibodies can increase the incidence of hyperglycemia in a dose-dependent manner; and dose reductions can help manage blood glucose levels. Further, the courts have stated "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); thus, it would have been prima facie obvious to one of ordinary skill in the art to determine by routine experimentation the optimum dose of anti-IGF-1R antibodies administered ensure blood glucose levels do not elevate more than 10%. Therefore, one would expect that reducing the dosage of the anti-IGF-1R antibody administered can effectively mitigate elevations in blood glucose.
Claim 93 is rejected under 35 U.S.C. 103 as being unpatentable over Shang in view of Navaratnarajah, Singh, White, and Calzone, as applied to claims 1, 36, 45, 75, 81, 82, 83, 84, 86, 87, 88, 89, 91, 95, and 96 above, and further in view of Tolcher et al (Tolcher, Anthony W., et al. "Phase I, pharmacokinetic, and pharmacodynamic study of AMG 479, a fully human monoclonal antibody to insulin-like growth factor receptor." Clin Oncol 25 (2007): 1390.), hereinafter Tolcher, and Salahudeen et al (Salahudeen, Mohammed Saji, and Prasad S Nishtala. “An overview of pharmacodynamic modelling, ligand-binding approach and its application in clinical practice.” Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society vol. 25,2 (2017): 165-175. doi:10.1016/j.jsps.2016.07.002), hereinafter Salahudeen).
The teachings of the Shang in view of Navaratnarajah, Singh, White, and Calzone, have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the anti-IGF-1R antibody is administered in an amount and for a duration effective to increase serum IGF-1 in the subject, compared to a measurement taken prior to the administration, by 10% to 40%.
However, Tolcher teaches that an anti-IGF-1R antibody that binds to IGF-1R and inhibits the binding of IGF-1 and IGF-2 (a similar mechanism of action as the anti-IGF-1R antibody of the instant claims) administered at an initial dose (20 mg/kg) increases serum IGF-1 in patients above baseline levels; and levels of IGF-1 remained relatively constant and significantly higher than baseline levels after subsequent doses, suggesting that that the magnitude of receptor occupancy at 20 mg/kg of the anti-IGF-1R antibody was sufficient to generate significant and durable impact on receptor binding of ligand (see Introduction: Paragraph 2; “Pharmacodynamic Analysis” section and Figure 1; and Discussion, Paragraphs 4-5).
Salahudeen further teaches that with respect to pharmacodynamics, in classical receptor theory, a drug binds to a receptor reversibly, which then provokes a series of biochemical and physiological changes to produce the observed drug effect. The maximum drug effect is achieved once all the receptors are occupied (Section 3.1, 2nd paragraph).
It would have been obvious to one of ordinary skill in the art to modify the method of treating or preventing one or more symptoms of aging in a menopausal/postmenopausal female subject with an anti-IGF-1R antibody taught by Shang in view of Navaratnarajah, Singh, White, and Calzone such that the anti-IGF-1R antibody is administered at an amount and for a duration of time effective to increase serum IGF-1 in the subject by 10 to 40% from baseline. One of ordinary skill in the art would have been motivated to do so since the increase in serum IGF-1 levels indicates an increase in receptor occupancy of the anti-IGF-1R antibody and thus an increase in maximum biologic effect of the anti-IGF-1R antibody. Further, the courts have stated "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); thus, it would have been prima facie obvious to one of ordinary skill in the art to determine by routine experimentation the optimum dose or duration of time for the anti-IGF-1R antibody to be administered in order to effectively increase serum IGF-1 levels by 10 to 40% from baseline. Therefore, one would expect that the dose and duration of time the anti-IGF-1R antibody administered can be adjusted to increase receptor occupancy (which will lead to an increase serum IGF-1 levels from baseline) and thus increase the maximum biologic effect of the anti-IGF-1R antibody.
Claims 97 and 100-102 are rejected under 35 U.S.C. 103 as being unpatentable over Shang et al. (US20090068110A1, of record) hereinafter Shang, in view of Calzone et al, (US20150274829A1, of record), hereinafter Calzone, and Navaratnarajah et al (Navaratnarajah, Arunraj, and Stephen HD Jackson. "The physiology of ageing." Medicine 45.1 (2017): 6-10.), hereinafter Navaratnarajah.
Shang discloses a method for treating or preventing cancer, aging, or age-related disorders in a subject comprising administering an anti-IGF1R antibody that specifically binds to human IGF-1R and blocks the interaction of an insulin-like growth factor (IGF, including IGF-I and IGF-II) with IGF-1R and thus reduce IGF-1R signaling (Abstract, Para. 0069, Para. 0166, Para. 0255, and Para. 0584). Pharmaceutical compositions comprising the anti-IGF-1R antibodies and a pharmaceutically acceptable carrier, diluent, or excipient are also disclosed (Para. 0098 , 0099, 0101, 0108, and 0562). A second therapeutic agent can also be provided in combination with the anti-IGF-1R antibody (Para. 0091). The term “treatment” refers to clinical intervention designed to alter the natural course of the individual or cell being treated, and can be performed either for prophylaxis or during the course of clinical pathology (Para. 0255). Preferably, the anti-IGF-1R antibodies inhibit aging for at least a subpopulation of mature (post-puberty) adult subjects defined by sex (i.e. male or female) and/or age, wherein the mature adult subject can be at least 40 years of age in particular (Para. 0241-246). The subject to be treated is preferably human (Para. 0113). The subject in which aging is to be treated or prevented thus includes human female subjects that are at least 45 years of age per instant claim 97. The antibodies can be administered by intravenous or subcutaneous routes (Routes of Administration: Para. 0590). The antibodies can also be administered at a dosage and frequency that is within the skill and judgment of the practicing physician, depending on various factors. This frequency includes twice a week, three times a week, once a week, bi-weekly, or once a month. In a preferred aspect of this method, the antibody is administered no more than about once every other week, more preferably about once a month. The anti-IGF-1R-binding antibodies of the invention can be administered to the patient chronically or intermittently. For repeated administrations over several days or longer, depending on the condition, the treatment is sustained until a desired suppression of disease symptoms occurs (Dosage: Para. 0584-0589). Chronic administration is continuous so as to maintain the initial therapeutic effect (activity) of a medicament for an extended period of time (Para. 0286). The progress of this therapy is easily monitored by conventional techniques and assay (Para. 0585); and the parameters for assessing efficacy or success of treatment of a disorder will be known to the physician of skill in the appropriate disease. Generally, the physician of skill will look for reduction in the signs and symptoms of the specific disease (Para. 0551). A subject is successfully “treated” for aging, for example, if after receiving a therapeutic amount of an antibody of the invention, the subject shows observable and/or measurable reduction in or absence of one or more signs and symptoms of the particular disease (Para. 0255). The method of treating aging thus encompasses reducing one or more symptoms of aging. An example of determining the efficacy of anti-IGF-1R treatment on clinical aging by measuring parameters of muscle strength and exercise capacity at baseline and during follow-up is presented in Example 11, Para. 0781. Specifically, in a treadmill exercise test, a standard Bruce protocol with the addition of a “stage 0” consisting of three minutes at a speed of one mile per hour with a 5% gradient is used. Exercise time and oxygen consumption at peak exercise adjusted for total body weight (peak VO2 in ml/kg/min) are measured as an index of the exercise capacity (Para. 0785). In a test of muscle strength, the maximum force that a muscle group (e.g. quadriceps) can produce against a resistance (e.g. elastic bands) is measured (Para. 0786). The anti-IGF-1R antibody treatment is expected to improve overall muscle performance. In order to determine that overall muscle performance is improved in a clinical aging study, the baseline (pre-treatment) and follow-up (post-treatment) values in the subjects would necessarily have to be compared. Further, as stated above, anti-IGF-1R antibody treatment can be sustained until a desired suppression of one or more symptoms of aging occurs or to maintain initial therapeutic effect (activity) for an extended period of time with chronic administration. As such, a practitioner can continue the anti-IGF-1R antibody treatment until inhibition of one or more symptoms of aging occurs in the subject or to maintain an initial therapeutic effect of the anti-IGF-1R antibody.
Shang does not teach that the method of treating or preventing one or more symptoms of aging in an adult subject at least 40 years of age comprising administering an inhibitory anti-IGF-1R antibody or antigen-binding fragment specifically includes treatment or prevention of a physiological decline in cardiac function, motor function, muscle strength, and/or exercise endurance nor that the inhibitory anti-IGF-1R antibody or antigen-binding fragment comprises the CDRs of SEQ ID NOs: 322-327 recited in the instant claims.
However, Navaratnarajah teaches that aging results in a progressive decline in cardiac function (attenuation in mechanical and contractile efficiency), muscle strength (sarcopenia), and motor function (reduction in the maximum amount of oxygen consumed per kg per minute and force of muscle contraction) (see entire document, in particular, Abstract, Introduction, “The Cardiovascular System” section, and “The musculoskeletal system” section).
Calzone further teaches an anti-IGF-1R antibody that binds to human IGF-1R and inhibits binding of IGF-1 and/or IGF-2 to said human IGF-1R having a variable light chain of SEQ ID NO: 104, which fully comprises the CDRs of SEQ ID NO: 322-324 of the instant claims, and a variable heavy chain of SEQ ID NO: 208, which fully comprises the CDRs of SEQ ID NOs: 325-327 of the instant claims (Abstract, Figures 2B and 3B).
It would have been obvious to one of ordinary skill in the art to modify the method of treating one or more symptoms of aging in a subject comprising administering an anti-IgF-1R antibody disclosed by Shang, wherein exercise capacity is measured at baseline and follow-up and the values compared to determine that inhibition of motor function deterioration in response to anti-IGF1R antibody treatment has occurred. One of ordinary skill in the art would have been motivated to do so since a decline or deterioration in motor function is one symptom of aging; and exercise capacity-a parameter of motor function per the instant claims-can be used to determine the impact of an intervention on motor function. In particular, artisans can adapt the method of Example 11 disclosed by Shang to assess motor function/muscle performance by measuring exercise capacity at baseline and after treatment with the anti-IGF-1R antibody to determine if said treatment is effective in improving muscle performance (or inhibiting deterioration of a motor function) in a female subject that is at least 40 years of age by comparing baseline and follow-up values after treatment. Further, it would have been obvious to substitute the anti-IGF-1R antibody of Shang with that disclosed by Calzone. One of ordinary skill in the art would have since they have the same function and can be used for the same purpose. An express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213USPQ 532 (CCPA 1982). Therefore, one of ordinary skill in the art would expect that the anti-IGF-1R antibodies disclosed by Calzone can be used to effectively inhibit deterioration of a motor function as assessed, for example, by exercise capacity, in a female human subject that is at least 40 years of age.
Claim 98 is rejected under 35 U.S.C. 103 as being unpatentable over Shang in view of Calzone, as applied to claims 97 and 100-102 above, and further in view of Goldman et al (Goldman, Jonathan W et al. “Hyperglycemia Associated With Targeted Oncologic Treatment: Mechanisms and Management.” The oncologist vol. 21,11 (2016): 1326-1336. doi:10.1634/theoncologist.2015-0519, of record), hereinafter Goldman.
The teachings of the Shang in view of Calzone have been discussed above and differ from the instantly claimed invention in that administering IGF-1R antibody at a dose that does not elevate blood glucose more than 10% is not specifically taught.
However, Goldman teaches that IGF-1R inhibitors/antibodies can increase the incidence of hyperglycemia in a dose-dependent manner. Indeed, the incidence of hyperglycemia for anti-IGF-1R antibody ranged from 10% to 100% (any grade) and from 0% to 46% (grade 3). As such, during treatment with anti-IGF-1R inhibitors patients can be monitored for hyperglycemia (with fasting and/or postprandial blood-glucose levels and periodic hemoglobin A1c testing) and for insulin resistance (with insulin levels). Mild treatment-related hyperglycemia may be sufficiently managed through modifications in diet and exercise. Management of grade 3 and 4 hyperglycemia may involve dose reductions and/or the use of oral antihyperglycemic agents. In many studies, dose reductions and use of antihyperglycemic agents were sufficient to manage hyperglycemia (see Abstract, “IGF-1R specific monoclonal antibodies” and “Screening, Monitoring, and Management” sections).
It would have been obvious to one of ordinary skill in the art to modify the dose of anti-IGF-1R antibodies administered to a human female that is at least 40 years of age to ensure that blood glucose levels do not elevate more than 10%. One of ordinary skill in the art would have been motivated to do so since IGF-1R inhibitors/antibodies can increase the incidence of hyperglycemia in a dose-dependent manner; and dose reductions can help manage blood glucose levels. Further, the courts have stated "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); thus, it would have been prima facie obvious to one of ordinary skill in the art to determine by routine experimentation the optimum dose of anti-IGF-1R antibodies administered ensure blood glucose levels do not elevate more than 10%. Therefore, one would expect that reducing the dosage of the anti-IGF-1R antibody administered can effectively mitigate elevations in blood glucose.
Claim 93 is rejected under 35 U.S.C. 103 as being unpatentable over Shang in view of Navaratnarajah, Singh, White, and Calzone, as applied to claims 97 and 100-102 above, and further in view of Tolcher et al (Tolcher, Anthony W., et al. "Phase I, pharmacokinetic, and pharmacodynamic study of AMG 479, a fully human monoclonal antibody to insulin-like growth factor receptor." Clin Oncol 25 (2007): 1390.), hereinafter Tolcher, and Salahudeen et al (Salahudeen, Mohammed Saji, and Prasad S Nishtala. “An overview of pharmacodynamic modelling, ligand-binding approach and its application in clinical practice.” Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society vol. 25,2 (2017): 165-175. doi:10.1016/j.jsps.2016.07.002), hereinafter Salahudeen).
The teachings of the Shang in view of Navaratnarajah, Singh, White, and Calzone, have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the anti-IGF-1R antibody is administered in an amount and for a duration effective to increase serum IGF-1 in the subject, compared to a measurement taken prior to the administration, by 10% to 40%.
However, Tolcher teaches that an anti-IGF-1R antibody that binds to IGF-1R and inhibits the binding of IGF-1 and IGF-2 (a similar mechanism of action as the anti-IGF-1R antibody of the instant claims) administered at an initial dose (20 mg/kg) increases serum IGF-1 in patients above baseline levels; and levels of IGF-1 remained relatively constant and significantly higher than baseline levels after subsequent doses, suggesting that that the magnitude of receptor occupancy at 20 mg/kg of the anti-IGF-1R antibody was sufficient to generate significant and durable impact on receptor binding of ligand (see Introduction: Paragraph 2; “Pharmacodynamic Analysis” section and Figure 1; and Discussion, Paragraphs 4-5).
Salahudeen further teaches that with respect to pharmacodynamics, in classical receptor theory, a drug binds to a receptor reversibly, which then provokes a series of biochemical and physiological changes to produce the observed drug effect. The maximum drug effect is achieved once all the receptors are occupied (Section 3.1, 2nd paragraph).
It would have been obvious to one of ordinary skill in the art to modify the method of treating or preventing one or more symptoms of a female human subject that is at least 40 years old with an anti-IGF-1R antibody taught by Shang in view of Calzone such that the anti-IGF-1R antibody is administered at an amount and for a duration of time effective to increase serum IGF-1 in the subject by 10 to 40% from baseline. One of ordinary skill in the art would have been motivated to do so since the increase in serum IGF-1 levels indicates an increase in receptor occupancy of the anti-IGF-1R antibody and thus an increase in maximum biologic effect of the anti-IGF-1R antibody. Further, the courts have stated "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); thus, it would have been prima facie obvious to one of ordinary skill in the art to determine by routine experimentation the optimum dose or duration of time for the anti-IGF-1R antibody to be administered in order to effectively increase serum IGF-1 levels by 10 to 40% from baseline. Therefore, one would expect that the dose and duration of time the anti-IGF-1R antibody administered can be adjusted to increase receptor occupancy (which will lead to an increase serum IGF-1 levels from baseline) and thus increase the maximum biologic effect of the anti-IGF-1R antibody.
Claim 103 is rejected under 35 U.S.C. 103 as being unpatentable over Shang in view of Calzone, as applied to claims 97 and 100-102 above, and further in view of LeBrasseur et al (LeBrasseur, Nathan K., et al. "Myostatin inhibition enhances the effects of exercise on performance and metabolic outcomes in aged mice." Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences 64.9 (2009): 940-948), hereinafter LeBrasseur.
The teachings of the Shang in view of Calzone have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the second therapeutic agent administered in combination with the anti-IGF-1R antibody to treat aging is a myostatin inhibitor.
However, LeBrasseur teaches that myostatin is a negative regulatory of muscle mass, leading to extreme muscle wasting; and neutralizing antibodies to myostatin (i.e. myostatin inhibitors) can increase muscle mass and improve measures of muscle performance, including grip strength and absolute twitch and tetanic force in subject. As such, myostatin blockade can provide an effective strategy to enhance muscle mass, physical function, and metabolism in aged mammals (Abstract and Introduction).
It would have been obvious to one of ordinary skill in the art to modify the method of treating or preventing aging -in particular a deterioration in muscle performance/motor function- in a female subject that is at least 40 years of age such that the second therapeutic agent administered in combination with the anti-IGF-1R antibody is a myostatin inhibitor. One of ordinary skill in the art would have been motivated to do so since myostatin inhibitors can enhance muscle mass, physical function, and metabolism in aged mammals. Therefore, one would expect that administering the anti-IGF-1R antibody in combination with a myostatin inhibitor can effectively inhibit deterioration of motor function in a human female subject that is at least 40 years of age.
Claim 104 is rejected under 35 U.S.C. 103 as being unpatentable over Shang in view of Calzone, as applied to claims 97 and 100-102 above, and further in view of Platt et al (Platt, Colin et al. “Using exercise to measure and modify cardiac function.” Cell metabolism vol. 21,2 (2015): 227-236. doi:10.1016/j.cmet.2015.01.014), hereinafter Platt.
The teachings of the Shang in view of Calzone have been discussed above and differ from the instantly claimed invention in that it is not specifically taught the method of treating one or more symptoms of aging includes a deterioration of at least one cardiac function, wherein the pre and post-treatment values of at least one cardiac function is measured and compared to determine that deterioration of at least one cardiac function is inhibited by anti-IGF-1R antibody treatment.
However, Platt teaches the cardiac response to exercise is a critical functional metric by which to gauge the end result of any cardiac intervention. The essence of the cardiac response to exercise is an increase in cardiac output elicited by an increase in workload (exercise-cardiac output); and exercise capacity can be used to assess cardiac output (“Acute exercise as a cardiovascular phenotyping tool” section, first two paragraphs). While the actual measure of exercise capacity is typically expressed either in terms of total work performed (Joules), peak power achieved (Joules/sec =Watts), or peak oxygen consumption (ml O2/min), surrogates of workload such as total distance traveled or total time on the treadmill can also be used (“Exercise capacity metrics” section). Thus, the method of using exercise time/capacity to assess a parameter of clinical aging taught by Shang can also be used to determine inhibition of a deterioration cardiac function in response to anti-IGF1R antibody treatment, wherein a baseline and follow-up measurements are taken and compared to determine if the parameter of clinical aging has been improved.
It would have been obvious to one of ordinary skill in the art to modify the method of treating one or more symptoms of aging in a subject comprising administering an anti-IgF-1R antibody disclosed by Shang, wherein exercise capacity is measured at baseline and follow-up and the values compared to further determine that inhibition of cardiac function deterioration in response to anti-IGF1R antibody treatment has occurred. One of ordinary skill in the art would have been motivated to do so since a decline or deterioration in cardiac function is one symptom of aging as taught by Navaratnarajah; and exercise capacity can be used to determine the impact of an intervention on cardiac function. Therefore, one would expect that exercise capacity can be measured at baseline and follow-up and the values compared to further determine that inhibition of cardiac function deterioration in response to anti-IGF1R antibody treatment has occurred.in a human female subject that is at least 40 years of age.
Response to Arguments
Applicant's arguments filed 12/01/2025 have been fully considered but they are not persuasive.
With respect to the rejections made under 35 USC 103, Applicant continues to argue the following:
Shang lacks any evidence that IFG-1R inhibition will improve healthspan in a healthy menopausal or post-menopausal female subject as presently claimed, or in females over 45 years old. In particular, Examples 1-8 of Shang pertain to antibody production and characterization, including anti-cancer properties, providing no data relevant to either aging or healthspan in healthy menopausal or post-menopausal female subjects who are free of cancer. Examples 9–11 are prophetic study proposals that provide no supporting data and do not meaningfully inform the claimed subject matter. Example 9 proposes studying aging in genetic mutant mouse strains modeling severe diseases, which does not establish relevance to normal aging. Example 10 proposes a 12-week study in military recruits, a population typically composed of younger individuals undergoing intensive training, and thus would not generate evidence relevant to healthy menopausal or postmenopausal females or women over 45. The study design also does not analyze such individuals as a subgroup and could only assess potential effects during short-term military training; moreover, published evidence suggests IGF-1R inhibition may be detrimental in younger subjects. Example 11 proposes a clinical study in cachectic patients with serious conditions such as congestive heart failure or muscle myopathy, a population likewise not representative of healthy menopausal or postmenopausal women. Accordingly, none of these examples would provide a reasonable expectation for success regarding the benefits of IGF1R inhibition in healthy menopausal or postmenopausal females.
There are deficiencies in the Office’s premise for there being a reasonable expectation of success. First, the fact that measures of healthspan decline with age is identification of an unmet need in healthcare, not evidence that any particular therapeutic intervention will be beneficial. Second, Shang's background focuses the involvement of IGF-1R in cancer; IGF-1/IGF-1R molecular biology and pathways; pathologies besides cancer, such as acromegaly and gigantism, atherosclerosis, and restenosis, diabetes, and psoriasis; and on IGF-1R antibodies. Even if it were known that the IGF-1/IGF-1R signaling pathway "played an integral role" in aging and age-related disorders, such knowledge does not answer the question of the effect that would be achieved from inhibiting the pathway in menopausal/postmenopausal women. Third, the fact that IGF-1R antibodies bind IGF-1R and reduce IGF-1R signaling is not evidence of the function/effects that such antibodies will have in vivo.
Shang fails to enable treatment relating to healthspan. The Office's position during examination has been that not all anti-IGF-1R inhibitory antibodies will yield therapeutic benefit. Thus, in the absence of any evidence in Shang (or the cited secondary references) that Shang's antibodies will have a healthspan benefit, the Office must reach a conclusion that no reasonable expectation of success existed from Shang with respect to providing a healthspan benefit and that Shang is non-enabling. Further, as noted in the present application, a benefit for male subjects was largely not observed in Applicants' experiments, and in fact, some of the experiments indicated a possible adverse effect in males. (Males would likely have formed a substantial percentage of subjects drawn from military recruits.) No basis existed in Shang for arriving at the present invention of treating healthy menopausal or post-menopausal human female, or for concluding that such treatment had a reasonable expectation of success.
All of the secondary references are devoid of any evidence contributing to a reasonable expectation of success that an antibody that binds to IGF-1 R will have a beneficial effect on healthspan parameters in a healthy menopausal or post-menopausal human female. The Office has identified references characterizing changes associated with aging generally, or menopause specifically, but not references that provide evidence of the effect of an anti-IGF-1 R antibody in a healthy menopausal subject.
Unexpected results: When normal, treatment-naïve mature female mice were given an IGF-1R inhibitor, Applicants observed profound beneficial effects across a spectrum of healthspan parameters, including exercise tolerance, grip strength, balance, diastolic function, and inflammatory markers. These striking results could not have been predicted from the prior art of record which lacked evidence of efficacy relevant to healthspan and which failed to identify the subpopulation of subjects expected to benefit from the treatment. The broad spectrum of improvements achieved by the Applicants in non-diseased female animals is unexpected.
In response to Applicant’s arguments, the Examiner reiterates that a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971) (see MPEP 2123). Thus, the teachings of Shang are not limited to the prophetic examples disclosed therein. Shang discloses a method for treating or preventing cancer, aging, or age-related disorders in a subject comprising administering an anti-IGF1R antibody that specifically binds to human IGF-1R and reduces IGF-1R signaling, wherein the subject includes human female subjects at least 40 years of age. Shang broadly discloses anti-IGF-1R antibodies that specifically bind to human IGF-1R and blocks the interaction of an insulin-like growth factor (IGF, including IGF-I and IGF-II) with IGF-1R to reduce IGF-1R signaling. Thus, the anti-IGF-1R antibodies disclosed by Shang reasonably encompass L2-Cmu antibody recited in the instant claims and known in the art to reduce IGF-1R signaling.
Given the following evidence:
1) there is an age-related decline or deterioration in various healthspan parameters such as cardiac function and motor function;
2) the IGF-1/IGF-1R signaling pathway plays an integral role in aging and age-related disorders (see Background of the Instant Specification) (the Examiner in the present or previous response was not referencing the background of Shang as Applicant asserts); and
3) the anti-IGF-1R antibodies disclosed by Shang bind to human IGF-1R and reduce IGF-1R signaling;
there is a reasonable expectation of success that the IGF-1R antibodies which specifically bind to human IGF-1R and reduce IGF-1R signaling disclosed by Shang can effectively inhibit deterioration of at least one healthspan parameter in aging human females. Thus, it would be neither surprising nor unexpected for an anti-IGF-1R inhibitory antibody to prevent an age-related decline or deterioration in the healthspan parameter of an aging female contrary to Applicant’s assertion.
The prior statement that “not all anti-IGF-1R inhibitory antibodies will be therapeutically beneficial” was made in the context of whether the specification provided adequate written description support for the genus of anti-IGF1R antibodies defined primarily by function. Prior to amendments made on March 8th 2025, the independent claim was directed to an antibody that binds to IGF-1R (or more specifically to the extracellular domain of IGF-1R per the amendments on 07/24/2023) and reduces IGF-1R signaling. The dependent claims further limited the functional activity to targeting the L2 domain of the alpha subunit of human IGF-1R and blocking both IGF1 and IGF2 binding. While the specification discloses several antibodies that target the IGF-1R pathway, such disclosure did not adequately represent the structural diversity of the claimed genus of antibodies having the functional properties recited at the time.
As previously explained, anti-IGF-1R antibodies can bind different epitopes and exhibit distinct biological activities: some block both IGF-1 and IGF-2, others only affect one ligand, and some bind the receptor without substantially inhibiting ligand-mediated signaling. The specification does not provide evidence that all anti-IGF-1R antibodies that were encompassed by the scope of the prior claims possessed all of the recited functional properties (e.g. binding the L2 domain of the alpha subunit of human IGF-1R, blocking both IGF-1 and IGF-2 binding, and inhibiting IGF-1R signaling) or could achieve the claimed therapeutic effects (i.e. preventing age-related decline in healthspan parameters).
Although the heterogeneity in anti-IGF-1R antibodies raised a written description issue with respect to the prior claims; it does not preclude a reasonable expectation of success for antibodies known to bind to IGF-1R and inhibit IGF-1R signaling in the treatment or prevention of aging or aging-related disorders as taught by the prior art. Even if other inhibitory antibodies, such as figitumumab (previously referenced in the Office Action of 09/288/2024), were not effective in cancer therapy, artisans would still reasonably expect L2-Cmu to produce the claimed effect in aging, because the prior art links IGF-1R inhibition to aging-related pathways. The fact that some antibodies may be less effective does not negate a reasonable expectation of success. Moreover, it is noted that obviousness does not require absolute predictability or conclusive proof of efficacy (MPEP 2143.02).
Further, a substantial body of prior art evidence discussed in the background of the instant specification as well as previously referenced in the Remarks of 07/24/2023 (see Pages 13-15), supports the role of IGF-1/IGF-1R signaling in aging and longevity. Reduced IGF-1 signaling has been shown to extend lifespan in multiple model organisms, particularly females. In humans, individuals with functional IGF-1R mutations resulting in partial IGF-1 resistance or with naturally low IGF-1 levels exhibit increased longevity, particularly women, and higher IGF-1 levels are associated with increased cancer risk. While much of this evidence arises from genetic models, these findings would have reasonably suggested to artisans that pharmacologic intervention of IGF-1R signaling could produce beneficial effects on physiological parameters associated with aging. These physiological parameters associated with aging were discussed in secondary references. As such, artisans would reasonably expect that the anti-IG1R antibody L2-Cmu that inhibits IGF-1R signaling to prevent an age-related decline or deterioration in the healthspan parameter of an aging female.
Therefore, the rejection under 35 USC 103 is maintained.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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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/LIA E TAYLOR/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641