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 .
1. Claims 1 – 12, 21, 28 – 29, 31, 33, 46, 48, 50, and 51 remain pending and are under consideration.
Withdrawn Claim Rejections
2. The rejection of claims 47, 49, and 51 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is rendered moot in view of Applicant’s cancellation of these claims.
3. The rejection of claim 47 under 35 U.S.C. 103 is rendered moot in view of Applicant’s cancellation of the claim.
4. The rejection of claim 49 under 35 U.S.C. 103 is rendered moot in view of Applicant’s cancellation of the claim.
5. The rejection of claim 51 under 35 U.S.C. 103 is rendered moot in view of Applicant’s cancellation of the claim.
6. The provisional rejection of claims 47, 49, and 51 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 4, 6, 8 – 13, and 20 – 21, of copending Application No. 17603646 (reference application) is rendered moot in view of Applicant’s cancellation of these claims.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
7. Claim(s) 1 – 9, 46, and 52 remain rejected under 35 U.S.C. 103 as being unpatentable over Cowan (WO-2017124037-A1; previously cited), hereinafter Cowan as evidenced by Guazzi (Guazzi, Marco, et. al. Circulation 126.8 (2012): 975-990; previously cited), hereinafter Guazzi and Chahine (Chahine J, et. al. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan; previously cited), hereinafter Chahine, in view of Gaile (Galie, Nazzareno, et al. European heart journal 30.20 (2009): 2493-2537; previously cited), hereinafter Gaile in view of Otterstad (Otterstad, J. E. European heart journal 14.suppl_F (1993): 2-6; previously cited), hereinafter Otterstad.
Regarding claims 1 and 6, Cowan teaches a method comprising administering a composition comprising isolated mitochondria to a subject where the subject has an ischemia-related disease (claim 1) where the composition can be injected into a blood vessel (claim 6) (page 3, lines 1 – 2; page 6, lines 28 – 32; page 7, lines 1 – 5; page 57, lines 13 – 16; page 58, lines 6 – 9; Table 1). Cowan teaches administering mitochondria to a subject placed on ECMO due to surgical complications of coronary insufficiency and that mitochondria were injected into the area of hypokinesis (page 56, lines 23 – 30). Cowan teaches administering mitochondria to a patient with severe LV dysfunction (page 57, 13 – 32). However, Cowan does not teach these patients have heart hypertrophy or pulmonary hypertension. Pulmonary hypertension due to left heart disease, classified as group 2, is believed to be the most common cause of pulmonary hypertension and is associated with high morbidity and mortality as evidenced by Guazzi (page 975, left col. para. 1 and 3; page 981, right col. last para.; page 982, left col. para. 4). Chronic or poorly controlled hypertension causes increased cardiac workload, which can lead to hypertrophy of the left ventricle and initially this hypertrophy serves as a compensatory mechanism, but long-term can lead to decreased left ventricular output as evidenced by Chahine (page 2, para. 2).
Regarding claim 2, Cowan teaches injection of mitochondria into the myocardium (page 56, lines 30 – 31).
Regarding claim 3, Cowan teaches the subject is on ECMO (“has or is at risk of developing heart failure”) and after multiple injections of mitochondria, the subject could tolerate an ECMO wean trial where the subject displayed vigorous RV function and good LV function but was unable to tolerate a full clamping of the circuit (page 57, lines 1 – 9). Cowan teaches administration of mitochondria to another subject with moderately depressed right ventricular function (“has or is at risk of” “right ventricular failure (RVF)”) (page 57, lines 13 – 20).
Regarding claims 4 and 5, Cowan teaches administration of mitochondria to another subject that has VACTERL syndrome with pulmonary stenosis (claim 4) with diminished right pulmonary artery blood flow and ventricular function varying between normal and moderately depressed (claim 5) (page 57, lines 13 – 20).
Regarding claims 7 – 9, Cowan teaches the mitochondria can be autogeneic (claim 7), allogenic (claim 8), or xenogeneic (claim 9) (page 3, lines 1 – 8 and 17 – 18).
Regarding claim 46, Cowan teaches administering mitochondria to a patient with severe LV dysfunction (page 57, 13 – 32) but does not teach the patient has pulmonary hypertension. However, pulmonary hypertension due to left heart disease, classified as group 2, is believed to be the most common cause of pulmonary hypertension and is associated with high morbidity and mortality as evidenced by Guazzi (page 975, left col. para. 1 and 3; page 981, right col. last para.; page 982, left col. para. 4).
Regarding claim 52, Cowan teaches administering mitochondria to a patient with severe LV dysfunction (page 57, 13 – 32) but does not teach the subject has heart hypertrophy. Chronic or poorly controlled hypertension causes increased cardiac workload, which can lead to hypertrophy of the left ventricle and initially this hypertrophy serves as a compensatory mechanism, but long-term can lead to decreased left ventricular output as evidenced by Chahine (page 2, para. 2).
Cowan teaches administering mitochondria to a patient with severe LV dysfunction (page 57, 13 – 32) but does not teach the patient has heart hypertrophy or pulmonary hypertension of claim 1 or claims 46 or 52. However, Cowan teaches administration of mitochondria to a patient with severe LV dysfunction resulting in improvement to mild dysfunction (page 58, lines 1 – 17). Cowan teaches a method of increasing blood flow or decreasing vascular resistance in an organ of a subject where the organ can be lung by administering a composition comprising isolated mitochondria to the subject in an amount sufficient to increase blood flow or decrease vascular resistance where the composition can be injected into a blood vessel (page 6, lines 28 – 32; page 7, lines 1 – 5). Cowan teaches there are no known and approved treatments that involve mitochondria and there is a need for such treatment and to utilize mitochondria for drug delivery and some other therapeutic and diagnostic purposes (page 2, lines 15 – 17). Cowan teaches after mitochondria are injected or infused, the mitochondria can transverse the artery wall and be taken up by cells of the patient’s tissues (page 2, lines 28 – 30). Cowan teaches the mitochondrial transplantation has potential to rescue cell function and replaced damaged or dysfunctional mitochondria and because symptoms for mitochondrial dysfunction disorder is more likely to manifest in a n organ that requires a continuous supply of energy the, the administration can specifically target such organs including the heart (page 39, lines 4 – 5).
Regarding “wherein the subject has pulmonary hypertension” of claim 1 and 46, Gaile teaches Group 2 pulmonary hypertension (PH) due to left heart disease is characterized by enlarged and thickened pulmonary veins and the mechanisms responsible for the increase in pulmonary arterial pressure (PAP) are multiple (page 2499, right col. para. 4; page 2500, left col. para. 2). Gaile teaches up to 60% of patients with severe LV systolic dysfunction and up to 70% of patients with isolated LV diastolic dysfunction may present with PH (page 2501, left col. para. 2). Gaile teaches virtually no progress has been made for treating PH in patients with left heart disease and there is no specific therapy (page 2526, right col. para. 2; page 2527, right col. para. 2). Gaile does not teach “wherein the subject has heart hypertrophy” of claim 1 and 52. However, Gaile teaches PH should be suspected in patients with LV hypertrophy (page 2526, right col. last para.). One would have been motivated to combine the teachings of Cowan and Gaile because Cowan teaches administration of mitochondria to a patient with severe LV dysfunction resulting in improvement to mild dysfunction and Gaile teaches severe LV dysfunction can cause PH and virtually no progress has been made for treating PH in patients with left heart disease and there is no specific therapy.
Regarding “wherein the subject has heart hypertrophy” of claim 1 and 52, Otterstad teaches left ventricular hypertrophy (LVH) is commonly associated with coronary heart disease and hypertensive patients with LVH and myocardial ischemia may be a particular risk (Abstract). Otterstad teaches a logical approach would be to improve the prognosis by reversing LVH and reducing ischemia (Abstract). Otterstad teaches the prevalence of LVH in male hypertensive patients is high and the prevalence of myocardial ischemia in patients with LVH is 24% or 14% depending of the test (page 4, left col. and right col. para. 1). Otterstad teaches ACE inhibitors produced the most pronounced regression of LVH but no documented anti-ischemic properties (page 5, left col. para. 2 and 4; Figure 4). Otterstad teaches patients with LVH have an unfavorable balance between oxygen demand and coronary blood flow reserve with the possibility of malignant arrhythmias and myocardia infarction causing sudden death (page 5, left col. para. 3).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Cowan regarding administering isolated mitochondria to patients with severe LV dysfunction or a subject with an ischemia-related disease with the teachings of Gaile regarding severe LV dysfunction can cause pulmonary hypertension with the teachings of Otterstad regarding LVH is commonly associated with coronary heart disease and hypertensive patients with LVH and myocardial ischemia may be a particular risk to arrive at the claimed method of treating or maintaining adaptation to heart hypertrophy in a subject, comprising administering to the subject a therapeutically effective amount of a composition comprising isolated mitochondria, wherein the subject has heart hypertrophy or pulmonary hypertension. One would have been motivated to combine the teachings of Cowan, Gaile and Otterstad in a method of treating heart hypertrophy or pulmonary hypertension as Cowan teaches there are no known and approved treatments that involve mitochondria and there is a need for such treatment and to utilize mitochondria for drug delivery and some other therapeutic and diagnostic purposes, Gaile teaches virtually no progress has been made for treating PH in patients with left heart disease and there is no specific therapy, and Otterstad teaches a logical approach would be to improve the prognosis by reversing LVH and reducing ischemia. One would have a reasonable expectation of success in combining the teachings as Cowan teaches administration of mitochondria to a patient with severe LV dysfunction resulted in improvement to mild dysfunction and Cowan teaches after mitochondria are injected or infused, the mitochondria can transverse the artery wall and be taken up by cells of the patient’s tissues and Cowan teaches the mitochondrial transplantation has potential to rescue cell function and replaced damaged or dysfunctional mitochondria and because symptoms for mitochondrial dysfunction disorder is more likely to manifest in an organ that requires a continuous supply of energy the, the administration can specifically target such organs including the heart.
8. Claim(s) 10 – 12, 21, 48, and 53 remain rejected under 35 U.S.C. 103 as being unpatentable over Cowan (WO-2017124037-A1; previously cited), hereinafter Cowan as evidenced by Hussain (Hussain K, et. al. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan; previously cited), hereinafter Hussain and Guazzi (Guazzi, Marco, et. al. Circulation 126.8 (2012): 975-990; previously cited), hereinafter Guazzi and Chahine (Chahine J, et. al. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan; previously cited), hereinafter Chahine in view of Gaile (Galie, Nazzareno, et al. European heart journal 30.20 (2009): 2493-2537; previously cited), hereinafter Gaile in view of Otterstad (Otterstad, J. E. European heart journal 14.suppl_F (1993): 2-6; previously cited), hereinafter Otterstad.
Regarding claims 10 and 11, Cowan teaches autologous mitochondria are injected into the myocardium (“administering” of claim 10 and “intramyocardial injection” of claim 11) of a patient with severe left ventricular dysfunction where the patient showed improvement of function to mild dysfunction (page 57, lines 13 – 32; page 58, lines 1 – 17; Table 1). Cowan teaches the method includes administering the composition comprising isolated mitochondria to a subject where the subject has an ischemia-related disease where the composition can be injected into a blood vessel (page 3, lines 1 – 2; page 6, lines 28 – 32; page 7, lines 1 – 5; page 57, lines 13 – 16; page 58, lines 6 – 9).
Regarding claim 12, Cowan teaches the patient has diminished right pulmonary artery blood flow and ventricular function varying between normal and moderately depressed and severe left ventricular dysfunction where the patient showed improvement of function to mild dysfunction (page 57, lines 13 – 32; page 58, lines 1 – 17). The most common cause of right heart failure is left ventricular failure, which increases pressure in the pulmonary vasculature as evidenced by Hussain (page 1, para. 1).
Regarding claim 21, Cowan teaches the patient has severe left ventricular dysfunction where the patient showed improvement of function to mild dysfunction (page 57, lines 13 – 32; page 58, lines 1 – 17).
Regarding claim 48, Cowan teaches administering mitochondria to a patient with severe LV dysfunction (page 57, 13 – 32) but does not teach the patient has pulmonary hypertension. However, pulmonary hypertension due to left heart disease, classified as group 2, is believed to be the most common cause of pulmonary hypertension and is associated with high morbidity and mortality as evidenced by Guazzi (page 975, left col. para. 1 and 3; page 981, right col. last para.; page 982, left col. para. 4). The most common cause of right heart failure is left ventricular failure, which increases pressure in the pulmonary vasculature as evidenced by Hussain (page 1, para. 1).
Regarding claim 53, Cowan teaches administering mitochondria to a patient with severe LV dysfunction (page 57, 13 – 32) but does not teach the subject has heart hypertrophy. Chronic or poorly controlled hypertension causes increased cardiac workload, which can lead to hypertrophy of the left ventricle and initially this hypertrophy serves as a compensatory mechanism, but long-term can lead to decreased left ventricular output as evidenced by Chahine (page 2, para. 2). The most common cause of right heart failure is left ventricular failure, which increases pressure in the pulmonary vasculature as evidenced by Hussain (page 1, para. 1).
Cowan teaches administering mitochondria to a patient with severe LV dysfunction (page 57, 13 – 32) but does not teach the patient has heart hypertrophy or pulmonary hypertension of claim 10 or claims 48 or 53. However, Cowan teaches administration of mitochondria to a patient with severe LV dysfunction resulting in improvement to mild dysfunction (page 58, lines 1 – 17). Cowan teaches a method of increasing blood flow or decreasing vascular resistance in an organ of a subject where the organ can be lung by administering a composition comprising isolated mitochondria to the subject in an amount sufficient to increase blood flow or decrease vascular resistance where the composition can be injected into a blood vessel (page 6, lines 28 – 32; page 7, lines 1 – 5). Cowan teaches there are no known and approved treatments that involve mitochondria and there is a need for such treatment and to utilize mitochondria for drug delivery and some other therapeutic and diagnostic purposes (page 2, lines 15 – 17). Cowan teaches after mitochondria are injected or infused, the mitochondria can transverse the artery wall and be taken up by cells of the patient’s tissues (page 2, lines 28 – 30). Cowan teaches the mitochondrial transplantation has potential to rescue cell function and replaced damaged or dysfunctional mitochondria and because symptoms for mitochondrial dysfunction disorder is more likely to manifest in a n organ that requires a continuous supply of energy the, the administration can specifically target such organs including the heart (page 39, lines 4 – 5).
Regarding “wherein the subject has pulmonary hypertension” of claim 10 and 48, Gaile teaches Group 2 pulmonary hypertension (PH) due to left heart disease is characterized by enlarged and thickened pulmonary veins and the mechanisms responsible for the increase in pulmonary arterial pressure (PAP) are multiple (page 2499, right col. para. 4; page 2500, left col. para. 2). Gaile teaches up to 60% of patients with severe LV systolic dysfunction and up to 70% of patients with isolated LV diastolic dysfunction may present with PH (page 2501, left col. para. 2). Gaile teaches virtually no progress has been made for treating PH in patients with left heart disease and there is no specific therapy (page 2526, right col. para. 2; page 2527, right col. para. 2). Gaile does not teach “wherein the subject has heart hypertrophy” of claim 10 and 53. However, Gaile teaches PH should be suspected in patients with LV hypertrophy (page 2526, right col. last para.). One would have been motivated to combine the teachings of Cowan and Gaile because Cowan teaches administration of mitochondria to a patient with severe LV dysfunction resulting in improvement to mild dysfunction and Gaile teaches severe LV dysfunction can cause PH and virtually no progress has been made for treating PH in patients with left heart disease and there is no specific therapy.
Regarding “wherein the subject has heart hypertrophy” of claim 10 and 53, Otterstad teaches left ventricular hypertrophy (LVH) is commonly associated with coronary heart disease and hypertensive patients with LVH and myocardial ischemia may be a particular risk (Abstract). Otterstad teaches a logical approach would be to improve the prognosis by reversing LVH and reducing ischemia (Abstract). Otterstad teaches the prevalence of LVH in male hypertensive patients is high and the prevalence of myocardial ischemia in patients with LVH is 24% or 14% depending of the test (page 4, left col. and right col. para. 1). Otterstad teaches ACE inhibitors produced the most pronounced regression of LVH but no documented anti-ischemic properties (page 5, left col. para. 2 and 4; Figure 4). Otterstad teaches patients with LVH have an unfavorable balance between oxygen demand and coronary blood flow reserve with the possibility of malignant arrhythmias and myocardia infarction causing sudden death (page 5, left col. para. 3).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Cowan regarding administering isolated mitochondria to patients with severe LV dysfunction or a subject with an ischemia-related disease with the teachings of Gaile regarding severe LV dysfunction can cause pulmonary hypertension with the teachings of Otterstad regarding LVH is commonly associated with coronary heart disease and hypertensive patients with LVH and myocardial ischemia may be a particular risk to arrive at the claimed method of treating or maintaining adaptation to heart hypertrophy in a subject, comprising administering to the subject a therapeutically effective amount of a composition comprising isolated mitochondria, wherein the subject has heart hypertrophy or pulmonary hypertension. One would have been motivated to combine the teachings of Cowan, Gaile and Otterstad in a method of treating heart hypertrophy or pulmonary hypertension as Cowan teaches there are no known and approved treatments that involve mitochondria and there is a need for such treatment and to utilize mitochondria for drug delivery and some other therapeutic and diagnostic purposes, Gaile teaches virtually no progress has been made for treating PH in patients with left heart disease and there is no specific therapy, and Otterstad teaches a logical approach would be to improve the prognosis by reversing LVH and reducing ischemia. One would have a reasonable expectation of success in combining the teachings as Cowan teaches administration of mitochondria to a patient with severe LV dysfunction resulted in improvement to mild dysfunction and Cowan teaches after mitochondria are injected or infused, the mitochondria can transverse the artery wall and be taken up by cells of the patient’s tissues and Cowan teaches the mitochondrial transplantation has potential to rescue cell function and replaced damaged or dysfunctional mitochondria and because symptoms for mitochondrial dysfunction disorder is more likely to manifest in an organ that requires a continuous supply of energy the, the administration can specifically target such organs including the heart.
9. Claim(s) 28, 29, 33, 50, and 54 remain rejected under 35 U.S.C. 103 as being unpatentable over Cowan (WO-2017124037-A1; previously cited), hereinafter Cowan as evidenced by Guazzi (Guazzi, Marco, et. al. Circulation 126.8 (2012): 975-990; previously cited), hereinafter Guazzi and Chahine (Chahine J, et. al. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan; previously cited), hereinafter Chahine and Eguchi (Eguchi, Kazuo, et al. The American journal of cardiology 101.12 (2008): 1787-1791; previously cited), hereinafter Eguchi, in view of Gaile (Galie, Nazzareno, et al. European heart journal 30.20 (2009): 2493-2537; previously cited), hereinafter Gaile in view of Otterstad (Otterstad, J. E. European heart journal 14.suppl_F (1993): 2-6; previously cited), hereinafter Otterstad.
Regarding claim 28, Cowan teaches a method comprising administering a composition comprising isolated mitochondria to a subject where the subject has an ischemia-related disease (claim 1) (page 3, lines 1 – 2; page 6, lines 28 – 32; page 7, lines 1 – 5; page 57, lines 13 – 16; page 58, lines 6 – 9; Table 1). Cowan teaches administering mitochondria to a subject placed on ECMO due to surgical complications of coronary insufficiency and that mitochondria were injected into the area of hypokinesis (page 56, lines 23 – 30; Table 1). Cowan teaches administering mitochondria to a patient with severe LV dysfunction (page 57, 13 – 32). However, Cowan does not teach these patients have heart hypertrophy or pulmonary hypertension. Pulmonary hypertension due to left heart disease, classified as group 2, is believed to be the most common cause of pulmonary hypertension and is associated with high morbidity and mortality as evidenced by Guazzi (page 975, left col. para. 1 and 3; page 981, right col. last para.; page 982, left col. para. 4). Chronic or poorly controlled hypertension causes increased cardiac workload, which can lead to hypertrophy of the left ventricle and initially this hypertrophy serves as a compensatory mechanism, but long-term can lead to decreased left ventricular output as evidenced by Chahine (page 2, para. 2).
Regarding “diabetes” of claim 33, Cowan teaches identifying a subject having or being at risk of a metabolic disorder and delivering mitochondria (page 43, lines 3 – 7). The metabolic disorder type II diabetes increases the risk of left ventricular hypertrophy as evidenced by Eguchi (Abstract; page 2, paragraph 1; page 4, paragraph 4 – 5; Table 2). Cowan teaches metabolic disorders include obesity and its associated metabolic diseases (type II diabetes) (page 43, line 33 – page 44, line 1).
Cowan teaches administering mitochondria to a patient with severe LV dysfunction (page 57, 13 – 32) but does not teach the patient has heart hypertrophy or pulmonary hypertension of claim 28 or claims 50 or 54 or “the subject is identified by measuring” “LV Peak developed pressure” or “LV end diastolic pressure” of claim 29. However, Cowan teaches administration of mitochondria to a patient with severe LV dysfunction resulting in improvement to mild dysfunction (page 58, lines 1 – 17). Cowan teaches a method of increasing blood flow or decreasing vascular resistance in an organ of a subject where the organ can be lung by administering a composition comprising isolated mitochondria to the subject in an amount sufficient to increase blood flow or decrease vascular resistance where the composition can be injected into a blood vessel (page 6, lines 28 – 32; page 7, lines 1 – 5). Cowan teaches there are no known and approved treatments that involve mitochondria and there is a need for such treatment and to utilize mitochondria for drug delivery and some other therapeutic and diagnostic purposes (page 2, lines 15 – 17). Cowan teaches after mitochondria are injected or infused, the mitochondria can transverse the artery wall and be taken up by cells of the patient’s tissues (page 2, lines 28 – 30). Cowan teaches the mitochondrial transplantation has potential to rescue cell function and replaced damaged or dysfunctional mitochondria and because symptoms for mitochondrial dysfunction disorder is more likely to manifest in a n organ that requires a continuous supply of energy the, the administration can specifically target such organs including the heart (page 39, lines 4 – 5).
Regarding “wherein the subject has pulmonary hypertension” of claim 28 and 50, Gaile teaches Group 2 pulmonary hypertension (PH) due to left heart disease is characterized by enlarged and thickened pulmonary veins and the mechanisms responsible for the increase in pulmonary arterial pressure (PAP) are multiple (page 2499, right col. para. 4; page 2500, left col. para. 2). Gaile teaches up to 60% of patients with severe LV systolic dysfunction and up to 70% of patients with isolated LV diastolic dysfunction may present with PH (page 2501, left col. para. 2). Gaile teaches virtually no progress has been made for treating PH in patients with left heart disease and there is no specific therapy (page 2526, right col. para. 2; page 2527, right col. para. 2). Gaile does not teach “wherein the subject has heart hypertrophy” of claim 28 and 54. However, Gaile teaches PH should be suspected in patients with LV hypertrophy (page 2526, right col. last para.).
Regarding “the subject is identified by measuring” “LV Peak developed pressure” or “LV end diastolic pressure” of claim 29, Gaile teaches the diagnosis of pulmonary hypertension due to left heart disease include measuring LV filling pressures and LV end-diastolic pressure (page 2527, left col. para. 1 – 2; Table 30). Gaile teaches factors favoring diagnosis of left ventricular diastolic dysfunction in the presence of pulmonary hypertension include obesity, metabolic syndrome, hypertension, and diabetes mellitus (Table 30). One would have been motivated to combine the teachings of Cowan and Gaile because Cowan teaches administration of mitochondria to a patient with severe LV dysfunction resulting in improvement to mild dysfunction and Gaile teaches severe LV dysfunction can cause PH and virtually no progress has been made for treating PH in patients with left heart disease and there is no specific therapy.
Regarding “wherein the subject has heart hypertrophy” of claim 28 and 54, Otterstad teaches left ventricular hypertrophy (LVH) is commonly associated with coronary heart disease and hypertensive patients with LVH and myocardial ischemia may be a particular risk (Abstract). Otterstad teaches a logical approach would be to improve the prognosis by reversing LVH and reducing ischemia (Abstract). Otterstad teaches the prevalence of LVH in male hypertensive patients is high and the prevalence of myocardial ischemia in patients with LVH is 24% or 14% depending of the test (page 4, left col. and right col. para. 1). Otterstad teaches ACE inhibitors produced the most pronounced regression of LVH but no documented anti-ischemic properties (page 5, left col. para. 2 and 4; Figure 4). Otterstad teaches patients with LVH have an unfavorable balance between oxygen demand and coronary blood flow reserve with the possibility of malignant arrhythmias and myocardia infarction causing sudden death (page 5, left col. para. 3).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Cowan regarding administering isolated mitochondria to patients with severe LV dysfunction or a subject with an ischemia-related disease with the teachings of Gaile regarding severe LV dysfunction can cause pulmonary hypertension with the teachings of Otterstad regarding LVH is commonly associated with coronary heart disease and hypertensive patients with LVH and myocardial ischemia may be a particular risk to arrive at the claimed method of treating or maintaining adaptation to heart hypertrophy in a subject, comprising administering to the subject a therapeutically effective amount of a composition comprising isolated mitochondria, wherein the subject has heart hypertrophy or pulmonary hypertension. One would have been motivated to combine the teachings of Cowan, Gaile and Otterstad in a method of treating heart hypertrophy or pulmonary hypertension as Cowan teaches there are no known and approved treatments that involve mitochondria and there is a need for such treatment and to utilize mitochondria for drug delivery and some other therapeutic and diagnostic purposes, Gaile teaches virtually no progress has been made for treating PH in patients with left heart disease and there is no specific therapy, and Otterstad teaches a logical approach would be to improve the prognosis by reversing LVH and reducing ischemia. One would have a reasonable expectation of success in combining the teachings as Cowan teaches administration of mitochondria to a patient with severe LV dysfunction resulted in improvement to mild dysfunction and Cowan teaches after mitochondria are injected or infused, the mitochondria can transverse the artery wall and be taken up by cells of the patient’s tissues and Cowan teaches the mitochondrial transplantation has potential to rescue cell function and replaced damaged or dysfunctional mitochondria and because symptoms for mitochondrial dysfunction disorder is more likely to manifest in an organ that requires a continuous supply of energy the, the administration can specifically target such organs including the heart.
10. Claim(s) 31 remains rejected under 35 U.S.C. 103 as being unpatentable over Cowan (WO-2017124037-A1; previously cited), hereinafter Cowan as evidenced by Guazzi (Guazzi, Marco, et. al. Circulation 126.8 (2012): 975-990; previously cited), hereinafter Guazzi and Chahine (Chahine J, et. al. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan; previously cited), hereinafter Chahine and Eguchi (Eguchi, Kazuo, et al. The American journal of cardiology 101.12 (2008): 1787-1791; previously cited), hereinafter Eguchi, in view of Gaile (Galie, Nazzareno, et al. European heart journal 30.20 (2009): 2493-2537; previously cited), hereinafter Gaile in view of Otterstad (Otterstad, J. E. European heart journal 14.suppl_F (1993): 2-6; previously cited), hereinafter Otterstad as applied to claims 28, 29, 33, 50, and 54 above, and further in view of Guclu (Güçlü A, et. al. Eur J Clin Invest. 2015 Dec;45(12):1252-9), hereinafter Guclu in view of Vignaud (Vignaud A, et. al. Magn Reson Med. 2006 Apr;55(4):725-30; previously cited), hereinafter Vignaud.
Cowan in view of Gaile and Otterstad make obvious the limitations of claim 28 as set forth above. Cowan, Gaile, and Otterstad do not teach measuring ventricular capillary density by MRI or angiographic imaging of microvascular circulation. However, Cowan teaches in Example 3 injecting dual-labeled mitochondria into hearts and acquiring images using MRI (page 51, lines 8 – 17 and 25 – 30). Cowan teaches coronary artery perfusion of exogenous mitochondria resulted in wide-spread distribution of the mitochondria throughout the heart using MRI (page 53, lines 3 – 15; Figure 2). Cowan teaches it is believed that infused mitochondria extravasate through the capillary wall (page 16, lines 19 – 20; page 26, lines 18 – 21; page 34, lines 7 – 8). Cowan teaches a mitochondrial agent for imaging by MRI that is an iron oxide nanoparticle and a composition comprising mitochondria and iron oxide nanoparticles and mitochondria and 18F-Rhodamine 6G and iron oxide nanoparticles (page 3, lines 9 – 12; page 4, lines 12 – 27; page 17, lines 17 – 25; page 32, lines 3 – 10; page 48, lines 20 – 23; page 49, lines 4 – 21).
Guclu teaches coronary microvascular dysfunction (CMD) is a feature of hypertrophic cardiomyopathy (HCM), which contributes negatively to symptoms and long-term outcome and CMD may be caused by reduced capillary density (Abstract). Guclu teaches measuring capillary density using immunofluorescence microscopy from myectomy samples (page 1253, left col. para. 2 and right col. para. 3). Guclu teaches a correlation between capillary density and HCM where HCM samples had lower capillary density (Figure 2c; page 1257, left col. para. 2 and right col. para. 2).
Vignaud teaches detection of myocardial capillary with intravascular iron-oxide nanoparticles and MRI (Abstract; page 1, paragraph 1). Vignaud teaches MRI spin-echo (SE) images in beating hearts and excised heart samples (page 2, paragraph 2 and 6; page 3, paragraph 3). Vignaud teaches SE provides a robust means of mapping capillary orientation in vivo (page 2, paragraph 3). Vignaud teaches the technique uses contrast-enhanced MRI to map the capillary network organization and the technique may reveal changes in capillary organization that may occur in microvascular disease, cardiomyopathy, and ventricular remodeling (page 5, paragraph 3).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Cowan regarding a combination of mitochondria and iron oxide nanoparticles for imaging with MRI with the teachings of Guclu regarding measuring capillary density by immunofluorescence microscopy with myectomy samples with the teachings of Vignaud regarding a method of imaging heart capillaries with iron oxide nanoparticles and MRI to arrive at the claimed method where ventricular capillary density is measured by MRI. One would have been motivated combine the teachings of Cowan, Guclu, and Vignaud in a method of maintaining ventricular capillary density where capillary density can be measured at the same time mitochondria are administered and to overcome the necessity of obtaining samples by myectomy for measuring capillary density as Cowan teaches there are no known and approved treatments that involve mitochondria and there is a need for such treatment and to utilize mitochondria for drug delivery and some other therapeutic and diagnostic purposes. One would have a reasonable expectation of success in combining the teachings as Vignaud teaches capillaries can be imaged with iron oxide nanoparticles and MRI in beating hearts.
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.
11. Instant claims 28 – 29, 31, and 33 remain and instant claims 1 – 12, 21, 46, 48, 50, and 52 – 54 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 3, 5, 7, 13, 19 – 22, 25, 28, 29, 41, and 94 – 97 of copending Application No. 17607975 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims anticipate the reference claims. Although maintained, note that the rejection is revised in light of the amendments to the claims.
Instant independent claims 1, 10, 28 recite method comprising a method step “administering to the subject a therapeutically effective amount of (1) a composition comprising isolated mitochondria or (2) a composition comprising a combined mitochondrial agent, wherein the mitochondria in the combined mitochondrial agent act as a carrier for delivering a therapeutic, diagnostic, and/or imaging agent, wherein the subject has heart hypertrophy or pulmonary hypertension”.
Reference independent claim 1 recites a method comprising “administering to the subject a therapeutically effective amount of a composition comprising isolated mitochondrial and/or a combined mitochondrial agent; and performing the medical procedure (e.g., a surgery , an organ transplantation)”. Reference independent claim 2 recites a method comprising “identifying a subject at risk for IRI; and administering to the subject a therapeutically effective amount of a composition comprising isolated mitochondrial and/or a combined mitochondrial agent, wherein the composition is administered to the subject prior to an ischemic event or an ischemic injury”. Reference independent claim 3 recites a method comprising “administering to a subject having at least one symptom of IRI a therapeutically effective amount of a composition comprising isolated mitochondrial and/or a combined mitochondrial agent; and performing the medical procedure”. Reference independent claim 5 recites a method comprising “identifying the subject at risk for, or having, cell damage, tissue damage, and/or organ damage associated with IRI; and administering to the subject a therapeutically effective amount of a composition comprising isolated mitochondrial and/or a combined mitochondrial agent, wherein the composition is administered prior to an ischemic event or an ischemic injury”. Therefore, the independent reference claims are in essence a “species” of the generic invention of instant claims 1, 10, and 28. It has been held that a generic invention is “anticipated” by a “species” within the scope of the generic invention. See In re Goodman, 29 USPQ2d 2010 (Fed. Cir. 1993).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
12. Instant claims 1 – 10 remain provisionally rejected and claims 11 12, 21, 28, 29, 31, 33, 46, 48, 50, and 52 – 54 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 4, 6, 8 – 13, and 20 – 21, of copending Application No. 17603646 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims anticipate and/or render obvious the instant claims. Although maintained, note that the rejection is revised in light of the amendments to the claims.
Instant independent claims 1, 10, 28 recite method comprising a method step “administering to the subject a therapeutically effective amount of (1) a composition comprising isolated mitochondria or (2) a composition comprising a combined mitochondrial agent, wherein the mitochondria in the combined mitochondrial agent act as a carrier for delivering a therapeutic, diagnostic, and/or imaging agent, wherein the subject has heart hypertrophy or pulmonary hypertension”. Reference claim 1 recites a method “comprising administering an aerosolized composition comprising a therapeutically effective amount of respiration-competent mitochondria to the subject”. Therefore, the independent reference claim is in essence a “species” of the generic invention of instant claims 1, 10, and 28. It has been held that a generic invention is “anticipated” by a “species” within the scope of the generic invention. See In re Goodman, 29 USPQ2d 2010 (Fed. Cir. 1993).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Applicant’s Arguments/ Response to Arguments
13. Applicant Argues: Applicant asserts that one of ordinary skill in the art would not have been motivated to modify Cowan using Guazzi, Chahine, Gaile, and/or Otterstad to arrive at the pending claims with a reasonable expectation of success. Applicant asserts that there is no support for the allegation that either of the subjects in Case Report 1 and Case Report 2 had heart failure, RVF, or were at risk of heart failure or RVF.
Response to Arguments: This is not found persuasive because Cowan teaches the patients of Case Report 1 and 2 were placed on ECMO. One of ordinary skill in the art recognizes that a person is placed on ECMO due to having heart failure or being at risk of heart failure. Cowan teaches Case Report 2 of treating a patient with VACTERL syndrome, tricuspid atresia 1B with pulmonary stenosis and ventricular septal defect and diminished right pulmonary artery blood flow. One of ordinary skill in the art recognizes that the patient of Case Report 2 with pulmonary stenosis and diminished right pulmonary artery blood flow has heart hypertrophy and it at risk for heart failure or RVF and Cowan teaches the patient had multiple runs of CPB for poor oxygenation and ventilation. Cowan teaches the patient of Case Report 2 showed an improvement in ventricular function in Table 1. Therefore, Cowan provides motivation to arrive at the pending claims with a reasonable expectation of success.
Applicant Argues: Applicant argues that based on the prior art at the time the present application was filed, one of ordinary skill in the art would not have been motivated to modify Cowan to administer mitochondria nor combined mitochondrial agents to a subject during heart hypertrophy and/or heart failure as it was well known that mitochondria are fragile and show significant functional and structural damage in heart failure and animal models.
Response to Arguments: This is not found persuasive because Cowan teaches in Table 1 that patients’ ventricular function improved following administration of mitochondria. Therefore, one of ordinary skill in the art would have been motivated to administer mitochondria to a subject having heart hypertrophy or pulmonary hypertension to treat heart failure or maintain adaptation to heart hypertrophy because Cowan teaches administration of mitochondria improves ventricular function measured at 10 days after administration. Thus, Cowan teaches administration of mitochondria conferred a therapeutic effect to treat heart failure.
Applicant Argues: Applicant asserts that Cowan addresses acute IRI (Example 3 and Figure 15) and provides no teachings or operational frameworks related to the treatment of chronic heart failure, nor does it address maintaining homeostatic adaptation to prolonged cardiac hypertrophy in subjects with underlying heart hypertrophy or pulmonary hypertension.
Response to Arguments: This is not found persuasive because Cowan teaches treating patients with heart failure with mitochondria where patients’ ventricular function improves following administration of mitochondria up to 10 days following treatment (Table 1). It is noted that the claims broadly recite “heart failure”, which is not limited to chronic heart failure. Should Applicant amend the claims to recite “chronic heart failure” and provide arguments that the patients of Cowan do not have heart failure, the rejection may be overcome upon further search and consideration.
Applicant Argues: Applicant requests reconsideration of the provisional obviousness-type double patenting rejections.
Response to Arguments: The rejections have been reconsidered and are maintained because the instant claims encompass heart failure and RV contractility due to IRI of copending application 17607975 and a respiratory disorder of copending application 17603646.
Conclusion
No claims 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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/Z.M.B./Examiner, Art Unit 1632
/MARCIA S NOBLE/Primary Examiner, Art Unit 1632
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