DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Interpretation
BRI of the claim term “treating” is based on the definition and discussion at para. [0022] of the specification: “partially or completely alleviating, ameliorating, relieving, mitigating, preventing, delaying onset of, inhibiting, or slowing progression of, reducing severity of, and/or reducing incidence of cardiac injury. Treatment can be administered to a subject who does not exhibit signs of cardiac injury and/or to a subject who exhibits signs of cardiac injury.”
BRI of the claim term “cardiac injury” is based on the definition and discussion at para. [0025] of the specification: “the state of having myocardial injury or damage. The myocardial injury can be acute or chronic. There is a broad spectrum of myocardial injury. Myocardial injury may be related to acute myocardial ischemia (e.g., atherosclerotic plaque disruption with thrombosis) or it may be related to acute myocardial ischemia because of oxygen supply/demand imbalance (e.g., reduced myocardial perfusion or increased myocardial oxygen demand). Other causes of myocardial injury include cardiac conditions (e.g., heart failure, myocarditis, cardiomyopathy, Takotsubo syndrome, coronary revascularization, catheter ablation, defibrillator shocks, cardiac contusion) or systemic conditions (e.g., sepsis, chronic kidney disease, stroke, pulmonary embolism, infiltrative disease, chemotherapeutic agents, critical illness, strenuous exercise). Myocardial injury includes myocardial necrosis, myocardial infarction (heart attack), cardiomyopathy, myocardial ischemia, and blunt cardiac injury.”
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-2, 8-13, 18-23, 25-28, 41, 47, and 49-50 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Chawla (US 2015/0164980 A1).
Regarding claim 1, Chawla discloses a method of administering angiotensin II to subjects with hypotension and exhibiting distributive shock and that the angiotensin II is effective to reduce or eliminate the need for catecholamine, thereby preventing the injury and toxic effects of catecholamines, and to improve survival in patients with shock, raise blood pressure to normal level, and improve and stabilize heart rate and hemodynamics (paragraph [0010]). Chawla also discloses that the angiotensin II can be used to treat shock that results from cardiac arrest or cardiogenic shock (paragraph [0024], [0059]).
In the response filed October 16, 2025, Applicant traverses the rejection on the grounds that Chawla does not teach all of the elements of claim 1. This argument is not persuasive.
Claim 1
Prior Art
Analysis
A method of treating cardiac injury in a subject comprising
Chawla teaches [0010]: administration of very low doses of angiotensin II to subjects having hypotension, e.g., exhibiting distributive shock (high output shock), the blood pressure can be raised to a normal level (e.g., a mean arterial pressure (MAP) of about 65 mm Hg or higher) and can be maintained at this level, even in the absence of, or with low doses of, other agents such as vasopressin or catecholamines (e.g., norepinephrine) that are generally administered to such subjects as the standard of care. The reduction or elimination of a need to administer a catecholamine (e.g., norepinephrine) is sometimes referred to herein as a catecholamine-sparing (norepinephrine-sparing) effect. Administering low doses of angiotensin II and of a catecholamine such as norepinephrine reduces undesirable side effects brought about by these drugs. High doses of catecholamines can be toxic, and the blunting of these toxic effects has been associated with improved survival in patient with shock. Maintenance of blood pressure during shock is critical to survival. In addition to raising blood pressure, heart rate and hemodynamics are improved or remain stable following administration of the low doses of angiotensin II.
The claimed genus of treating cardiac injury includes the prior art indication because [0010] of the specification indicates that treating includes mitigating, preventing, delaying onset of, inhibiting, or slowing progression of, reducing severity of, and/or reducing incidence. In addition, [0025] of the specification indicates that cardiac injury includes patients who suffer acute myocardial conditions and systemic conditions that affect the heart, including shock that results from cardiac arrest or cardiogenic shock.
In addition, as evidenced by instant claims 10, 25-28, 41, 49-50, subjects in need thereof include subjects who would benefit from a reduction in the amount of catecholamine and/or vasopressin administered while raising and/or maintaining MAP. These agents used to raise and/or maintain MAP can cause cardiac injury. Therefore, by lowering the dose of catecholamine and/or vasopressin needed, the cardiac injury is treated.
administering a therapeutically effective amount
Chawla teaches [0027]: The dose of angiotensin II can be administered at a rate of from about from about 1.25 ng/kg/min to about 20 ng/kg/min, about 1.25 ng/kg/min to about 10 ng/kg/min, or from about 1.25 ng/kg/min to about 5 ng/kg/min. The dose can be about 1 ng/kg/min, about 1.25 ng/kg/min, about 1.5 ng/kg/min, about 2 ng/kg/min, about 2.5 ng/kg/min, about 3 ng/kg/min, about 3.5 ng/kg/min, about 4 ng/kg/min, about 4.5 ng/kg/min, about 5 ng/kg/min, about 5.5 ng/kg/min, about 6 ng/kg/min, about 7.5 ng/kg/min or about 10 ng/kg/min.
As evidenced by instant dependent claim 47, each of these prior art doses fall within the range of therapeutically effective amount defined by the instant application, 1 ng/kg/min to 20 ng/kg/min.
of angiotensin II
Chawla teaches [0013]: angiotensin II is Asp-Arg-Val-Tyr-Ile-His-Pro-Phe, also called 5-isoleucine angiotensin II.
This is the same compound defined in [0028] of the instant specification.
to a subject in need thereof.
Chawla teaches [0003] that critically ill patients with shock requiring vasopressors, catecholamines and vasopressin type peptides, are in at risk of cardiotoxicity.
These subjects fall within the claimed genus of subjects in need thereof because [0010] of the specification indicates that treating includes mitigating, preventing, delaying onset of, inhibiting, or slowing progression of, reducing severity of, and/or reducing incidence. In addition, [0025] of the specification indicates that cardiac injury includes patients who suffer acute myocardial conditions and systemic conditions that affect the heart, including shock that results from cardiac arrest or cardiogenic shock.
In addition, as evidenced by instant claims 10, 12, 25-28, 41, 49-50, subjects in need thereof include subjects who would benefit from a reduction in the amount of catecholamine and/or vasopressin administered while raising and/or maintaining MAP. These agents used to raise and/or maintain MAP can cause cardiac injury. Therefore, by lowering the dose of catecholamine and/or vasopressin needed, the cardiac injury is treated.
Therefore, Chawla teaches all of the limitations of claim 1 and anticipates the claims.
Regarding claim 2, Chawla discloses that the angiotensin II can be used to treat shock that results from cardiac arrest or cardiogenic shock (paragraph [0024], [0059], [0095]).Patients with cardiac arrest or cardiogenic shock have cardiac injury.
Regarding claim 8, Chawla teach that the angiotensin II is therapeutically effective to maintain the mean arterial pressure at 65 mm of Hg and to reduce the need for catecholamine such as norepinephrine, thereby reducing the toxic effects of the catecholamine (paragraph [0080]). The method of administering the same compound to the same patients in a therapeutically effective amount inherently achieves the claimed effect of preventing further progression of cardiac injury.
Regarding claim 9, Chawla discloses a method of administering angiotensin II to subjects with hypotension and exhibiting distributive shock and that the angiotensin II is effective to reduce or eliminate the need for catecholamine, thereby preventing the injury and toxic effects of catecholamines, and to improve survival in patients with shock, raise blood pressure to normal level, and improve and stabilize heart rate and hemodynamics (paragraph [0010]). These subjects do not necessarily have cardiac injury but rather benefit from prevention, consistent with the broad genus “treatment” and “cardiac injury” as defined in paragraphs [0022] and [0025] of the specification.
Regarding claim 10, Chawla teach that the angiotensin II is therapeutically effective to maintain the mean arterial pressure at 65 mm of Hg and to reduce the need for catecholamine such as norepinephrine, thereby reducing the toxic effects of the catecholamine (paragraphs [0010], [0080]).
Regarding claim 11, Chawla teach that the angiotensin II is therapeutically effective to maintain the mean arterial pressure at 65 mm of Hg and to reduce the need for catecholamine such as norepinephrine, thereby reducing the toxic effects of the catecholamine (paragraph [0080]). The method of administering the same compound to the same patients in a therapeutically effective amount inherently achieves the claimed effect of preventing cardiac injury.
Regarding claim 12, Chawla teaches a method comprising administering to a subject having shock (e.g., septic shock or shock from other causes, such as cardiac arrest or cardiogenic shock) and undergoing treatment with a catecholamine at a dose equivalent to at least about 0.2 mcg/kg/min of norepinephrine a dose of angiotensin II which is effective to raise the blood pressure of the subject to a MAP of about 65 mm Hg or above, and which is effective to reduce the dose of the catecholamine required to maintain a MAP of about 65 mm Hg to the equivalent of about 0.05-0.2 mcg/kg/min norepinephrine or less, or to the equivalent of about 0.05 mcg/kg/min norepinephrine or less (paragraph [0059]).
Regarding claim 13, Chawla teaches the patient has cardiac arrest or cardiogenic shock, which is a cardiac injury (paragraph [0059]).
Regarding claim 18, Chawla teaches that the angiotensin II is therapeutically effective to maintain the mean arterial pressure at 65 mm of Hg and to reduce the need for catecholamine such as norepinephrine, thereby reducing the toxic effects of the catecholamine (paragraph [0080]). The method of administering the same compound to the same patients in a therapeutically effective amount inherently achieves the claimed effect of preventing increase in blood troponin.
Regarding claim 19, Chawla teaches that the subject is undergoing standard-of-care treatment with a catecholamine (e.g., epinephrine, norepinephrine, dopamine, phenylephrine, ephedrine) or with vasopressin at or prior to the time the angiotensin II is administered (paragraph [0062]).
Regarding claim 20, Chawla teaches that the angiotensin II is effective to reduce the dose of the catecholamine required to maintain a MAP of about 65 mm Hg to the equivalent of about 0.05-0.2 mcg/kg/min norepinephrine or less, or to the equivalent of about 0.05 mcg/kg/min norepinephrine or less (paragraph [0059]).
Regarding claim 21, Chawla teaches that for some patients catecholamines were completely weaned off with angiotensin II treatment (paragraph [0080]).
Regarding claim 22, Chawla teach that the angiotensin II is therapeutically effective to maintain the mean arterial pressure at 65 mm of Hg and to reduce the need for catecholamine such as norepinephrine, thereby reducing the toxic effects of the catecholamine (paragraph [0080]). The method of administering the same compound to the same patients in a therapeutically effective amount inherently achieves the claimed effect of preventing further progression of cardiac injury.
Regarding claim 23, Chawla discloses a method of administering angiotensin II to subjects with hypotension and exhibiting distributive shock and that the angiotensin II is effective to reduce or eliminate the need for catecholamine, thereby preventing the injury and toxic effects of catecholamines, and to improve survival in patients with shock, raise blood pressure to normal level, and improve and stabilize heart rate and hemodynamics (paragraph [0010]). These subjects do not necessarily have cardiac injury.
Regarding claim 25, Chawla teach that the angiotensin II is therapeutically effective to maintain the mean arterial pressure at 65 mm of Hg and to reduce the need for catecholamine such as norepinephrine, thereby reducing the toxic effects of the catecholamine (paragraph [0080]). The method of administering the same compound to the same patients in a therapeutically effective amount inherently achieves the claimed effect of preventing catecholamine-associated and/or vasopressin-associated cardiac injury.
Regarding claim 26, Chawla teach that the angiotensin II is therapeutically effective to maintain the mean arterial pressure at 65 mm of Hg and to reduce the need for catecholamine such as norepinephrine, thereby reducing the toxic effects of the catecholamine (paragraph [0080]).
Regarding claim 27, Chawla teaches that for some patients catecholamines were completely weaned off with angiotensin II treatment (paragraph [0080]), meaning that the method comprises administering the angiotensin II to the subject and discontinuing administration of the catecholamines.
Regarding claim 28, Chawla teaches that the use of angiotensin II in combination with other vasopressors, such as vasopressin and/or vasopressin analogues and/or with catecholamines allows for the use of much lower doses of the vasopressin and/or vasopressin analogues and/or catecholamine than are currently administered as the standard of care, thereby reducing side effects of those agents and increasing efficiency (paragraph [0089]), meaning that the method comprises administering the angiotensin II to the subject and reducing the amount of the catecholamines to a dose that is below the initial dose.
Regarding claim 41, Chawla teach that the angiotensin II is therapeutically effective to maintain the mean arterial pressure at 65 mm of Hg and to reduce the need for catecholamine such as norepinephrine, thereby reducing the toxic effects of the catecholamine (paragraph [0080]). The method of administering the same compound to the same patients in a therapeutically effective amount inherently achieves the claimed effect of clinically significant reduction in blood troponin.
Regarding claim 47, Chawla teach the dose of angiotensin II is about 1 ng/kg/min, about 1.25 ng/kg/min, about 1.5 ng/kg/min, about 2 ng/kg/min, about 2.5 ng/kg/min, about 3 ng/kg/min, about 3.5 ng/kg/min, about 4 ng/kg/min, about 4.5 ng/kg/min, about 5 ng/kg/min, about 5.5 ng/kg/min, about 6 ng/kg/min, about 7.5 ng/kg/min or about 10 ng/kg/min (paragraph [0096]), which fall within the claimed range.
Regarding claim 49, Chawla teach that the angiotensin II is therapeutically effective to maintain the mean arterial pressure at 65 mm of Hg and to reduce the need for catecholamine such as norepinephrine, thereby reducing the toxic effects of the catecholamine (paragraph [0080]).
Regarding claim 50, Chawla teaches that the angiotensin II is effective to reduce the dose of the catecholamine required to maintain a MAP of about 65 mm Hg to the equivalent of about 0.05-0.2 mcg/kg/min norepinephrine or less, or to the equivalent of about 0.05 mcg/kg/min norepinephrine or less (paragraph [0059]), which falls within the claimed range.
Response to Arguments
Applicant traverses the rejection on the grounds that Chawla fails to teach each and every element of the claims. This argument is not persuasive for the reasons presented above (see especially the table presenting a map of the claim limitations to the prior art).
Regarding Applicant’s argument pertaining to SOFA score, even if Chawla is using the score as a indication of distributive shock, this is not sufficient to overcome the rejection. Chawla is directed to the use of angiotensin II to reduced the amount of vasopressin and/or catecholamine to treat distributive shock, which in turn has the effect of preventing cardiac injury caused by high doses of these agents. This use of angiotensin II falls within the BRI of treating cardiac injury presented in [0010] and [0025] of the instant specification and is the same as the narrower embodiment claimed in instant claims 10, 12, 25-28, 41, and 49-50.
Regarding Applicant’s argument that Chawla in Table 3 teaches that angiotensin II administration was not effective and Applicant’s arguments in traverse of inherency, Applicant is ignoring the rest of the data and evidence in the reference:
[0080] Further studies showed that subjects who are administered as little as 1.25 or 2.5 ng/kg/min of angiotensin II show an increase in blood pressure and maintain it, even in the absence of, or with very low doses of, a catecholamine, such as norepinephrine. The standard of care for patients with high-output shock is to maintain the mean arterial pressure at 65 mm of Hg with catecholamines and/or vasopressin. The inability to maintain blood pressure in mammals for an extended period of time is uniformly fatal. In the study illustrated in FIG. 4, the standard of care was to administer norepinephrine. 20% of the patients responded to very low doses of angiotensin II (1.25-2.5 ng/kg/min) such that the MAP rose markedly. Per standard protocol, the catecholamine dose was decreased as pushing the MAP above normal in high- output shock patients is non-standard. Even as the catecholamines were completely weaned off, the low dose of Angiotensin II resulted in a MAP>85 mm of Hg.
[0081] ATII was shown to be an effective pressor agent at a dose range of 1-40 ng/kg/min More specifically, a starting dose of 2-10 ng/kg/min may be an appropriate starting dose in the treatment of high output shock when used in conjunction with standard-of-care vasopressors.
The prior art of Chawla supports the conclusion that angiotensin II has the effect of reducing the needed dose of other vasopressors (i.e. catecholamines and vasopressin), thereby reducing the toxicity and resulting cardiac injury of these agents (see also Chawla [0083]).
For these reasons, the rejection is maintained.
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 3, 5-6, 14, and 38-39 are rejected under 35 U.S.C. 103 as being unpatentable over Chawla (US 2015/0164980 A1), as applied to claims 1-2, 8-13, 18-23, 25-28, 41, 47, and 49-50, in view of Kim et al. (NPL 20; IDS 3/23/2023).
Chawla teach methods of treating subjects exhibiting a variety of types of shock, such as, e.g., high output shock, septic shock or shock from cardiac arrest or cardiogenic shock with angiotensin II (paragraph [0024], [0059], [0086]).
Chawla does not teach that the patients have elevated blood troponin I levels or the measurement of blood troponin I levels.
Kim et al. teach that myocardial dysfunction is common in patients with sepsis. Kim et al. teach that measurement of troponin I levels can be used to identify sepsis-induced myocardial dysfunction (abstract).
It would have been obvious to combine the method of treating shock caused by sepsis taught by Chawla with the method for monitoring blood troponin I levels in sepsis patients taught by Kim et al. and to include the patients of Kim et al. in the treatment method of Chawla. In doing so, the angiotensin II would be administered to patients with elevated blood troponin I, satisfying claims 3, 5, and 14. One of ordinary skill in the art would have been motivated to do so given that Chawla teach a successful means for maintaining the mean arterial pressure at 65 mm of Hg while reducing the need for catecholamine such as norepinephrine, thereby reducing the toxic effects of the catecholamine (paragraph [0080]). There would have been a reasonable expectation of success given that Kim et al. teach that troponin can be easily assayed in a clinical setting (p. 11).
With respect to claim 6, it would have been obvious to include all patients with elevated troponin, including those with a level above of the 99th percentile of a reference given that Chawla teach an effective treatment.
With respect to claims 38-39, it would have been obvious to conduct an assay for blood troponin I before, during, and after angiotensin II administration to monitor the effect of angiotensin II treatment. There would have been a reasonable expectation of success given that Kim et al. teach that troponin can be easily assayed in a clinical setting and that repeated measurements can be conducted readily and cost-effectively (p. 11).
Response to Arguments
Applicant traverses the rejection on the grounds that Kim et al. does not demonstrate the use of troponin as a biomarker for cardiac injury, or as useful in a method of treating cardiac injury or administering angiotensin II. This argument is not persuasive. The claims do not require that troponin is a biomarker for cardiac injury or treats cardiac injury. Rather, the claims require that patients have elevated blood troponin I levels and/or that the method includes the measurement of blood troponin I levels. This difference is supplied by Kim et al. for the reasons presented above.
Regarding the allegation of unexpected results, Applicant continues to argue that Chawla evidences an increase in adverse events and/or no effect on cardiac output. However, this argument ignores the entire reference, including Figure 4 and paragraphs [0080]-[0081], [0083], which describe the therapeutic benefit of angiotensin II. The results relied upon by Applicant are consistent with, not unexpected in view of the prior art.
For these reasons, the rejection is maintained.
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA MARCHETTI BRADLEY whose telephone number is (571)272-9044. The examiner can normally be reached Monday-Friday, 7 am - 3 pm.
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/CHRISTINA BRADLEY/Primary Examiner, Art Unit 1654
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