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 .
Election/Restrictions
Applicant's election with traverse of the method of claims 11-12 and 14--20 as the elected method, hear failure as the elected heart condition, and renin inhibitor as the elected treatment in the reply filed on 06/14/2024 is acknowledged and maintained.
Priority
This application is a continuation-in-part and claims benefit of PCT Application No. PCT/US19/60078, filed November 6, 2019, which claims benefit of U.S. Provisional Patent Application No. 62/756,427, filed November 6, 2018.
Claims status
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on December 18, 2025. Claims 1, 4-11 and 14-15, 17-20 and new claims 21-25 are pending. Claims 2-3, and 12-13 are canceled. Claims 1, 4-10 are withdrawn. Claims 11, 14-15, and 17-25 are examined in accordance to the elected species.
Action Summary
Claims 11, 14-15, and 17-20 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, are withdrawn in light of the claim amendment.
Claims 11, 14-15, and 17-20 rejected under 35 U.S.C. 101, are withdrawn in light of the claim amendment.
Claims 11, 14-15, and 17-19 remain rejected under 35 U.S.C. 103 as being unpatentable over McMurray et al (Circ Heart Fail. 2008; 1:17-24.) in view of Zanna et al (US2014/0248284A1), Nijst et al (J Renin Angiotensin Aldosterone Syst. 2017 Jul-Sep; 18(3)), Masson et al (Journal of Cardiac Failure, Volume 16, Issue 12, December 2010, Pages 964-970), and Arnal et al (The American Journal of Medicine, Volume 90, Issue 1, January 1991, Pages 17-22), are maintained, but modified and revisited in light of the claim amendment.
Claim 20 rejected under 35 U.S.C. 103 as being unpatentable over McMurray et al (Circ Heart Fail. 2008; 1:17-24.) in view of Zanna et al (US2014/0248284A1), Nijst et al (J Renin Angiotensin Aldosterone Syst. 2017 Jul-Sep; 18(3)), Masson et al (Journal of Cardiac Failure, Volume 16, Issue 12, December 2010, Pages 964-970), and Arnal et al (The American Journal of Medicine, Volume 90, Issue 1, January 1991, Pages 17-22) as applied to claims 11, 14-15, and 17-19 in further view of Stecker et al (Am Heart J. 2006 Apr;151(4):820-8), is maintained, but modified and revisited in light of the claim amendment.
New Rejection necessitated by claim amendment
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 11, 14-15, and 17-25 are rejected 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. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. The claim recites “determining a status of the patient with suspected heart failure or with heart failure.” However, the specification as originally filed does not describe or suggest determining a status of the patient with suspected heart failure or with heart failure using the recited method. Because this subject matter was not present in the originally filed disclosure, the amendment constitutes new matter.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION. —The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 11, 14-15, and 17-25 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The claimed language suspected heart failure or heart failure renders the claim indefinite because it does not clearly define when the determination step applies. If the patient is suspected to have heart failure, what criteria trigger the assessment. And if the patient already has heart failure, how does the step differ? Without a clear demarcation, a person of ordinary skill in the art cannot determine the scope of the claim. In other words, the claim mixes these two categories (suspected heart failure or heart failure) without a precise boundary. In fact, the specification does not clearly set the boundaries-like describing a particular determining step applies only if a patient is still suspected or a different set of steps for a confirmed case. Then the claim can be interpreted as covering both categories. It leaves the person skilled in the art guessing which situation applies.
With respect to the baseline level. Specifically, the claim does not define what the baseline level is. Then a person of ordinary skill in the art cannot determine the bassline plasma renin activity level from a healthy subject. Each healthy individual may have a different plasma renin activity (PRA) level because PRA depends on may physiological factors such as age, salt intake, posture, medications, kidney function, time of the day. So, there does not appear to be a single universal PRA value for healthy people. So, when the claim recites baseline level from a healthy subject, then which patient? One individual, an average, a population reference or a control sample. Because different baseline produces different 5% threshold, for example, if baseline = 0.8, then 5% increase = 2.3; if baseline = 2.3 then 5% increase = 21.415. Those are very different thresholds, meaning the scope of the claim changes depending on which healthy patient is used.
With respect to the treatment recited in claims 11, 14-15, and 20-25, the claim recites administered a treatment but does not specify what the treatment is. This renders the claim indefinite because it relies on an unrecited, subjective mental step or even a particular diet.
Claim 11 recites if the patient has a decrease plasma renin activity of more than 5% below the baseline level and the patient does not have heart failure, no treatment is administered. Such recitation renders the claim indefinite because if no treatment is needed due to a decrease of plasma renin activity of more than 5% below the baseline, then the effectiveness of a treatment cannot be determined. This makes the claim illogical and inoperable.
With respect to the structure or sequence of the method step (“determine a status… comprising obtaining…”) renders the claim indefinite because the claim steps are ambiguous and lack a clear sequence. The claim needs to recite consistent and sequential steps (e.g., first determine then measure… etc.…) so that each step is distinct and non-overlapping. Without this clarity, it is difficult to determine what actions must be performed in order.
The claim also recites a method of monitoring treatment effectiveness in a patient who is already diagnosed with heart failure, but the steps rely on measuring plasma renin activity to guide treatment changes. As a result, the method’s purpose is circular. It attempts to measure effectiveness after the diagnosis is already known, which leaves the claim’s scope unclear. By circular the Examiner means that the claim is a hybrid claim. The claim mixes a diagnostic step-identifying or confirming heart failure-with a treatment step-altering or maintaining therapy. And that hybrid structure is precisely what can create the confusion and ambiguity, because it’s not a pure diagnostic claim, nor is it purely a treatment claim.
Acknowledgement is made of the receipt and entry of Applicant’s remarks/arguments filed on December 18, 2025.
Applicant’s argument
Applicant argues claims 11, 14-15, and 17-20 stand rejected under 35 U.S.C. § 112 (b) as allegedly being unclear. However, claims 1 and 11 have been amended to clarify the invention by expressly specifying what is being measured, namely plasma renin activity (PRA) and plasma (pro)-renin receptor (PRR) in claims 1 and 11, and PRA alone in newly added claim 21. These amendments remove any ambiguity and provide clear notice of the claim scope
Response to argument
In response, Applicant’s argument is not persuasive. The amended claims resolve the previous ambiguities but introduce several new issues. As detailed in the modified and revised rejection, multiple terms-such as (“suspected heart failure or heart failure”, “baseline level”, “treatment recited in claims 11, 14-15, and 20-25”, “if the patient has a decrease plasma renin activity of more than 5% below the baseline level and the patient does not have heart failure, no treatment is administered”, “the structure or sequence of the method step (“determine a status… comprising obtaining…”)”, and “a method of monitoring treatment effectiveness in a patient who is already diagnosed with heart failure, but the steps rely on measuring plasma renin activity to guide treatment changes”)-still lack clarity. For full details, please refer to the updated rejection above, which outlines each ambiguity, and why it prevents clear scope.
New Rejection necessitated by claim amendment
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 11, 14-15, and 17-25 are rejected under 35 U.S.C. 101, because it is directed to an abstract idea without adding an inventive concept.
Claim 11 recites a method of determining effectiveness of a treatment in a patient with suspected heart failure or heart failure, comprising the steps of:
determining a status of the patient with suspected heart failure or heart failure by:
i. obtaining a blood sample from the patient;
ii. directly measuring plasma renin activity;
wherein plasma renin activity includes plasma renin activity (PRA), plasma renin activity concentration (PRAC), active renin concentration (ARC), and/or active plasma renin concentration (APRC); and
iii. determining a status of the heart condition in said patient or risk of death of said patient based on measured PRR levels and measured PRA, PRAC, ARC, and/or APRC, and/or measured pro-renin activity;
wherein if the patient has an increase of plasma renin activity by more than 5% compared to the baseline level and the patient is determined to have heart failure a treatment is administered to the patient;
wherein if the patient has a decrease of plasma renin activity of more than 5% below compared to the baseline level and the patient does not have heart failure. no treatment is administered to the patient;
wherein the baseline level comprises plasma renin activity levels from a healthy subject.
Claim 21 recites a method of monitoring effectiveness of a treatment in a patient with heart failure or suspected heart failure, wherein the treatment is currently being administered to said patient, comprising the steps of:
determining a status of the patient with suspected heart failure or heart failure by:
i. obtaining a blood sample from the patient; and
ii. directly measuring plasma renin enzymatic activity in the blood sample using a method that does not depend on levels of angiotensinogen;
wherein if the patient has an increase of plasma renin activity by more than 5% compared to the baseline level, a different treatment is administered to the patient;
wherein if the patient has a decrease of plasma renin activity of more than 5% below the baseline level, the patient maintains the current treatment;
wherein the baseline level comprises plasma renin activity levels from a healthy subject.
Step 1- the claim is directed to a process of determining the effectiveness of a treatment by measuring plasma renin activity in a patient suspected of heart failure or with heart failure. Thus, the claim is a process, and therefore to one of the statutory categories.
Step 2a- the claim is directed to a natural relationship between plasma renin activity and heart failure or suspected heart failure. Thus, this is a law of nature and thus a judicial exception (JE).
The determining step by obtaining the blood sample, directly measuring PRA activity and PRR levels are assay steps, and determining a status of the heart condition appears to be an abstract idea- a series of mental steps.
Claim 21 also recites the additional step of determining if the increase or decrease of plasma renin activity can be correlated with the same of different treatment. Such step also appears to be an abstract idea-a series of mental steps that correlate the PRA with a treatment regimen. Although the levels are not recited in the claim, there is enough of a correlation for this rejection. The dependent claims provide more specificity regarding treatments but do not correlate to the wherein clause at the end of claims 11 and 21. So, it is not clear which treatment relates to increases or decreases in plasma renin levels. However, this step does not integrate the JE because it is data that is used by the JE- i.e. the PRA level is what is compared to the first determine step. Therefore, this step is considered to be insignificant extra-solution activity that fails to integrate the JE into a practical application.
Step 2b- As with step 2a, recites drawing a blood sample, measuring plasma renin activity and are conventional medical steps. They do not introduce a specific technological improvement. Thus, the claim recites nothing that amount to significantly more than the abstract idea.
Based on this analysis, claim is directed to patent ineligible subject matter under 35 USC 101.
Acknowledgement is made of the receipt and entry of Applicant’s remarks/arguments filed on December 18, 2025.
Applicant’s argument
Applicant argues the claims are not abstract because they lead to specific, real-world treatment actions-like giving or withholding treatment based on biological measures.
Response to argument
In response, Applicant’s argument is not persuasive. Applicant contends that amended claim 11 is directed to eligible subject matter because it requires real-world treatment actions based on measured biological parameters. However, this argument is not persuasive.
Under the 2019 PEG (Step 2A, Prong 2), the claim must integrate the judicial exception into a practical application. Here, claim 11 recites determining a status based on plasma renin activity and, based on that determination, administering or withholding treatment.
This “if-then” decision-making—i.e., if a certain biomarker level is observed, then administer or adjust treatment; otherwise maintain or withhold treatment—constitutes a mental process or abstract evaluation of a natural law. The additional steps do not impose a meaningful limit on the judicial exception.
In particular, the claim does not recite any specific treatment, dosage, or technological implementation. The term “treatment” is broadly recited and encompasses any conventional or unspecified action, including non-technological activities (e.g., lifestyle changes or general medical decisions). As such, the claim merely links the natural correlation to a generic instruction to act, which does not integrate the exception into a practical application.
Furthermore, under Step 2B, the additional elements—obtaining a blood sample and measuring plasma renin activity—are well-understood, routine, and conventional in the field. The claimed “treatment” step, being unspecified and conventional, does not amount to an inventive concept.
Accordingly, claim 11 remains directed to a judicial exception without significantly more.
Applicant argues that the claims are directed to real-world treatment actions and thus are eligible. However, this argument is not persuasive with respect to claim 20.
Under the 2019 PEG (Step 2A, Prong 2), claim 20 recites determining plasma renin activity and making a treatment decision based on that determination. The claim follows a conditional logic: if plasma renin activity changes relative to a baseline, then modify treatment; otherwise maintain treatment. This constitutes an abstract mental process applied to a natural correlation.
The additional recitation of treatment involving devices such as pacemakers, defibrillators, or artificial hearts does not integrate the exception into a practical application. These devices are well-known, conventional medical tools, and the claim does not recite any improvement in their operation or any specific technological implementation.
Rather, the claim merely uses these conventional devices as tools to carry out the abstract decision, which is insufficient under the 2019 PEG.
Under Step 2B, the additional elements—measuring renin activity and applying known treatment modalities—are routine and conventional. The inclusion of generic medical devices, without any technological improvement or specific implementation, does not provide an inventive concept.
Therefore, claim 20 remains directed to a judicial exception without significantly more.
Modified and revisited rejection
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 non-obviousness.
Claims 11, 14-15, and 17-19 remain rejected and 21, 22, and 24-25 are under 35 U.S.C. 103 as being unpatentable over McMurray et al (Circ Heart Fail. 2008; 1:17-24.) in view of Zanna et al (US2014/0248284A1), Nijst et al (J Renin Angiotensin Aldosterone Syst. 2017 Jul-Sep; 18(3)), Masson et al (Journal of Cardiac Failure, Volume 16, Issue 12, December 2010, Pages 964-970), and Arnal et al (The American Journal of Medicine, Volume 90, Issue 1, January 1991, Pages 17-22).
McMurray teaches a method for monitoring a therapeutic effect of Aliskiren (an oral direct renin inhibitor) in a patient with symptomatic heart failure that is currently being administered an ACE inhibitor or ARB, the method comprising administering aliskiren orally in the amount of 150 mg daily in an ACE inhibitor (or angiotensin receptor blocker) and -blocker. (See Abstract; third paragraph of right column of page 18; and Table 2.) McMurray teaches patients were evaluated at 2, 4, 8, 12 weeks blood sample was obtained after each of the time points. (See second paragraph of right column of page 18.) The patients with heart failure had experienced the compensatory rise in plasma renin (and other downstream RAAS components) caused by ACE inhibitor–induced (or ARB–induced) loss of negative feedback inhibition of renin secretion. This reads on PRA levels or concentrations were previously inherently measure at initial presentation and also reads on determining a status of heart attack based on changes in plasma renin activity. (See second paragraph of right column of page 22.)
McMurray does not teach directly measuring plasma renin activity (PRA) or levels wherein directly measuring plasma renin activity comprises measuring plasma renin activity present in the blood sample using a method that does not depend on levels of angiotensinogen. Additionally, McMurray does not teach if the patient has an increase of plasma renin activity and PRR of more than 5% compared to a baseline level, administering a treatment to the patient; wherein the baseline level comprises plasma renin activity levels from a healthy subject as recited in claim 11 and if the patient has an increase of plasma renin activity by more than 5% compared to the baseline level and the patient is determined to have heart failure, a different treatment is administered to the patient; wherein if the patient has a decrease of plasma renin activity of more than 5% below compared to the baseline level and the patient does not have heart failure. no treatment is administered to the patient maintains the wherein the baseline level comprises plasma renin activity levels from a healthy subject as recited in new claim 21.
Zannad teaches a method for detecting cardiac remodeling in a subject without clinical signs of heart failure, comprising measuring a renin level in a blood sample obtained from said subject, he method further comprising a step of comparing the renin level in the blood sample with a reference value, wherein detecting a differential between the renin level in the blood sample and the reference value is indicative of detecting cardiac remodeling in a Subject without clinical signs of heart failure. (See claims 1 and 2) The reference value is derived from the level of renin in a control sample derived from one or more subjects who are substantially healthy (i.e., having no cardiac remodeling). (See paragraph [0030].) Moreover, Zannad teaches Measuring the renin level may be assessed by any of a wide variety of well-known methods for measuring protein including contacting the blood sample with a binding partner capable of selectively interacting with renin present in the blood sample. The binding partner may be an antibody that may be polyclonal or monoclonal, preferably monoclonal. The binding partner may also be an aptamer. (See paragraph [0017 & [0018].) An inhibitor of the renin angiotensin aldosterone system can be used for the prevention or treatment of heart failure in a subject not afflicted with arterial hypertension wherein said heart failure was previously detected in said subject by the method according to the invention. Typically, the levels of renin in a subject have cardiac remodeling is deemed to be higher than the reference value obtained from healthy subjects who have developed cardiac remodeling. (See Paragraph [0035].) Zannad teaches the inhibitor of the renin angiotensin aldosterone system includes renin inhibitors such as aliskiren. (See paragraph [0036] and [0047].) Furthermore, Zannad teaches the method may also be particularly useful for monitoring the efficacy of a treatment for a cardiac remodeling. (See paragraph [0031].)
Nijst teaches neurohormonal blocker use was high in both cohorts of HFREF patients. However, compared to chronic ambulatory HFREF patients, fewer patients with acute decompensated HFREF were on maintenance therapy with an ACE-i or ARB (50% vs 87%) and it was determined that PRA was measured to be 1.4 ng/ml/h in healthy patient and 7.6 ng/ml/h in ambulatory chronic HFRER which give rise to PRA levels of more than 5% compared to baseline level or healthy patient. (See Table 1 and first and second paragraphs of right column of page 3.) Moreover, Nijst teaches ACE-i and ARB tend to lower aldosterone concentrations, but increase PRA, while beta-blockers might lower both, and MRA increase both. (See last paragraph of right column of page 6, and first paragraph of left column of page 7.)
Masson teaches Plasma renin activity (PRA) is a powerful prognostic marker of death over a wide range of concentrations in patients with chronic HF. (See Abstract.) Moreover, Masson teaches only at baseline, PRA is one estimate of the biologic activity of the renin system. The availability of the substrate angiotensinogen may become limiting for renin activity in case of severe HF. Direct measurement of renin by immunometric methods is less laborious and more used in clinical practice than the method based on angiotensin I generation, but it may be imprecise at low renin concentrations. The direct renin assay yields a high correlation with PRA in patients with primary aldosteronism or chronic HF. Although direct renin measurement may be superior to PRA as a prognostic marker in patients with HF, activity assays and immunoassays usually provide equivalent information about the amount of enzymatically active renin in plasma in the absence of renin inhibition. (See second paragraph of the right column of page 969.)
Arnal teaches low levels of plasma renin substrate can be considered as an indirect index of the severity of heart failure that reflects both the high level of circulating active renin and the decrease in hepatic protein output. In patients with class IV heart failure, low levels of renin substrate led to a marked underestimation of active renin concentration from measurements of PRA. In contrast, direct immunoradiometric assay (IRMA) of active renin measures the true plasma active renin concentration, independent of plasma renin substrate, and closely reflects renin secretion. (See Abstract.)
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the method taught by McMurray to include the steps of obtaining a blood sample from the patient with symptomatic heart failure that is currently being administered an ACE inhibitor or ARB and directly measuring the plasma renin activity by using a method that does not depend on levels of angiotensinogen and determining changes in plasma renin activity compared to a baseline level where the baseline level comprising PRA levels from a healthy subject to give Applicant’s claimed method. The motivation to do so is because McMurray teaches loss of negative feedback inhibition of renin release during chronic treatment with an angiotensin converting enzyme (ACE) inhibitor leads to a compensatory rise in renin secretion and downstream components of the renin-angiotensin-aldosterone (RAAS) cascade, but does not teach the method for showing the increase in PRA levels by more than 5% compared to baseline. Said deficiency is remedied by the teaching of Nijst. Additionally, the motivation to modify the method of McMurray is also provided by Zannad which teaches the step of obtaining a biological sample of renin, measuring the PRA and determining a status of the heart condition based on the measured PRA, by direct measurement of renin by immunometric methods is less laborious and more used in clinical practice than the method based on angiotensin I generation, but it may be imprecise at low renin concentrations. The direct renin assay yields a high correlation with PRA in patients with primary aldosteronism30 or chronic HF as taught by Masson, and by the fact Arnal teaches direct immunoradiometric assay (IRMA) of active renin measures the true plasma active renin concentration, independent of plasma renin substrate. One would reasonably expect the modified method to monitor the effectiveness of Aliskiren in a patient with symptomatic heart failure that is currently being administered an ACE inhibitor or ARB successfully by directly measuring PRA. Lastly one would reasonably expect to maintain the treatment of Aliskiren in combination with ACE inhibitor or ARB as said combination had favorable neurohumoral effects in heart failure and appeared to be well tolerated be effective and safe as taught by McMurray.
Claims 11, 14-15, 17-19, 20, 21, 22, and 24-25 are rejected under 35 U.S.C. 103 as being unpatentable over McMurray et al (Circ Heart Fail. 2008; 1:17-24.) in view of Zanna et al (US2014/0248284A1), Nijst et al (J Renin Angiotensin Aldosterone Syst. 2017 Jul-Sep; 18(3)), Masson et al (Journal of Cardiac Failure, Volume 16, Issue 12, December 2010, Pages 964-970), and Arnal et al (The American Journal of Medicine, Volume 90, Issue 1, January 1991, Pages 17-22) as applied to claims 11, 14-15, 17-19, and 21, 22, and 24-25 in further view of Stecker et al (Am Heart J. 2006 Apr;151(4):820-8).
The teachings of McMurray, Zannad, and Nijst, Masson, and Arnal have been discussed in the second rejection set forth above.
McMurray, Zannad, and Nijst, Masson, and Arnal collectively do not teach treatment further comprising devices that improve or stabilize cardiac function comprising pacemaker as applied to claim 20.
Stecker teaches prophylactic pacemaker insertion to facilitate beta-blocker treatment in patients with CHF with low resting heart rates has the potential to produce clinical benefits in a highly cost-effective manner. (Abstract.)
It would have been prima facie obvious for a person of ordinary skill in the art at the time of the invention was filed to combine the modified method disclosed by McMurray, Zannad, and Nijst, Masson, and Arnal with the method set forth by Stecker because each is taught by the prior art to be useful for the same purpose (i.e., treating heart failure). See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Further, a person of ordinary skill in the art would reasonably have expected to be successful because both compositions were shown to be useful separately for the exact same purpose and thus would be expected to be similarly useful when used together.
Acknowledgement is made of the receipt and entry of Applicant’s remarks/arguments filed on December 18, 2025.
Applicant’s argument
Applicant argues assuming arguendo that there is a motivation to either modify the primary cited prior reference or to combine the primary cited prior reference with other references, the primary cited prior reference by itself, or in combination with other references, must suggest or teach every feature of the claimed invention in order to make obvious the claimed invention. Applicant respectfully asserts that Examiner is using improper hindsight and is simply choosing certain teachings from the aforementioned cited prior arts to construct the methods presently claimed.
Response to argument
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In the present case, the combination is based on explicit teachings in the prior art, not on applicant’s disclosure. Specifically, Murray teaches that ACE inhibitor use triggers a compensatory rise in renin, provide a clear rational to target renin directly. Other references, like Zamad or Njist. Show methods to measure renin activity or related markers. One of ordinary skill would naturally connect these known steps to address the known issue-thus, the combination is guided by the references themselves, not hindsight.
Applicant’s argument
Applicant argues first, McMurray teaches away from using a renin inhibitor to treat heart failure, let alone from monitoring treatment effectiveness based on plasma renin activity (PRA). McMurray expressly reports that "there was no difference between treatments for change in symptoms or signs between baseline and the end of the study," and that there were "no differences in echocardiographic measurements of wall thickness, chamber volumes, or LVEF" (page 20, left column, last paragraph). Critically, four patients treated with aliskiren discontinued the study due to worsening heart failure (pages 20-21). These results would discourage, rather than motivate, a person of ordinary skill in the art from using a renin inhibitor to treat heart failure or from using renin-related measurements to guide treatment decisions. Thus, McMurray not only fails to teach Applicant's claimed method, but affirmatively teaches away from the use of renin inhibition as an effective heart failure therapy.
Second, Applicant respectfully disagrees with the Examiner's interpretation of Zannad as teaching a method of detecting cardiac remodeling or heart failure by measuring renin levels. Although Zannad reports renin measurements, the data do not support a meaningful correlation between renin levels and cardiac remodeling. Specifically, Table 1 of Zannad shows that active renin levels are not statistically different between the compared groups (p = 0.12). In contrast, left ventricular mass (LVM)-a recognized marker of cardiac remodeling is statistically significant between the groups (p = 0.003). Thus, Zannad's own data demonstrate that renin levels do not track with cardiac remodeling, undermining the Examiner's assertion that Zannad teaches or suggests such a relationship. Moreover, Zannad does not teach heart failure treatment, monitoring, or prognosis. Accordingly, a person of ordinary skill in the art would have no reason to combine Zannad's teachings with McMurray's heart failure study, absent impermissible hindsight. There is no logical or scientific basis for linking Zannad's renin measurements to McMurray's heart failure treatment.
Third, Nijst does not establish a convincing relationship between changes in PRA and heart failure severity or remodeling. As shown in Table 1 (and Figure 1), there is no statistically significant difference in PRA between healthy subjects and patients with severe heart failure. In other words, PRA levels in these two groups are essentially indistinguishable. Although Nijst reports differences in PRA between healthy subjects and patients with less severe heart failure, PRA fails to account for differences in cardiac remodeling when the full set of clinical variables is considered. Indeed, the multivariate analysis in Table 2 (including LVEF) demonstrates that PRA is not independently predictive. Further, Nijst does not teach direct measurement of PRA, but instead relies on an indirect assay based on angiotensin I generation, which is dependent on substrate availability. This stands in direct contrast to Applicant's claimed invention, which requires direct PRA measurement independent of angiotensinogen.
Fourth, Masson does not teach that PRA is a reliable prognostic marker for mortality in heart failure patients. Masson expressly acknowledges that mortality outcomes are confounded by ACE inhibitor dosage and other medications (pages 697-698), all of which directly alter renin levels. As such, PRA cannot be interpreted in isolation and does not provide a clear or actionable prognostic signal.
Similarly, Arnal highlights the unresolved analytical difficulties associated with PRA measurement, noting the cumbersome and technically challenging nature of PRA assays (page 269). Arnal further explains that substrate availability (angiotensinogen) becomes limiting in severe heart failure, rendering PRA measurements unreliable and difficult to interpret. Importantly, Arnal expressly acknowledges that it is unknown whether reducing PRA through pharmacological intervention improves clinical outcomes, demonstrating fundamental uncertainty in the field.
Taken together, the cited references describe a field that is highly uncertain and unpredictable, in which renin and PRA measurements are inconsistent, technically challenging, and confounded by concurrent therapies. The prior art repeatedly acknowledges that renin or PRA levels do not reliably correlate with heart failure outcomes, that PRA assays present significant analytical limitations, that commonly used heart failure medications directly alter renin levels, and that it remains unclear whether modifying PRA through pharmacological intervention leads to improved patient outcomes. In view of these acknowledged limitations and uncertainties, a person of ordinary skill in the art would not have been motivated to combine the teachings of McMurray, Zannad, Nijst, Masson, Arnal, and Nguyen to arrive at the claimed invention, and any such combination can only be reached through impermissible hindsight reconstruction.
Response to argument
In response, Applicant’s argument is not persuasive.
1. Applicant’s argument that McMurray “teaches away” is not persuasive. A reference teaches away only when it criticizes, discredits, or discourages the claimed approach. Here, McMurray does not do so. Rather, McMurray expressly administers Aliskiren to heart failure patients already receiving ACE inhibitor or ARB therapy and evaluates its effects, thereby affirmatively teaching the very use alleged to be discouraged. While McMurray reports that certain endpoints did not show statistically significant improvement, such neutral or mixed results do not constitute teaching away, but instead reflect routine clinical variability. Importantly, McMurray further reports favorable neurohormonal effects and acceptable tolerability, which would have encouraged, not discouraged, further investigation and monitoring of renin-related parameters. The fact that McMurray studied it → that is not teaching away.
2. Applicant’s reliance on the lack of statistical significance in a particular dataset in Zannad is not persuasive. A reference need not demonstrate statistical significance to be relevant prior art. Zannad expressly measures renin levels in heart failure patients, thereby confirming that renin-related biomarkers were recognized in the art as clinically relevant parameters.Moreover, the fact that other markers (e.g., LVM) showed stronger statistical correlation does not negate the teaching of measuring renin, but instead reflects that multiple biomarkers were understood to contribute to assessment of cardiac status. A person of ordinary skill in the art would have considered renin measurements as part of a broader diagnostic framework, not in isolation.
3. Applicant’s argument improperly demands that Nijst establish a definitive or exclusive correlation between PRA and heart failure severity. However, obviousness does not require that a reference demonstrate perfect predictive capability. Nijst teaches that PRA levels vary with treatment and physiological conditions in heart failure patients, thereby confirming that PRA reflects biological activity of the renin system. Such teachings would have motivated a person of ordinary skill in the art to monitor PRA as a relevant physiological parameter, even if not determinative in isolation.
4. Applicant’s argument that PRA is confounded by other variables does not negate its recognized utility. As acknowledged by Masson, PRA is a prognostic marker associated with heart failure outcomes, even if influenced by concomitant therapies.The presence of confounding variables is common in clinical biomarkers and would have motivated further refinement and measurement, not abandonment. Thus, Masson supports the relevance of PRA in assessing heart failure status.
5. Applicant’s reliance on Arnal’s discussion of analytical limitations is not persuasive. Arnal does not discourage the use of renin-related measurements, but rather identifies technical limitations associated with indirect PRA assays, particularly due to substrate dependence. Notably, Arnal further teaches that direct measurement methods (e.g., immunometric assays) provide more accurate assessment of active renin, thereby suggesting improvement rather than abandonment of renin measurement techniques.Thus, Arnal would have motivated a person of ordinary skill in the art to utilize or develop improved direct measurement approaches, consistent with the claimed method.
Applicant’s arguments improperly attack the references individually and require each reference to independently establish the claimed invention. However, obviousness is determined based on the combined teachings of the prior art. Collectively, the cited references establish that:
The Renin-Angiotensin-Aldosterone System is central to heart failure pathology (McMurray);
Renin and PRA were measured and recognized as clinically relevant biomarkers (Zannad, Nijst, Masson);
Limitations of existing assays were known, and improved direct measurement techniques were suggested (Arnal).
These teachings would have led a person of ordinary skill in the art to monitor renin-related parameters, including via direct measurement, to assess and guide treatment in heart failure patients, with a reasonable expectation of obtaining clinically meaningful information.
Applicant’s assertion of “uncertainty” does not negate obviousness, but rather reflects a predictable and evolving field in which routine optimization and combination of known techniques would have been obvious.
New Rejection necessitated by claim amendment
Claims 11, 14-15, 17-19, 21, 22, 23, and 24-25 rejected under 35 U.S.C. 103 as being unpatentable over McMurray et al (Circ Heart Fail. 08; 1:17-24.) in view of Zanna et al (US2014/0248284A1), Nijst et al (J Renin Angiotensin Aldosterone Syst. 2017 Jul-Sep; 18(3)), Masson et al (Journal of Cardiac Failure, Volume 16, Issue 12, December 2010, Pages 964-970), Arnal et al (The American Journal of Medicine, Volume 90, Issue 1, January 1991, Pages 17-22), and Nguyen et al (Hypertension. 2014; 63:297-302).as applied to claims 11, 14-15, 17-19, 21, 22, and 24-25 in further view of Schmiedt et al (AJVR, Vol. 70, No. 11, November 2009).
The teachings of McMurray, Zannad, and Nijst, Masson, Arnal, and Nguyen have been discussed in the second rejection set forth above.
McMurray, Zannad, and Nijst, Masson, Arnal, and Nguyen collectively do not teach exogenous fluorescent resonance transfer peptide.
Schmiedt hypothesizes that the fluorimetric renin assay would provide sufficient dose-response linearity and sensitivity for measurement of renin concentration in feline plasma samples to enable detection of changes in that clinicopathologic variable attributable to ischemia reperfusion injury of the kidneys in cats. (See second paragraph of the right column of page 1316.) Moreover, Schmiedt teaches the study data indicated that the assay involving the FRET peptide substrate of renin is potentially a rapid and specific method for measurement of plasma renin concentration in cats. (See Abstract.)
It would have been prima facie obvious for a person of ordinary skill in the art at the time of the invention was filed to modify the method disclosed by McMurray, Zannad, and Nijst, Masson, Arnal, and Nguyen by using the exogenous fluorescent resonance transfer peptide as taught by Schmiedt to give Applicant’s claimed method. One would have been motivated to so, because Schmiedt teaches the study data indicated that the assay involving the FRET peptide substrate of renin is potentially a rapid and specific method for measurement of plasma renin concentration in cats. One would reasonably expect said FRET assay to efficiently and rapidly measure plasma renin activity.
Conclusion
Claims 11, 14-15, and 17-25 are not 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEAN P CORNET whose telephone number is (571)270-7669. The examiner can normally be reached Monday-Thursday from 7.00am-5.30pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy L Clark can be reached on 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JEAN P CORNET/ Primary Examiner, Art Unit 1628