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 .
The amendment filed 22 July 2026 has been received, entered and considered. The following information has been made of record in the instant amendment:
1. Claims 1-15, 17-18, and 21-23 have been canceled. Claims 17-18 and 21-23 were canceled in the instant filing.
2. No new Claims have been added.
3. Claims 16 and 24 have been amended.
4. Remarks drawn to objections to drawings and rejections under 35 USC 103
The following objection(s)/rejection(s) has/have been overcome:
The objection to Figures 2-4 and 6-7 has been overcome by providing replacement drawings that are clear.
Claims 16, 19-20 and 24-30 are pending in the case.
The following rejections are necessitated by Applicant's amendment filed 22 July 2026 wherein the limitations in pending claims 16 and 24 have been amended.
The rejection of Claim(s) 17-18 and 21-23 under 35 U.S.C. 103 as being unpatentable over Zhang et al (Journal of Molecular and Cellular Cardiology, 2017, 112, 64-73) in view of Borlaug et al (European Heart Journal, 2011, 32, 670-679) has been rendered moot by cancelation.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 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 16, 19-20 and 25-30 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for the method of treating heart failure with preserved ejection fraction via administration of a therapeutically effective amount of a compound of formula (I), does not reasonably provide enablement for the method via administration of any compound of formula (I) wherein R7 is the substitution
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as broadly encompassed by claim 16. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
A conclusion of lack of enablement means that, based on the evidence regarding each of the factors below, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation.
(A) The breadth of the claims
(B) The state of the prior art
(C) The level of predictability in the art
(D) The amount of direction provided by the inventor
(E) The existence of working examples
(F) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The breadth of the claims
Claim 16 is drawn to a method of treating heart failure with preserved ejection fraction via administration of a therapeutically effective amount of a compound of formula (I). Claim 16 does not define the substitution R9 in the above formula. This means tht any substitution can be used for R9.
The state of the prior art
According to Gazewood et al (American Family Physician, 2017, 96 (9), 582-588) patients with heart failure with preserved ejection fraction are treated with specific drugs, and even in such cases some treatments failed to show reduction in mortality or hospitalization (page 585-see under sub-heading: Data from Clinical Trials, and eTableA). From the teaching of Gazewood one of ordinary skill in the art will recognize that a compound with any substitution for R9 in the moiety:
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will treat heart failure with preserved ejection fraction. Derivatives have to be made and tested.
The teaching of Gazewood tells the artisan that not all derivatives with the substitution as above are suitable. This indicates that undue experimentation is needed in order to use the compound of formula (I) having the above moiety as active agents in the claimed method.
Therefore, one of ordinary skill in the art would not extrapolate the information in the prior art to the instant method as broadly encompassed by claim 16 and dependents thereof.
The level of predictability in the art
Based on the teaching of the prior art it is highly unpredictable that any derivative of as broadly encompassed would treat heart failure with preserved ejection fraction.
The amount of direction provided by the inventor
The instant specification is not seen to provide enough guidance that would allow a skilled artisan to extrapolate from the disclosure and the examples provided to enable the claimed method of treating heart failure with preserved ejection fraction using the compound of formula (I) as broadly encompassed by claim 16. Only one compound, namely compound 001 (structural formula recited in claim 24) has been tested in a hamster model and compared to vardenafil, and vardenafil and compound 001 combination.
The existence of working examples
The above working example set forth in the instant specification is drawn to the effect of compound 001 on a hamster model on cardiac function. Despite this example there is little enabling disclosure, especially in view of the state of the art, for the claimed method using any derivative having the substitution above as broadly encompassed for R9. One of ordinary skill in the art, in view of the prior art cited above, will not conclude that any derivative of NMN can be used in the claimed method. Applicant is therefore not entitled to claim a method of treating heart failure with preserved ejection fraction using any derivative having the substitution above as broadly encompassed for R9.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
In view of the information set forth, the instant disclosure is not seen to be sufficient to enable the use of any derivative as above in a method of treating heart failure with preserved ejection fraction. One of ordinary skill in the art would have to carry out undue experimentation with several different derivatives to determine the efficacy of the compounds in the claimed method with no assurance of success.
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 16, 19-20 and 24-30 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.
In amended claim 16 the definition for R9 has been deleted. R9 appears in the Markush member:
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which is one of the substitutions for R7. The metes and bounds as to what all are intended for R9 is unknown. This renders claim 16 and dependents thereof indefinite.
Claims 19-20 and 24-30, which depend from a rejected base claim that is unclear/indefinite are also rendered unclear/indefinite and are rejected for the same reasons. All claims which depend from an indefinite claim are also indefinite. Ex parte Cordova, 10 U.S.P.Q. 2d 1949, 1952 (P.T.O. Bd. App. 1989).
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 24 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 24 recites structural formulas 009-014. The said formulas show two phosphate groups linking the two ribose moieties bearing the nicotinamide groups, which is defined as one of the substitutions for R7. Claim 24 depends from independent claim 16. In claim 16 the formula
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is defined as one of the substitutions for R7. However, this substitution has the group R9 on it, and R9 has not been defined in claim 16. Therefore, claim 24 does not further limit claim 16.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
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.
Claim(s) 16, 19-20 and 24-30 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al (Journal of Molecular and Cellular Cardiology, 2017, 112, 64-7; of record) in view of Borlaug et al (European Heart Journal, 2011, 32, 670-679; of record).
Zhang et al teaches that heart failure is associated with mitochondrial dysfunction so that restoring or improving mitochondrial health is of therapeutic importance. Reduction in NAD+ levels and NAD+ mediated deacetylase activity has been recognized as negative regulators of mitochondrial function. Using a cardiac specific KLF4 deficient mouse lines that is sensitive to stress, it was found that mitochondrial protein hyperacetylation coupled with reduced Sirt3 and NAD+ levels in the heart rate before stress, suggesting that KLF4 deficient heart is predisposed to NAD+ associated defects. Administration of nicotinamide mononucleotide, which is a precursor of NAD+, successfully protected the mutant mice from pressure overload-induced heart failure. Nicotinamide mononucleotide preserved mitochondrial ultrastructure, reduced ROS and prevented cell death in the heart (Abstract; page 65, left col., first full para, last three lines; page 68, para 3.1 through page 71, para 3.5, and discussion; compound of formula (I) and heart failure as in claim 16, and limitations of claims 19-20, 24 (formula 001)). The mice were administered b-nicotinamide mononucleotide in PBS (page 65, right col., last four lines of the top para; limitation of claim 30).
Zhang et al does not expressly teach heart failure with preserved ejection fraction as in claim 16, the use of some of the compounds of formula (I) in claim 16 as active agents in the method, part of the limitations of claim 24, and the limitations of claims 25-29.
Borlaug et al teaches that half of the patients with heart failure have a preserved left ventricular ejection fraction, denoted by HFpEF (Abstract; heart failure with preserved ejection fraction as in claim 16). Patients with HFpEF have dyspnea, fatigue, impaired diastolic function (page 674, left col., lines 2-3 in para below figure; page 674, right col., first full para, lines 6-7; symptoms recited in claims 25 and 26). Such patients also have pulmonary arterial hypertension and >40% left ventricular ejection fraction (page 671, right col., first full para, last line; page 676, right col., last para, lines 6-8; limitation of claims 27 and 28). Active agents like angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARB) and beta blockers have been used for treatment of patients with HFpEF patients (page 676, right col. last para, lines 1-4; active agents recited in claim 29).
It can be seen that the combined teachings of the prior art suggest that nicotinamide mononucleotide, which falls under the definition for compound of formula (I), can be used as an active agent in a method of treating heart failure with preserved ejection fraction in a subject as in claim 16, including subjects having symptoms and comorbidities as in claims 25-28. The compound of formula can also be administered with the active agents recited in claim 29.
One of ordinary skill in the art, in view of the combined teachings of the prior art, will also administer all the other compounds encompassed by formula (I) in claim 16, the compound having the substitution as in claim 22, and compounds 002 through 014 as in claim 24 as active agents in the claimed method since they are all structural variants of nicotinamide mononucleotide. There is a reasonable expectation that all these derivatives of formula (I) will act as precursors of NAD+, since reduction in NAD+ levels and NAD+ mediated deacetylase activity has been recognized as negative regulators of mitochondrial function which leads to HFpEH. The artisan would also administer the claimed active agents to subjects that have all the other symptoms and comorbidities as in claims 25 and 28 and would also administer the other active agents recited in claim 29 with the compounds of formula (I) since the symptoms and comorbidities, and the other active agents are related. The artisan would look for combinations of the other active agents with formula (I) in view of the prior art teachings, which have enhanced treatment effects.
MPEP 2141 states, "The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit. The Court quoting In re Kahn, 441 F.3d 977, 988, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006), stated that "[R]ejections on obviousness cannot be sustained by mere conclusatory statements; instead, there must be some articulated reasoning with some rational underpinning to support the legal conclusion of obviousness.'" KSR, 550 U.S. at, 82 USPQ2d at 1396. Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) " Obvious to try " choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention."
According to the rationale discussed in KSR above, the rationale in (G) above is seen to be applicable here since based on the prior art teachings, nicotinamide mononucleotide is suggested in the art as a potential active agent for treating HFpEF in a subject. Thus, it is obvious to arrive at the claimed method of treatment in view of the combined teachings of the prior art.
Thus, the claimed invention as a whole would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention over the combined teachings of the prior art. Method improvement is the motivation. One of ordinary skill in the art would look for structurally close/similar alternatives to nicotinamide mononucleotide as active agents with enhanced treatment effects in the claimed method.
Response to Applicants’ Remarks
Applicant has traversed the rejection of claims 16, 19-20 and 24-30 under 35 USC 103 as it applies now arguing that Zhang teaches that short term administration of NMN successfully protected KLF4-deficient mice from pressure overload-induced heart failure. It does not disclose the interest in using NMN for treatment of heart failure with preserved ejection fraction (HFpEF). The model used by Zhang is an acute model of heart failure. This model induces both diastolic and systolic dysfunctions. The CMK4KO mice subjected to transverse aortic constriction which induces pressure overload. This presents a systolic dysfunction. Therefore, Zhang suggests that NMN has a positive effect of systolic dysfunction. Even if the model used by Zhang presents diastolic dysfunction, the effects of NMN on diastolic dysfunctions are not explored in Zhang. Therefore, Zhang provides no indication on the effects of NMN on diastolic dysfunction, and therefore, does not provide information on the treatment of HFpEF which is characterized by diastolic dysfunction in the absence of systolic dysfunction.
Borlaugh teaches that HFpEF is characterized by simultaneous presence of signs and/or symptoms of HF, evidence of normal systolic LV function, and evidence of diastolic LV dysfunction or of surrogate markers of diastolic LV dysfunction (page 675, right col). The evidence of normal systolic LV function comprises a preserved ejection fraction and a normal fractional shortening. This was observed in the present application, in which diastolic dysfunction was clearly observed in parallel (para 0223, Figs 2-3). In some cases, regional measures of systolic function are mildly impaired in HFpEF patients while global measures of systolic function appear preserved (page 672, right col). However, in such cases, systolic function is clearly not as impaired in HFrEF as in HFrEF (page 673, right col). The presence of some impairment of regional measures of systolic function in some HFpEF patients may reflect the fact that the patient is transitioning from HFpEF to complete heart failure with both diastolic and systolic dysfunction. Therefore, systolic dysfunction is, in no way, a characteristic of HFpEF. A person of ordinary skill in the art would not be motivated to perform the proposed combination. The instant claims are not obvious, and withdrawal of the rejection is requested. (Remarks-pages 12-16).
Applicants’ arguments are not persuasive. According to Borlaugh in some cases, regional measures of systolic function are mildly impaired in HFpEF patients while global measures of systolic function appear preserved. However, in such cases, systolic function is clearly not as impaired in HFpEF as in HFrEF. The presence of some impairment of regional measures of systolic function in some HFpEF patients may reflect the fact that the patient is transitioning from HFpEF to complete heart failure with both diastolic and systolic dysfunction. This teaching of Borlaugh suggests to one of ordinary skill in the art that a patient can also have HFpEF with diastolic dysfunction too with systolic not as impaired as in HFrEF. So, it can be a case wherein the patient is having HFpEF.
According to applicant Zhang’s model induces both diastolic and systolic dysfunctions, and Zhang uses NMN as the active agent to treat heart failure. This indicates that NMN can also be administered as an active agent to treat HF with diastolic dysfunction (HFpEF), especially in cases where systolic function is clearly not as impaired in HFpEF as in HFrEF. Zhang may not have explored the effects of NMN on diastolic dysfunction. The artisan would not understand this to mean that NMN does not have an effect on diastolic dysfunction. The effect of an active agent on some aspect of a disease not explored does not necessarily mean that it won’t have an effect on it or it will not treat that disease or condition. In view of Zhang not having explored the effect of NMN on diastolic dysfunction, and in view of the teaching of Borlaugh as pointed out by the applicant, one of ordinary skill in the art would look into the effect of NMN on diastolic dysfunction too. The artisan would have a reasonable expectation of success in treating a patient with HFpEF using NMN as an active agent in view of the teachings of Zhang and Borlaugh.
In view of the above teaching of Zhang and Borlaugh one of ordinary skill in the art would be motivated to arrive at the claimed method since based on the teachings of the prior art NMN can treat HF with both HFrEF and HFpEF. The rejection is maintained.
Conclusion
1. Pending claims 16, 19-20 and 24-30 are rejected.
2. Claims 1-15, 17-18, and 21-23 have been canceled.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GANAPATHY KRISHNAN whose telephone number is (571)272-0654. The examiner can normally be reached M-F 8.30am-5pm.
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/GANAPATHY KRISHNAN/Primary Examiner, Art Unit 1693
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