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 .
DETAILED ACTION
The office acknowledges Applicants response to the restriction election requirement and filing of the amended claims on 5/30/2025. Applicants have elected Group I, claims 1-5 and HDAC6 inhibitor, givinostat as the species for examination. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.03(a)). The restriction requirement is made Final. Claims 1-23 are pending. Claims 6-23 are withdrawn from further consideration pursuant to 37 C.F.R. 1.142(b), as being drawn to non-elected subject matter. The claims corresponding to the elected subject matter are 1-5 and are herein acted on the merits.
Application Priority
This application filed 06/01/2022 is a National Stage entry of PCT/US2020/ 062943, International Filing Date:12/02/2020, PCT/US2020/062943 Claims Priority from Provisional Application 62942410, filed 12/02/2019.
Information Disclosure Statement
The information disclosure statement(s) (IDS) filed on 11/18/2022, 5/30/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS is being considered by the Examiner.
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.
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 no obviousness.
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) 1-5 are rejected under 35 U.S.C. 103 as being unpatentable over Jeong et al. (IDS: Sci. Transl. Med. 10, 0144 (2018) and Zile (Circulation, Volume 131, Issue 14, 7 April 2015; Pages 1247-1259).
Jeong teach that heart failure with preserved ejection fraction (HFpEF) is characterized by increased left ventricular (LV) filling pressure, increased LV stiffness, and prolonged relaxation in the presence of normal systolic function (p 1, col. 1, para 1). The giant myofibrillar protein titin has been implicated in the regulation of cardiomyocyte relaxation (16), and the abundance of specific titin isoforms, as well as the phosphorylation state of titin, affects the stiffness of cardiomyocytes independently of fibrosis, both in experimental models and in hearts of patients with HFpEF (p 1, col.2, para 2). Jeong has demonstrated that the HDAC inhibitor ITF2357 (givinostat, currently in a phase 3 trial in patients with Duchenne muscular dystrophy), improves relaxation of the heart in rodent models of diastolic dysfunction with preserved EF. ITF2357 did not elicit discernable toxicity, and efficacy was independent of alterations in blood pressure, cardiac hypertrophy, cardiac fibrosis, or cardiac titin and MyHC isoform expression. We define impaired myofibril relaxation as an HDAC-dependent mechanism for diastolic dysfunction and demonstrate that patients with restrictive cardiomyopathy (RCM) characterized by diastolic dysfunction with preserved EF also exhibit diminished myofibril relaxation properties. The data suggest that stress stimuli impinge on myofibrils to promote diastolic dysfunction, and HDAC inhibitors or other agents that target myofibrils could be used to improve diastolic function of the heart in the context of HFpEF (p 1, col. 2 last para to page col. 1, para 1). Further taught is that HDAC inhibition attenuates diastolic dysfunction in Dahl salt-sensitive rats (See p 2, col. 1, Results). HDAC inhibition blunts age-dependent diastolic dysfunction and myofibril relaxation impairment in mice (see p 5, col. 2, para 2). Translating the findings to humans, cardiac myofibrils from patients with diastolic dysfunction and preserved EF also exhibited compromised relaxation. These data suggest that agents such as HDAC inhibitors, which potentiate cardiac myofibril relaxation, hold promise for the treatment of HFpEF in humans (See Abstract).
Zile et al. disclose that patients with hypertension and heart failure with preserved ejection fraction (HFpEF) have markedly increased passive myocardial stiffness due to increases in the contribution of both collagen and titin. These results suggest that the development of HFpEF is linked to a major increase in passive stiffness caused by changes in both collagen and titin homeostasis (See Conclusions p 1247 and p 1257).
From the teachings of Jeong a person skilled in the art before the effective filing date of the invention would have found it obvious to administer an effective amount of givinostat to patients with heart failure with preserved ejection fraction (HFpEF). Zile teach that patients with hypertension and heart failure with preserved ejection fraction (HFpEF) have markedly increased passive myocardial stiffness due to increases in the contribution of both collagen and titin. Hence administration of an effective amount of givinostat to the subject with HFpEF (a patient in need thereof) will modulate the cardiac stiffness and increase the titin compliance. Thus claim 1 is addressed. As to claim 2, a person skilled in the art would have found it obvious to further administer givinostat to the subjects to maintain therapeutic efficacy and effects. It is noted that claims 3-5 are mechanisms that result from the administration of an effective amount of non-selective HDAC6 inhibitor. As to claims 3-4 it would have been obvious to a skilled person in the art that administration of the elected agent, givinostat in the method would result in modulation of titin stiffness without titin stiffening, modulation of myofibril tension as Jeong teach that HDAC inhibition by givinostat blunts age-dependent diastolic dysfunction and myofibril relaxation impairment in mice. As to claim 5, Zile teach that HFpEF is linked to a major increase in passive stiffness caused by changes in both collagen and titin homeostasis. Hence administration of givinostat to patients with HFpEF will result in the modulation of cardiac muscle passive stiffness.
Claim(s) 1-5 are rejected under 35 U.S.C. 103 as being unpatentable over Barefield et al. (Journal of the American Heart Association, Volume 7, Issue 22, 20 November 2018), McNamara et al. (Circ Res. 2018 October 12; 123(9): 1024–1029), Linke (IDS: Annual Review of Physiology, 2018. 80:389–411) and Zile (Circulation, Volume 131, Issue 14, 7 April 2015; Pages 1247-1259).
Barefield teach that “Timothy McKinsey, PhD from the University of Colorado presented his work on inhibition of histone deacetylases to treat diastolic dysfunction in HFpEF. Dr McKinsey’s study used the histone deacetylase (HDAC) givinostat to treat fibrosis and improve myofilament relaxation. HDAC inhibition has been shown to reduce fibrosis by limiting fibroblast proliferation through epigenetic modulation of fibroblasts. However, in Dr McKinsey’s work, the direct effect of HDAC inhibition on myofilament relaxation was evaluated using direct measurements of single myofibril relaxation. This work showed that HDAC inhibition by givinostat reversed the slowed myofibril relaxation found in 2 small animal models of diastolic heart failure. This provides a novel role for HDACs directly altering posttranslational modifications on myofilament proteins. HDAC inhibitors are already used clinically as a cancer therapy, and these data demonstrate a promising potential alternative use of HDAC inhibitors to treat HFpEF” (page 2, col. 2, para 1).
McNamara teach that heart failure with preserved ejection fraction (HFpEF) is an emerging epidemic cardiovascular disease and a hot topic these days. The effect of givinostat, a histone deacetylase inhibitor, in the treatment of diastolic dysfunction and HFpEF was presented by Dr. Tim McKinsey. Of note, he showed that HFpEF and diastolic dysfunction directly slowed myofilament relaxation and that treatment with givinostat abolished this effect (p 2, para 3).
Linke is explicit in teaching that altered I-band titin phosphorylation is found in failing hearts and thought to cause pathological myocardial stiffening in patients with systolic or diastolic heart failure (See 2.2.3., page 393).
Zile as discussed above.
From the teachings of Barfield, McNamara a person skilled in the art before the filing date of the invention would have found it obvious that HDAC inhibition by givinostat reversed the slowed myofibril relaxation found in 2 small animal models of diastolic heart failure; HFpEF and diastolic dysfunction directly slowed myofilament relaxation and that treatment with givinostat abolished this effect. From Linke it is obvious that altered I-band titin phosphorylation is found in failing hearts and thought to cause pathological myocardial stiffening in patients with systolic or diastolic heart failure. From Zile it is obvious that HFpEF patients have markedly increased passive myocardial stiffness due to increases in the contribution of both collagen and titin. It would have been obvious to a skilled artisan from the teachings of Barfield, McNamara to use givinostat (non-selective HDAC6 inhibitor) in treating HFpEF in patients. A person skilled in the art would have been motivated to administer to an effective amount of givinostat to a subject with HFpEF to derive therapeutic effects. As to the limitation of modulating cardiac stiff muscle by increasing titin compliance, it is noted that myocardial stiffening is associated with titin in patients with systolic or diastolic heart failure and administration of givinostat to HFpEF subjects with diastolic dysfunction will render such effects. Thus claim 1 is addressed. As to claim 2, a person skilled in the art would have found it obvious to further administer givinostat to the subjects to maintain therapeutic efficacy and effects. It is noted that claims 3-5 are mechanisms that result from the administration of an effective amount of non-selective HDAC6 inhibitor, herein givinostat (elected species). Hence administration of the elected agent, givinostat in the patients in need thereof (HFpEF with diastolic dysfunction) would result in modulation of titin stiffness without titin stiffening, modulation of myofibril tension. As to claim 5, Zile teach that HFpEF is linked to a major increase in passive stiffness caused by changes in both collagen and titin homeostasis. Hence administration of givinostat to patients with HFpEF will result in the modulation of cardiac muscle passive stiffness.
Claim Rejections - 35 USC § 112
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.
Claim 2 is 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.
Applicants elected givinostat as the species for non-selective HDAC6 inhibitor for examination. Claim 2 is to further comprising administering givinostat. It is not clear how ‘givinostat’ is further administered when it is administered in claim 1 method step(s). Is it the same administered again or a different non-selective HDAC6 inhibitor being administered? Clarification is required.
Note: For examination purposes the claim has been examined based on the interpretation that givinostat is further administered (repeat dose).
Conclusion
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/Umamaheswari Ramachandran/ Primary Examiner, Art Unit 1627