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
This Office Action is responsive to the Response to Election/Restriction and Amendment filed 09/18/2025, wherein the amendment amended claims 4, 7, 9, 11, 13, 15, 17, 21, 44, and 45, and cancelled claim 1.
Claims 4, 7, 9, 11, 13, 15, 17, 21, and 41-48 are pending.
Note: Independent claim 21 is preceded by dependent claims 1, 4, 7, 9, 11, 13, 15, and 17. If the application is allowed, the claims will be renumbered, such that the independent claim precedes any dependent claims.
Priority
This application claims the following priority:
PNG
media_image1.png
100
669
media_image1.png
Greyscale
Election/Restrictions
Applicant’s election without traverse of Group II, a method of use, and a) a combination of HDAC inhibitor and MR antagonist as the “combination of two or more histone acetylation code agents,” b) valproic acid as the HDAC inhibitor and canrenone as the MR antagonist, and c) ischemic damage as the single disclosed disease or condition that causes tissue and/or organ injury, in the reply filed on 09/18/2025, is acknowledged.
In the course of the search, the MR antagonist was broadened to include spironolactone and eplerenone, and the disease was broadened to include myocardial infarction.
Claims 7, 11, 13, 15, and 48 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claim.
Claims 4, 9, 17, 21, and 41-47 are examined on the merits herein.
Claim Objections
Claim 9 is objected to because of the following informalities:
-In claim 9, there should be no space between “spironolactone” and the comma following it.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 4, 9, 17, 21, and 41-47 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 claim 4, line 2, the term “electrophilic ketone” renders the claim indefinite. Since a ketone, by nature is electrophilic, it is not clear if the “electrophilic” adjective is superfluous, or if it denotes a specific class of ketones with a certain measure of electrophilicity.
-In claim 21, in the phrases “organic/tissue,” “therapeutic/prophylactic,” and “treatment/prevention,” lines 1-4, the “/” renders the claim indefinite. Specifically, it is not clear if the slash means “and,” or if the slash means “or.” As such, it is not possible to determine the scope of the claim.
In view of compact prosecution, for the purpose of applying prior art, the “/” is interpreted as “or.”
All other claims not specifically recited are rejected for depending from an indefinite claim and failing to cure the deficiency.
Claim Rejections - 35 USC § 112(a)-Scope of Enablement
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 4, 9, 21, and 41-47 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a a) method of treating ischemic damage in a subject that has suffered a myocardial infarction by administering valproic acid and a MR antagonist, b) a method of treating ischemic damage in a patient with heart disease, heart attack, apoplexy, accident surgery, or extremity reperfusion by administering hydroxamic acid and deferoxamine, a NRF2 activator, and c) a method of treating heart failure by administering a HDAC inhibitor and a promotor of HAT, does not reasonably provide enablement for a method of treating/preventing organ/tissue injury in a subject comprising administering to the subject a combination of therapeutic prophylactic agents comprising two or more histone acetylation code agents selected from the group consisting of HDAC inhibitor, BET inhibitor, promoter of HAT activity, MR antagonist, NRF2 activator, and ALDH agonist. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The criteria for enablement set out in the In re Wands, MPEP 2164.01(a), considers the following factors:
Breadth of the Claims
The instant claims are directed toward a method of treating or preventing any organ or any tissue injury in a subject comprising administering to the subject any combination of therapeutic prophylactic agents comprising two or more histone acetylation code agents selected from the group consisting of any HDAC inhibitor, any BET inhibitor, any promoter of HAT activity, any MR antagonist, any NRF2 activator, and any ALDH agonist.
As such, the breadth of the claims is great.
Level of Skill in Art
The level of skill in the art is a clinical or an artisan with a PhD.
State of the Prior Art
Wang (US 2018/0325850, PTO-892) teaches a method of reducing the risk of myocardial infarction (MI) and/or reducing tissue damage caused by MI in a subject comprising administering an effective a dose of valproic acid or a related form thereof (pg. 8, claims 1, 4).
Wang teaches co-administering, in a single formulation, the valproic acid with an additional agent, wherein aspirin is taught as an additional agent (pgs. 8-9, claims 6-7, 11-12, 22-25). As evidenced by Jian, aspirin in a NRF2 activator (title, abstract).
de Groot (US 2003/0215781, PTO-892) teaches a protective solution for avoiding ischemic storage or ischemia/reperfusion injury to organs, wherein the solution comprising hydroxamic acid or a derivative thereof (pgs. 6-8, claims 1, 30). de Groot teaches adding deferoxamine to the solution (pg. 7, claim 6). As evidenced by Guo, deferoxamine is a NRF2 activator (abstract, PTO-892).
de Groot teaches its solution for use for protection against ischemic or reperfusion injuries, such as following infarcts or other inflammatory reaction, and specifically teaches it for subjects with heart diseases, heart attacks, apoplexy, accident surgery, or extremity reperfusion (pg. 8, claims 30-31).
Willis (US 2018/0140722, IDS of 09/26/2024) teaches methods of treating heart failure by administering HDAC inhibitors and/or HAT activators (title, abstract).
Thus, the prior art teaches specific combinations of specific compounds or classes of compounds for the treatment of specific patient populations.
Predictability in the Art
Maron (Initial Invasive or Conservative Strategy for Stable Coronary Disease, The New England Jn of Medicine, published 2020, PTO-892) teaches that among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than those who receive medical therapy alone is uncertain (abstract; paragraphs spanning pgs. 1403-1404).
Bell (What to know about soft issue injuries. MedicalNewsToday, PTO-892) teaches that soft tissue injuries cover a range of conditions that damage the muscles, tendons, ligaments, and other connective tissues, and include conditions such as sprains, contusions, tendinitis, and bursitis (pgs. 2-3).
Bell teaches that different soft tissue injuries often present distinct symptoms and have distinct causes (pg. 3).
Bell teaches that treatment for soft tissue injuries depends on several factors including severity, type of injury, and the particular joint, muscle, or limb affected (pg. 4). See also, Summary, pgs. 5-6.
In view of the limited teaching of specific combinations of specific compounds for the treatment of specific organ/tissue injuries, and the teachings of Maron and Bell, the art of treating and preventing organ or tissue injury in a subject, is unpredictable.
Working Examples
The instant specification provides zero working examples of the instantly claimed method.
Fig. 2 shows that canrenone improves murine donor heart function after cold storage followed by ex vivo perfusion.
Fig. 3 shows cardiomyocyte specific deletion of mineral-corticoid receptor improves murine donor heart function after cold storage followed by ex vivo perfusion.
Fig. 4 shows that canrenone improves murine donor heart function after cold storage followed by heterotopic transplantation.
Fig. 5 shows that canrenone improves pig donor heart function after cold storage followed by ex vivo prefusion.
Fig. 7, shows that VPA improves donor heart ischemic tolerance in part through upregulated Irgl.
While the specification provides these figures, the data in these figures do not appear to be derived from any examples in the instant specification. Moreover, these figures are limited to the individual effect of two species, canernone and valproic acid, on murine donor heart function after cold storage and ex vivo prefusion, and the improvement of donor heart ischemic tolerance.
As such, the instant specification provides zero examples of the instantly claimed method.
Direction and Guidance
In view of the lack of working examples, the unpredictability of the art, and the prior art only teaching specific combinations of species as treating specific ischemia that result from specific diseases/disorders, the instant specification lacks sufficient direction and guidance to use the instantly claimed invention.
Quantity of Experimentation
The amount of experimentation required to determine which organ and which tissue injuries are treated and/or prevented by which combination of two or more histone acetylation code agents selected from at least one of any known HDAC inhibitor, at least one of any known BET inhibitor, at least one of any known promotor of HAT activity, at least one of any known MR antagonist, at least one of any known NRF2 activator, and at least one of any ALDH agonist, is astronomical and amounts to an undue amount of experimentation. This amount of experimentation amounts to invention, not development.
Thus, while being enabling for a a) method of treating ischemic damage in a subject that has suffered a myocardial infarction by administering valproic acid and a MR antagonist, b) a method of treating ischemic damage in a patient with heart disease, heart attack, apoplexy, accident surgery, or extremity reperfusion by administering hydroxamic acid and deferoxamine, a NRF2 activator, and c) a method of treating heart failure by administering a HDAC inhibitor and a promotor of HAT, the instant specification does not reasonably provide enablement for a method of treating/preventing organ/tissue injury in a subject comprising administering to the subject a combination of therapeutic prophylactic agents comprising two or more histone acetylation code agents selected from the group consisting of HDAC inhibitor, BET inhibitor, promoter of HAT activity, MR antagonist, NRF2 activator, and ALDH agonist.
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 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 4, 17, 21, and 41-47 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by US 2018/0325850 to Wang (published 2018, PTO-829), as evidenced by Jian (Aspirin induces Nrf2-mediated transcriptional activation of haem oxygenase-1 in protection of human melanocytes from H2O2-induced oxidative stress, Jn of Cell and Molec Med, published 2016, PTO-892).
Regarding claims 4, 21, 41-46, Wang teaches a method of reducing the risk of myocardial infarction (MI) and/or reducing tissue damage caused by MI in a subject comprising administering an effective a dose of valproic acid or a related form thereof (pg. 8, claims 1, 4).
Wang teaches co-administering, in a single formulation, the valproic acid with an additional agent, wherein aspirin is taught as an additional agent (pgs. 8-9, claims 6-7, 11-12, 22-25). As evidenced by Jian, aspirin in a NRF2 activator (title, abstract).
Regarding claim 47, Wang teaches oral or injection administration (pg. 8, claim 5).
Wang specifically teaches its methods as reducing tissue damage caused by the MI (pg. 8, claim 11).
Claims 4, 17, 21, and 41-46 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by US 2003/0215781 to de Groot (published 2003, PTO-892), as evidenced by Guo (Deferoxamine Alleviates Osteoarthritis by Inhibiting Chondrocyte Ferroptosis and Activating the Nrf2 Pathway, Frontiers in Pharmacology, published 2022, PTO-892).
Regarding claims 21, 17, and 4, de Groot teaches the use of a protective solution for avoiding ischemic storage or ischemia/reperfusion injury to organs, for the protection against ischemic reperfusion injuries, e.g. following infarcts or other inflammatory reactions, wherein the solution comprises hydroxamic acid or a derivative thereof (pgs. 6-8, claims 1, 30). de Groot teaches adding deferoxamine to the solution (pg. 7, claim 6). As evidenced by Guo, deferoxamine is a NRF2 activator (abstract).
Regarding claims 41-46, de Groot teaches its solution for use for protection against ischemic or reperfusion injuries, such as following infarcts or other inflammatory reaction, and specifically teaches it for subjects with heart diseases, heart attacks, apoplexy, accident surgery, or extremity reperfusion (pg. 8, claims 30-31).
Though administration to a subject is not explicitly stated the composition is taught for use to protect against ischemia/reperfusion injury to organs, for use following infarcts, for use with heart diseases, heart attacks, apoplexy, accident surgery, or extremity reperfusion. As such, de Groot implicitly teaches administration of the composition for the treatment of the above.
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 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.
Claims 4, 9, 17, 21, and 41-47 are rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0325850 to Wang (published 2018, PTO-829), in view of Le (Low-Dose Spironolactone Prevents Apoptosis Repressor With Caspase Recruitment Domain Degradation During Myocardial Infarction, Hypertension, published 2012, PTO-892) as evidenced by Jian (Aspirin induces Nrf2-mediated transcriptional activation of haem oxygenase-1 in protection of human melanocytes from H2O2-induced oxidative stress, Jn of Cell and Molec Med, published 2016, PTO-892).
Wang is applied to claims 4, 21, and 41-47 as discussed above and incorporated herein.
Regarding claim 9, while Wang teaches a method of treating MI and/or reducing tissue damage caused by MI, by administering valproic acid, it differs from that of instant claim 9, in that it does not teach an MR antagonist, such as spironolactone or epilerenone.
Le teaches that when hearts from rats are subjected to regional ischemia followed by reperfusion, and then treated with low dose spironolactone or eplerenone, the infarct size is significantly reduced. Spironolactone also prevents cleavage of the apoptotic chromatin condensation inducer in the nucleus of the inhibitor of caspase activated DNAse induced by ischemic-reperfusion, thereby abolishing chromatin condensing and inter-nucleosome cleavage. Ischemia-reperfusion induced activation of caspases 2, 3, and 9, is prevented by spironolactone. Low-dose spironolactone and eplerenone prevents loss of the apoptosis repressor with the caspase recruitment domain and reduced myocyte death. Thus, low dose MR antagonists, such as spironolactone and eplerenone, reduce infarct size and apoptosis in the re-perfused myocardium by preventing apoptosis repressor with caspase recruitment domain degradation (abstract; pg. 1168).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to add the spironolactone or eplerenone of Le to the valproic acid compositions of Wang, to arrive at instant claim 9. One of ordinary skill in the art would have been motivated to make such an addition, with a reasonable expectation of success, because:
-Wang teaches co-administering the valproic acid with an additional prophylactic agent in a coformulation,
-Wang specifically teaches the additional agent as reducing tissue damage resulting from MI and/or reperfusion ([0050]-[0052]),
-Le teaches that MR antagonists, such as spironolactone and eplerenone, reduce infarct size and apoptosis in the re-perfused myocardium, and
-"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). MPEP 2144.06
As such, an ordinary skilled artisan would have been motivated to make such an addition to predictably arrive at a more therapeutically effective method of treating MI by decreasing infarct size and apoptosis.
Claims 4, 9, 17, 21, and 41-47 are rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0325850 to Wang (published 2018, PTO-829), in view of Bossard (Mineral-corticoid receptor antagonists in patients with acute myocardial infarction—A systematic review and meta-analysis of randomized trials, published 2018, PTO-892) as evidenced by Jian (Aspirin induces Nrf2-mediated transcriptional activation of haem oxygenase-1 in protection of human melanocytes from H2O2-induced oxidative stress, Jn of Cell and Molec Med, published 2016, PTO-892).
Wang is applied to Claims 4, 21, and 41-47 as discussed above and incorporated herein.
Regarding claim 9, while Wang teaches a method of treating MI and/or reducing tissue damage caused by MI, by administering valproic acid, it differs from that of instant claim 9, in that it does not teach an MR antagonist, such as canrenone.
Bossard teaches that administration of MR antagonists reduces mortality after acute myocardial infarction, especially in patients with heart failure (abstract; pg. 67).
Bossard teaches canrenone as a MR antagonist (pg. 61, Col. 2; pg. 62, Fig. 1).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to add the canrenone taught by Bossard to the valproic acid compositions of Wang to arrive at instant claim 9. One of ordinary skill in the art would have been motivated to make such an addition, with a reasonable expectation of success, because:
-Wang teaches co-administering the valproic acid with an additional prophylactic agent in a coformulation,
-Wang specifically teaches the additional agent as reducing tissue damage resulting from MI and/or reperfusion ([0050]-[0052]),
-Bossard teaches that administration of MR antagonists, such as canrenone, reduces mortality after acute myocardial infarction, especially in patients with heart failure, and
-"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). MPEP 2144.06
As such, an ordinary skilled artisan would have been motivated to make such an addition to predictably arrive at a therapeutically effective method of treating MI in patients with heart failure.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAUREN WELLS whose telephone number is (571)272-7316. The examiner can normally be reached M-F 7:00-4:30.
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, James (Jim) Alstrum-Acevedo can be reached on 571-272-5548. 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.
/LAUREN WELLS/Examiner, Art Unit 1622