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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on February 27, 2026, has been entered.
Response to Arguments
Applicant has amended the claims to require either TH1834 or pentamidine as Tip60 inhibitor rather than NU9056. Applicant argues that Zhang does not disclose TH1834 nor pentamidine as Tip60 inhibitor.
The examiner applies the following references in view of the amendments to the claims: 1. Guo et al., “Rational design and validation of a Tip60 histone acetyltransferase inhibitor,” Scientific Reports 4:5372, June 20, 2014.
Guo teaches that TH1834 significantly inhibits Tip60. See Abstract. Further, Gao explains that Pentamidine was also recent reported to inhibit the activity of Tip60 by decreasing its histone H2A acetylation. See p2, 1st full par. TH1834 was demonstrated to inhibit Tip60 and Tip60-dependent signaling in vivo and in vitro. See p6, last par.
The examiner also applies:
2. Kobayashi et al., “Bisbenzamidine derivative, pentamidine represses DNA damage response through inhibition of histone H2A acetylation,” Molecular Cancer 2010, 9:34.
Kobayashi teaches pentamidine repressed the activity of Tip60 acetyltransferase which is a known acetyl histone H2A and that knockdown of Tip60 by siRNA reduced HR activity. Further, “Pentamidine treatment also reduced Tip60-dependent acetylation of p53 in MRC5SV cells (Fig. 6D), suggesting that pentamidine could inhibit Tip60 acetyltransferase activity in vivo.” See p6, last par.
As such, a rejection is set forth below.
Status of the Claims
Claims 1, 5-9, 11-13, 15-21 are pending and examined.
Note: The examiner interprets administered transiently to include a short duration of administration, rather than a longer continuous administration. There is no definition in the Specification.
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.
Claims 1, 5-9, 11-13, and 15-21 are rejected under 35 U.S.C. 103 as being unpatentable over Gogna et al., “p53’s choice of myocardial death or survival: Oxygen protects infarct myocardium by recruiting p53 on NOS3 promoter through regulation of p53‐Lys118 acetylation,” EMBO Mol Med (2013) 5, 1662-1683, in view of Guo et al., “Rational design and validation of a Tip60 histone acetyltransferase inhibitor,” Scientific Reports 4:5372, June 20, 2014, in view of Kobayashi et al., “Bisbenzamidine derivative, pentamidine represses DNA damage response through inhibition of histone H2A acetylation,” Molecular Cancer 2010, 9:34, and in view of O’Brien et al., (US2009/0117090) (of record).
Gogna teaches a role of a p53 pathway in the infarct heart through acetylation at lysine residue which is related to oxygen-dependent expression of Tip60. See Abstract. Silencing TIP60 resulted in an increase in survival of serum deprived cells. Addition of exogenous TIP60 also showed an increase in cardiomyocyte death and even oxygen treatment could not prevent cardiomyocyte apoptosis while normally treatment with oxygen would do so. See p1674, 1st par. There is an oxygen-mediated deacetylation of TIP60 and activation of NOS3 that produces a cardioprotective survival pathway. See p1674, 1st full par. Gogna establishes a new prosurvival role of p53 for cardioprotection that protects infarct myocardium. Oxygenation of the infarct heart inhibits expression of TIP60 acetylase and abolishes interaction with p53 and lysine residue in the infarct heart. See p1674, Discussion 1st par. This lack of acetylation results in activation of NOS3 promoter, while suppressing the activation of apoptotic genes including BAX. See Id. In the infarct myocardium p53 is an apoptotic transcription factor. When the infarct myocardium is oxygenated, p53 becomes prosurvival and activates NOS3 and is unacetylated at the lysine residue. Oxygen is found to inhibit the expression of TIP60 acetylase and the oxygen induced inhibition in the rat infarct myocardium and rat cardiomyocytes result in lack of acetylation at the p53 lysine residue. The regulation of TIP60 appears to serve as the molecular mechanism through which oxygen regulates p53. See p. 1677, 2nd and 3rd full par. The results suggest that when TIP60 is inhibited (i.e., repressed), this results in a lack of p53 acetylation and lack of p53 apoptosis and the initiation of p53 prosurvival mechanism through NOS3. See Id. There is no indication that a subject should wait any period of time prior to administration and while healing is taking place, administration would appear to be necessary to prevent cell death. Thus, an administration of a TIP60 inhibitor would be continued to promote cardiomyocyte survival.
Gogna does not teach TH1834 and pentamidine to be TIP60 inhibitors.
Guo teaches that TH1834 significantly inhibits Tip60. See Abstract. Further, Gao explains that Pentamidine was also recent reported to inhibit the activity of Tip60 by decreasing its histone H2A acetylation. See p2, 1st full par. TH1834 was demonstrated to inhibit Tip60 and Tip60-dependent signaling in vivo and in vitro. See p6, last par.
Kobayashi teaches pentamidine repressed the activity of Tip60 acetyltransferase which is a known acetyl histone H2A and that knockdown of Tip60 by siRNA reduced HR activity. Further, “Pentamidine treatment also reduced Tip60-dependent acetylation of p53 in MRC5SV cells (Fig. 6D), suggesting that pentamidine could inhibit Tip60 acetyltransferase activity in vivo.” See p6, last par.
Guo and Kobayashi do not teach a GSK-3 inhibitor.
O’Brien teaches administration of a device to treat vascular disease, coronary artery disease, and ischemic heart disease by administering a stent coated with a GSK-3 inhibitor. See abstract. The technology can be useful after a myocardial infarction. See par. 4.
It would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the instant application to administer a TIP60 inhibitor to a subject that has experienced a myocardial infarction. One would be motivated to do so because Gogna teaches that TIP60 inhibition allows for p53 to provide prosurvival mode and activates NOS3 while suppressing apoptotic genes. When TIP60 is inhibited (i.e., repressed), this results in a lack of p53 acetylation and lack of p53 apoptosis and the initiation of p53 prosurvival mechanism through NOS3. Thus, administering a known TIP60 inhibitor to a subject that has experienced an MI would have a reasonable expectation of success in promoting a p53 survival and protective mechanism after an MI. Guo and Kobayashi teach TH1834 and pentamidine to be Tip60 inhibitors, including inhibiting p53 acetylation, e.g., and thus would be envisaged as an agent that can propagate the prosurvival mechanism taught by Gogna. O’Brien teaches administration of a device to treat vascular disease, coronary artery disease, and ischemic heart disease by administering a stent coated with a GSK-3 inhibitor. See abstract. The technology can be useful after a myocardial infarction. See par. 4. "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). Further, to the degree that a specific dosage or amount of TIP60 inhibitor is required to effectuate a claimed result: In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985); and Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). While the examiner acknowledges that proliferation of adult cardiomyoctes is not taught to be induced by administration of a TIP60 inhibitor, the optimization of administration of a TIP60 inhibitor is taught as a result-effective variable that would be optimized and is motivated to be administered after an MI. Thus, absent evidence to the contrary, an optimized dosage would optimally treat MI and this can include inducing the proliferation of CMs.
With regard to administration transiently, the examiner notes that administration of a result effective variable would be optimized to achieve a desired dosage and effect of administration through nothing more than routine experimentation. The prior art does not appear to require a long duration of continuous administration.
Claims 1, 5-9, 12-13, and 17-21 are rejected under 35 U.S.C. 103 as being unpatentable over Dietz et al., (US2020/0253932), in view of Cornuz et al., “Risk factors for asymptomatic abdominal aortic aneurysm,” European Journal of Public Health 2004; 14; 343-349, and in view of Alcorn et al., “Risk Factors for Abdominal Aortic Aneurysms in Older Adults Enrolled in the Cardiovascular Health Study,” Atherosclerosis, Thrombosis, and Vascular Biology Volume 16, Issue 8, August 1996, pages 963-970.
Dietz teaches a method for treating or preventing an aortic aneurysm syndrome in a subject by administering TH1834. See prior art claim 1.
Cornuz teaches myocardial infarction is a risk factor for aortic aneurysm. See Abstract. As shown in Table 4, e.g., a history of myocardial infarction is a risk factor for aortic aneurysm. See p347.
Alcorn teaches variables significantly related to aortic aneurysm includes myocardial infarction. See Abstract. Aneurysm prevalence was higher among individuals with a history of clinical atherosclerotic disease. “The prevalence of AAA was correlated with history of angina (P<.0001), history of myocardial infarction (P<.0001), and history of CHD (P<.0001).” Table 5 shows that those with aortic aneurysm that had a heart attack (16.0%) was about twice the percentage of those that had a heart attack without aortic aneurysm (8.6%).
With regard to administration transiently, the examiner notes that administration of a result effective variable would be optimized to achieve a desired dosage and effect of administration through nothing more than routine experimentation. The prior art does not appear to require a long duration of continuous administration.
It would have been prima facie obvious to a person having ordinary skill in the art prior to the filing of the instant application to combine the prior art and prevent or treat an aortic aneurysm. One would be motivated to do so because risk of an aortic aneurysm increased after a MI. As such, if a subject is interested in preventing an AA, they would consider administration of TH1834 taught to prevent AA after the occurrence of a risk factor for the same. This also includes administration of TH1834 after a subject has a heart attack. When such active step is initiated whether the subject had atherosclerotic disease, angina, MI, or other known risk factor, the results of administration would therefore be what they are. In other words, when a subject has a myocardial infarction or an aortic aneurysm, the obvious step of administration of TH1834 to treat and prevent the same would appear, absent evidence to the contrary, to ameliorate cardiac injury, regenerate heart tissue, and/or induce proliferation of adult CMs because this is what results from administration of an optimized dosage of TH1834 as the result-effective variable in the claimed subject population.
As such, no claim is allowed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JARED D BARSKY whose telephone number is (571)272-2795. The examiner can normally be reached on 9-5 M-F.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy 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.
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/JARED BARSKY/Primary Examiner, Art Unit 1628