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
Applicant’s amendment dated 10 July 2025, in which claims 2-4, 6-13, 15 have been amended, and new claim 28 has been added, is acknowledged.
Claims 1-4, 6-13, 15-21, 28 are pending in the instant application.
Claims 1-4, 6-13, 15-21, 28 are examined herein.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 26 February 2025 is acknowledged and considered.
Response to arguments of 10 July 2025
In view of Applicant’s amendment of 10 July 2025, the objection to claims 2, 3, 7, 8, 10, 12, 15; the objection to claims 6, 7, 8, 9, 10; the objection to claim 6; and the objection to claim 11, are herein withdrawn. Applicant has clarified the claim language.
In view of Applicant’s amendment of 10 July 2025, the rejection of claims 2, 3, 7, 8, 10, 12, 15 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite, is herein withdrawn. Applicant has removed phrases “for example”, “such as”, and instances of broad/narrow limitations from the claims.
In view of Applicant’s amendment of 10 July 2025, the rejection of claims 11, 12 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite, is herein withdrawn. The claim language has been clarified.
In view of Applicant’s amendment of 10 July 2025, the rejection of claim 13 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite, is herein withdrawn. Applicant has deleted the term “relevant” from claim 13.
In view of Applicant’s amendment of 10 July 2025, the rejection of claim 4 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite, is herein withdrawn. Applicant has deleted the term “at least” from claim 4.
Applicant’s arguments (Remarks of 10 July 2025, pages 11-12) against the rejection of claims 1-4, 6-13, 15-21 under 35 U.S.C. 103 over Larsson, in view of Saluveer and Scheer, in further view of Furlan, have been considered.
Applicant attacks each of the references individually and argues that:
Larsson does not provide any direction or guidance that the timing of administration of an HDAC inhibitor should in any way correspond to the maximum plasma concentration (Cmax) of PAI-1, let alone at a time as specific as from four hours before to one hour after the maximum plasma concentration (Cmax) of PAI-1 or within the therapeutic window of the HDAC inhibitor in order to treat a pathological condition associated with excess fibrin deposition and/or thrombus formation, as claimed;
Scheer describes circulating levels of PAI-1 in healthy adults;
Saluveer describes the effects of valproic acid on the main enzymes of the fibrinolytic system in healthy subjects; Saluveer administers valproic acid twice daily for 2 weeks in depot tablets without providing any suggestion or guidance with respect to the impact of this treatment regime on daily levels of PAI-1 or to the peak level or time of maximum plasma concentration (Cmax) of PAI-1 in the patient, and Saluveer further fails to teach or suggest that delivering an HDAC inhibitor just a few hours before the peak would have any effect or be sufficient to provide a therapeutic or prophylactic effect; and
Furlan describes a phase I safety and pharmacokinetics of ITF2357 (givinstat) in healthy males.
Applicant argues (page 12, second paragraph) no reasonable expectation that the administration of an HDAC inhibitor at a time as specific as from four hours before to one hour after the maximum plasma concentration (Cmax) of PAI-1 or within the therapeutic window of the HDAC inhibitor would lower plasma PAI-1 antigen levels in a subject to treat a pathological condition associated with excess fibrin deposition and/or thrombus formation, as claimed.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In this case,
Larsson teaches a method of treating myocardial infarction with HDAC inhibitor givinostat; and Larsson teaches measuring Cmax of the HDAC drug givinostat upon administration; and Larsson teaches that high circulating levels of PAI-1 are associated with myocardial infarction in patients;
Saluveer teaches that treatment with an HDAC inhibitor (valproic acid) lowers plasma PAI-1 antigen levels, which reduces the incidence of myocardial infarctions in patients; and
Scheer teaches that the human circadian system causes a morning peak corresponding to ∼6:30 AM in circulating levels of PAI-1, which is related to increased thrombosis in critical vessels and an observed increase in morning adverse cardiovascular events.
Thus, based on the combined teachings of Larsson and Saluveer, the person of ordinary skill in the art would have administered the HDAC inhibitor givinostat to a patient suffering from or at risk of developing myocardial infarction, in the method taught by Larsson, and would have measured PAI-1 plasma levels in the patient before and after givinostat administration, with the expectation that treatment with HDAC inhibitor ginvinostat will lower plasma PAI-1 levels, as in instant claims 15, 28, which reduces the incidence of myocardial infarction in the patient.
Further, based on the combined teachings of Larsson, Saluveer and Scheer, the person of ordinary skill in the art would have administered HDAC inhibitor ginvinostat in such manner that plasma levels of ginvinostat coincide with peak plasma levels of PAI-1, with the expectation that such timing of the administration of ginvinostat will allow for an advantageous effect in treatment of pathological conditions associated with excess fibrin deposition and/or thrombus formation, such as reduced incidence of myocardial infarctions in patients.
The person of ordinary skill in the art
would have measured Cmax of the HDAC drug givinostat upon administration, in the method of Larsson,
would have monitored the plasma concentration of PAI-1 in the patient as in Scheer,
and would have timed the administration of givinostat such that the maximum plasma concentration (Cmax) of givinostat in the patient occurs around the time when the maximum plasma concentration (Cmax) of PAI-l occurs in the patient, at ∼6:30 AM (Scheer), which coincides with the temporal peak incidence for thrombotic events, such as myocardial infarction, with the expectation that such timed administration of ginvinostat (which will lower plasma PAI-1 levels) will result in optimum treatment/reduction in risk of myocardial infarction in the patients.
Regarding claims 6, 7, 8, 9, 10, the person of ordinary skill in the art would have administered givinostat to the patient at 4 am or 5 am, because Furlan teaches (Figure 2) that Tmax is about 2 hours upon oral administration of 50 mg, or 100 mg givinostat to a human patient, which is consistent with the maximum plasma concentration (Cmax) of givinostat in the patient occurring at 6 am or 7 am, which is around the time ∼6:30 AM (Scheer) when the maximum plasma concentration (Cmax) of PAI-l occurs in the patient.
For all the reasons above, the rejection of claims 1-4, 6-13, 15-21 under 35 U.S.C. 103 over Larsson, in view of Saluveer and Scheer, in further view of Furlan, is herein maintained, and a modified rejection is made below, based on Applicant’s amendment of 10 July 2025.
Claims 1-4, 6-13, 15-21, 28 have been examined to the extent they read on the elected species, namely Givinostat as the specific HDAC inhibitor, and myocardial infarction as the pathological condition associated with excess fibrin deposition and/or thrombus formation to be treated (see response filed on 7 November 2024), and the following objections and rejections are made below.
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.
Claim interpretation: in claims 9, 10, the recitation “substantially all” of the HDAC inhibitor is interpreted to mean, based on the definition in Applicant’s Specification, page 59, lines 35-37, at least 60% of the total amount of HDAC inhibitor present in the pharmaceutical composition.
In claim 16, the recitation “plasma concentration of the HDAC inhibitor […] during a 24-hour period mimics the plasma concentration of PAI-1 during the same period” is interpreted (see Specification, page 48, lines 14-20) to mean that the relative plasma levels of the two agents follow substantially similar patterns of variation e.g. the curves obtained by plotting the plasma concentrations of the two agents may be substantially superimposable, although the absolute levels/concentrations of the two agents may be different. The term "mimics" has its ordinary meaning in the art, i.e. to resemble, simulate, approximate, follow, but not necessarily replicate exactly precisely.
In claims 4, 13, the term “plasma concentration of HDAC inhibitor […] that is within the therapeutic window for the HDAC inhibitor” is understood (Specification, page 15, lines 19-22) to refer to plasma levels of the HDAC inhibitor at which the therapeutic effect of that compound will typically be observed.
Claims 1-4, 6-13, 15-21, 28 are rejected under 35 U.S.C. 103 as obvious over Larsson et al. (US 20140051716, cited in IDS), in view of Saluveer et al. (PLOS one, October 2014, 9 (10), e107582, published 8 October 2014, cited in IDS), and Scheer et al. (Blood 2014, 123 (4), 590-593, cited in IDS), in further view of Furlan et al. (Mol Med 2011, 17 (5-6), 353-362, cited in PTO-892).
Larsson (US 20140051716) teaches ([0058]-[0059]) a method for the treatment of pathological conditions associated with excess fibrin deposition and/or thrombus formation, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of an HDAC inhibitor, such as, for example, Givinostat (ITF2357), which is Applicant’s elected species.
Larsson teaches [0067] pathological conditions that can be treated in accordance with the invention are those that are caused wholly or at least in part by an increased fibrin deposition and/or reduced fibrinolytic capacity due to local or systemic inflammation, such as myocardial infarction (Applicant’s elected species), or ischemic stroke, as in instant claims 17, 18.
Larsson teaches the method wherein the patient is a human [0030], as in instant claim 19.
Larsson teaches [0037] the method, wherein the patient is at risk of thrombotic cardiovascular events, as in instant claim 20.
Larsson teaches [0603] that the HDAC inhibitor may be administered in combination with one or more anti-platelet agents such as aspirin or clopidogrel, as in instant claim 21.
Larsson teaches [0566] measuring Cmax of the HDAC drug upon administration.
Larsson teaches [0504] the method, wherein the pathological condition is caused wholly or at least in part by an increased fibrin deposition and/or reduced fibrinolytic capacity. Larsson teaches [0505] that high circulating levels of PAI-1 (the main inhibitor of t-PA) are generally considered to be indicative of poor fibrinolysis, and this can be measured by commercially available methods.
Larsson teaches [0532] that the maximum tolerated dose of givinostat in human patients is 200 mg/day. Larsson teaches [0545] the dose of givinostat in the method as 10-180 mg/day, or 20-150 mg/day, or 100 mg/day or 50 mg/day.
Larsson does not teach administering to the patient at least one dose of the HDAC inhibitor, such that the maximum plasma concentration (Cmax) of the HDAC inhibitor, or a salt and/or metabolite thereof, in the patient occurs during a time period that is from four hours before to one hour after the maximum plasma concentration (Cmax) of PAI-l in the patient, as in the instant claims.
Saluveer teaches (Abstract) that treatment with an HDAC inhibitor (valproic acid) lowers plasma PAI-1 antigen levels and changes the fibrinolytic balance measured as t-PA/PAI-1 ratio in the profibrinolytic direction. Saluveer teaches that this may explain the reduction in incidence of myocardial infarctions by valproic acid treatment observed in recent pharmaco epidemiological studies.
Scheer teaches (Key points) that the human circadian system causes a morning peak corresponding to ∼6:30 AM in circulating levels of PAI-1, independent of any behavioral or environmental influences. Scheer teaches (abstract) that plasminogen activator inhibitor-1 (PAI-1), which inhibits fibrinolysis, is a key circulating prothrombotic factor that rises in the morning in humans. Serious adverse cardiovascular events peak in the morning, possibly related to increased thrombosis in critical vessels. If this large endogenous morning peak in PAI-1 persists in vulnerable individuals, it could help explain the morning peak in adverse cardiovascular events.
Furlan teaches a pharmaceutical composition comprising ITF2357 (synonym givinostat) in the form of a capsule (page 354, central column, second paragraph) for oral administration, formulated such that at least 60% of the total amount (“substantially all” as in instant claims 9, 10) administered is released during a period of 6 hours after administration (Figure 2).
PNG
media_image1.png
240
428
media_image1.png
Greyscale
Figure 2 in Fulan (see above) shows that 6 hours after oral administration of a single oral dose of ITF2357, the amount of drug ITF2357 absorbed systemically (as plasma AUC over the time interval [0, 8h]) is at least 60% of the total amount of drug ITF2357 absorbed systemically upon administration of said dose (AUC over the interval [0,∞]).
Further, Furlan teaches (Figure 2, also Abstract) that, for a single daily dose of 50 mg, or 100 mg ITF2357 (synonym givinostat) administered to a human patient, Tmax is about 2 hours.
It would have been obvious to combine the teachings of Larsson, Saluveer, Scheer and Furlan to arrive at the instant invention.
The person of ordinary skill in the art would have been motivated to optimize the timing of administration of at least one dose of a HDAC inhibitor givinostat to a patient suffering from or at risk of developing myocardial infarction, in the method taught by Larsson, based on the following teachings of the prior art:
Larsson teaches a method of treating myocardial infarction with HDAC inhibitor givinostat; and Larsson teaches measuring Cmax of the HDAC drug givinostat upon administration, and
Larsson teaches that high circulating levels of PAI-1 (the main inhibitor of t-PA) are indicative of poor fibrinolysis, and reduced fibrinolytic capacity is associated with myocardial infarction;
Saluveer teaches that treatment with an HDAC inhibitor (valproic acid) lowers plasma PAI-1 antigen levels, which reduces the incidence of myocardial infarctions in patients; and
Scheer teaches (Key points) that the human circadian system causes a morning peak corresponding to ∼6:30 AM in circulating levels of PAI-1, which is related to increased thrombosis in critical vessels and an observed increase in morning adverse cardiovascular events.
Thus, based on the combined teachings of Larsson and Saluveer, the person of ordinary skill in the art would have administered the HDAC inhibitor givinostat to a patient suffering from or at risk of developing myocardial infarction, in the method taught by Larsson, and would have measured the PAI-1 plasma levels before and after administration of givinostat to the patient, with the expectation that treatment with HDAC inhibitor ginvinostat will lower plasma PAI-1 levels, as in instant claims 15, 28, which reduces the incidence of myocardial infarction in the patient.
Further, based on the combined teachings of Larsson, Saluveer and Scheer, the person of ordinary skill in the art would have administered HDAC inhibitor ginvinostat in such manner that plasma levels of ginvinostat coincide with peak plasma levels of PAI-1, with the expectation that such timing of the administration of ginvinostat will allow for an advantageous effect in treatment of pathological conditions associated with excess fibrin deposition and/or thrombus formation, such as reduced incidence of myocardial infarctions in patients. The person of ordinary skill in the art
would have measured Cmax of the HDAC drug givinostat upon administration, in the method of Larsson,
would have monitored the plasma concentration of PAI-1 in the patient as in Scheer,
and would have timed the administration of givinostat such that the maximum plasma concentration (Cmax) of givinostat in the patient occurs around the time when the maximum plasma concentration (Cmax) of PAI-l occurs in the patient, at ∼6:30 AM (Scheer), which coincides with the temporal peak incidence for thrombotic events, such as myocardial infarction, with the expectation that such timed administration of ginvinostat (which will lower plasma PAI-1 levels) will result in optimum treatment/reduction in risk of myocardial infarction in the patients.
Regarding claims 6, 7, 8, 9, 10, the person of ordinary skill in the art would have administered givinostat to the patient at 4 am or 5 am, because Furlan teaches (Figure 2) that Tmax is about 2 hours upon oral administration of 50 mg, or 100 mg givinostat to a human patient, which is consistent with the maximum plasma concentration (Cmax) of givinostat in the patient occurring at 6 am or 7 am, which is around the time ∼6:30 AM (Scheer) when the maximum plasma concentration (Cmax) of PAI-l occurs in the patient.
As such, claims 1-4, 6-13, 15-21, 28 are rejected as prima facie obvious.
Conclusion
Claims 1-4, 6-13, 15-21, 28 are rejected.
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 IRINA NEAGU whose telephone number is (571)270-5908. The examiner can normally be reached Mon-Fri 8-5.
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, JEFFREY S. LUNDGREN can be reached on (571)272-5541. 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.
/IRINA NEAGU/Primary Examiner, Art Unit 1629