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 .
Election/Restrictions
Applicant’s election without traverse of Group (I) in the reply filed on 04/07/2025 is acknowledged.
Applicant’s election of the levosimendan as the elected compound species, a human subject having a left ventricular ejection fraction of at least 40%, an improvement in the human subject’s six (s) minute walk distance of 5 to 150 meters as the treatment species, PH-HFpEF as the elected heart condition species, and any one of the cardiovascular drugs as the elected cardiovascular drug species, in the reply filed on 04/07/2025 is acknowledged and maintained.
Claims Status
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on November 03, 2025.
Claims 1-3, 6-7, 22-29, 31, and 57-62 are pending and under examination. Claims 4, 5, 8-21, 30, and 32-56 are canceled. Claims 3, 5, 6, 28, and 60-61 are withdrawn. Claims 1-2, 7, 22-27, 29, 31, 57-59, and 62 are examined in accordance to the elected species.
Priority
This application is a continuation of U.S. Application No. 17/122,921, filed December 15, 2020, claiming the benefit of U.S. Provisional Application Nos. 63/064,671 filed August 12, 2020, 63/033,773 filed June 2, 2020, 62/988,720 filed March 12, 2020, 62/967,920 filed January 30, 2020, and 62/948,735 filed December 16, 2019.
Action Summary
The information disclosure statement (IDS) submitted on 12/09/2024 & 03/29/2024 has been considered by the examiner.
Claim Objections
The objection to claims 22 and 23 is withdrawn in light of the claim amendment insetting a comma after levosimendan.
Claim 31 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the claim amenemt.
Claims 1-2, 7, 29, 31, and 59 are rejected under 35 U.S.C. 103 as being unpatentable over NCT03541603, Clinical Trial.gov, May 30, 2018 in view of Rosenkranz et al (International Journal of Cardiology, Volume 272, Supplement, 1 December 2018, Pages 53-62) and Altenberger et al (Eur J Heart Fail. 2014 Aug;16(8):898-906). NCT03541603 can be found in parent case # 17/410,897, are withdrawn in light of the deletion of edema in claim 1.
Claims 1-2, 7, 22-27, 29, 31, and 59 are rejected under 35 U.S.C. 103 as being unpatentable over NCT03541603, Clinical Trial.gov, May 30, 2018 in view of Rosenkranz et al (International Journal of Cardiology, Volume 272, Supplement, 1 December 2018, Pages 53-62) and Altenberger et al (Eur J Heart Fail. 2014 Aug;16(8):898-906) as applied to claims 1-2, 7, 29, 31, and 59, in further view of Guazzi et al (Circulation. 2011; 124:164-174), are withdraw in light of the amendment to claim 1.
Claims 1-2, 7, 29, 31, and 57-59 rejected under 35 U.S.C. 103 as being unpatentable over NCT03541603, Clinical Trial.gov, May 30, 2018 in view of Rosenkranz et al (International Journal of Cardiology, Volume 272, Supplement, 1 December 2018, Pages 53-62) and Altenberger et al (Eur J Heart Fail. 2014 Aug;16(8):898-906) as applied to claims 1-2, 7, 29, 31, and 59, in further view of Kundra et al (Annals of Cardiac Anaesthesia 21(3): p 328-332, Jul–Sep 2018) and Valjakka-Koskela et al (European Journal of Pharmaceutical Sciences 11 (2000) 343–350), are withdraw in light of the amendment to claim 1.
Claims 1-2, 7, 22-27, 29, 31, and 57-59 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of prior U.S. Patent No. US11,969,424 B2 in view of Rosenkranz et al (International Journal of Cardiology, Volume 272, Supplement, 1 December 2018, Pages 53-62), Kundra et al (Annals of Cardiac Anaesthesia 21(3): p 328-332, Jul–Sep 2018), and Valjakka-Koskela et al (European Journal of Pharmaceutical Sciences 11 (2000) 343–350), are maintained, but modified and revisited in light of the inclusion of left ventricular ejection fraction of at least 40.
Claims 1-2, 7, 22-27, 29, 31, and 57-59 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of prior U.S. Patent No. US11,607,412 B2 in view of Rosenkranz et al (International Journal of Cardiology, Volume 272, Supplement, 1 December 2018, Pages 53-62), Kundra et al (Annals of Cardiac Anaesthesia 21(3): p 328-332, Jul–Sep 2018), and Valjakka-Koskela et al (European Journal of Pharmaceutical Sciences 11 (2000) 343–350), ), are maintained, but modified and revisited in light of the inclusion of left ventricular ejection fraction of at least 40.
Claims 1-2, 7, 22-27, 29, 31, and 57-59 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of prior U.S. Patent No. US11,701,355 B2 in view of Rosenkranz et al (International Journal of Cardiology, Volume 272, Supplement, 1 December 2018, Pages 53-62), Kundra et al (Annals of Cardiac Anaesthesia 21(3): p 328-332, Jul–Sep 2018), and Valjakka-Koskela et al (European Journal of Pharmaceutical Sciences 11 (2000) 343–350), are maintained, but modified and revisited in light of the inclusion of left ventricular ejection fraction of at least 40.
Claims 1-2, 7, 22-27, 29, 31, and 57-59 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5, 11, 20, 24-25, 28, 30, 32, 41, 43, 45, and 49 of copending Application No 18/725,602 in view of Rosenkranz et al (International Journal of Cardiology, Volume 272, Supplement, 1 December 2018, Pages 53-62), Kundra et al (Annals of Cardiac Anaesthesia 21(3): p 328-332, Jul–Sep 2018), and Valjakka-Koskela et al (European Journal of Pharmaceutical Sciences 11 (2000) 343–350), are maintained, but modified and revisited in light of the inclusion of left ventricular ejection fraction of at least 40.
Claims 1-2, 7, 22-27, 29, 31, and 57-59 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 5, 7, 9, 11-12, 18-26, 28-30, and 32 of copending Application No 18/714,318 in view of Rosenkranz et al (International Journal of Cardiology, Volume 272, Supplement, 1 December 2018, Pages 53-62), Kundra et al (Annals of Cardiac Anaesthesia 21(3): p 328-332, Jul–Sep 2018), and Valjakka-Koskela et al (European Journal of Pharmaceutical Sciences 11 (2000) 343–350), are maintained, but modified and revisited in light of the inclusion of left ventricular ejection fraction of at least 40.
New Rejection necessitated by claim amendment
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 (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 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.
Claims 1-2, 7, 29, 31, and 59 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by o NCT03541603 (Clinical Trial.gov, May 30, 2018).
NCT03541603 teaches a method of treating PH-HFpEF (Pulmonary Hypertension Patients with Heart Failure and Preserved Left Ventricular Ejection Fraction) patient with limited exercise capacity and has a left ventricular ejection fraction of at least 40%, the method comprising administering levosimendan to a human subject and the human subject as the ability to walk at least 50 meters, but not more than 550 meters, in a six-minute walk test. (See Study Design Section, and Arms and Interventions and Inclusion Criteria Sections.)
According to the following limitation: “wherein treating comprising improvement in the human’s subject six (6) minute walk distance of 5 to 150 meters”; “wherein treating comprising improving of quality of life”; “wherein no rest, atrial or ventricular, are observed when comparing baseline electrocardiographic monitoring with 72-hour monitoring after 5 weeks of treatment and/or wherein treating presents no more statistically significant adverse events than the matching placebo”; and” wherein a weekly 24- hour dosing of levosimendan results in steady state blood levels of metabolite OR1896 in the range of 0.20 ng/mL to 25.00 ng/mL”. These limitations simply express the intended outcome of the method step. The fact that the prior art method and the claimed method are the same, said intended outcomes would necessarily be achieved. In the absence of evidence to the contrary, the burden is on the applicant to prove that the claimed method is different from that taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
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 non-obviousness.
Claims 1-2, 7, 29, 31, 59, and 62 are rejected under 35 U.S.C. 103 as being unpatentable over NCT03541603 (Clinical Trial.gov, May 30, 2018), as applied to claims 1-2, 7, 29, 31, and 59 as set forth in the 102-rejection above, in view of Rosenkranz et al (International Journal of Cardiology, Volume 272, Supplement, 1 December 2018, Pages 53-62) and Altenberger et al (Eur J Heart Fail. 2014 Aug;16(8):898-906).
NCT03541603 teaches a method of treating PH-HFpEF (Pulmonary Hypertension Patients with Heart Failure and Preserved Left Ventricular Ejection Fraction) patient with limited exercise capacity and has a left ventricular ejection fraction of at least 40%, the method comprising administering levosimendan to a human subject and the human subject as the ability to walk at least 50 meters, but not more than 550 meters, in a six-minute walk test. (See Study Design Section, and Arms and Interventions and Inclusion Criteria Sections.)
NCT03541603 does not teach the human subject exhibits edema as recited in claim 62.
Rosenkranz teaches factors which suggest the presence of pulmonary hypertension due to left heart disease (PH-LHD), e.g., HFpEF in patients with suspected pulmonary hypertension include, but no limited to pulmonary edema. (See Table 3.and “Introduction section.)
Altenberger teaches levosimendan improves the human subject’s six-minute walk distance to 16 meters in a human subject with advanced heart failure. (See Abstract and Table 1)
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to use the method taught by NCT03541603 by including a subject exhibiting edema to treat PH-HFpEF and to improve the human subject’s six-minute walk distance to 16 meters to give Applicant’s claimed invention. One would have been motivated to do so, because Rosenkranz teaches the presence of pulmonary edema in HFpEF patients and also because Altenberger teaches levosimendan improves the human subject’s six-minute walk distance to 16 meters in a human subject with advanced heart failure. One would reasonably expect the method taught by NCT03541603 to effectively treat PH-HFpEF (Pulmonary Hypertension Patients with Heart Failure and Preserved Left Ventricular Ejection Fraction) in a human subject exhibiting edema and limited exercise capacity with success by improving the human subject’s six-minute walk distance to 16 meters.
Claims 1-2, 7, 22-27, 29, 31, and 59 are rejected under 35 U.S.C. 103 as being unpatentable over NCT03541603, Clinical Trial.gov, May 30, 2018 as applied to claims 1-2, 7, 29, 31, and 59 in the 102-rejection set forth above in view of Guazzi et al (Circulation. 2011; 124:164-174).
The teachings of NCT03541603 have been discussed in the first rejection above.
NCT03541603 does not teach a cardiovascular drug in this case a PDE5 inhibitor as recited in claims 22-27.
Guazzi teaches PDE5 inhibitor can be used to treat PH-HFpEF. (See fourth paragraph of the right column of page 172.)
It would have been prima facie obvious for a person of ordinary skill in the art at the time of the invention was filed to combine the method disclosed by NCT03541603 with method set forth by Guazzi because each is taught by the prior art to be useful for the same purpose (i.e., treating PH-HFpEF). See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Further, a person of ordinary skill in the art would reasonably have expected to be successful because both compositions were shown to be useful separately for the exact same purpose and thus would be expected to be similarly useful when used together.
Claims 1-2, 7, 29, 31, 57, 58, and 59 are rejected under 35 U.S.C. 103 as being unpatentable over NCT03541603, Clinical Trial.gov, May 30, 2018 as applied to claims 1-2, 7, 29, 31, and 59 in the 102-rejection set forth in view of Kundra et al (Annals of Cardiac Anaesthesia 21(3): p 328-332, Jul–Sep 2018) and Valjakka-Koskela et al (European Journal of Pharmaceutical Sciences 11 (2000) 343–350).
The teachings of NCT03541603 have been discussed in the first rejection above.
NCT03541603 does not teach the administration is delivered via transdermal delivery of a transdermal formulation as recited in claim 58. Moreover, NCT03541603 does not teach the administration is delivered via inhalation of an inhaled formulation as recited in claim 57.
Kundra teaches inhaled levosimendan may act as selective pulmonary vasodilator and avoid systemic side effects of intravenous levosimendan, which include decrease in systemic vascular resistance (SVR) and systemic hypotension, but with same beneficial effect on pulmonary artery pressure (PAP) and right ventricular (RV) function. Inhaled levosimendan is a selective pulmonary vasodilator. It causes decrease in PAP and improvement in RV function, without having a significant effect on SVR. (See Abstract).
Valjakka-Koskela teaches therapeutic concentrations of levosimendan in plasma are achieved with intravenous infusion at doses of 0.05–0.2 μg/kg/min. The clearance of levosimendan is 300–360 ml/min and it seems to be mainly eliminated by metabolism. Continuous, controlled, and non-invasive delivery of levosimendan via a transdermal route might provide convenient administration with long duration of activity and less risk of excessive drug concentrations.
It would have been prima facie obvious for a person of ordinary skill in the art at the time of the invention was filed to substitute the administration taught by NCT03541603 with the inhaled administration taught by Kundra and/or the transdermal administration taught by Valjakka-Koskela. One would have been motivated to do so, because Kundra teaches the inhaled administration of levosimendan has the same beneficial effect on pulmonary artery pressure (PAP) and right ventricular (RV) function, but avoids the systemic side effects associated with intravenous levosimendan and also because Valjakka-Koskela teaches transdermal route might provide convenient administration with long duration of activity and less risk of excessive drug concentrations as compared to the intravenous administration. One would be expected the substitution to effectively treat PH-HFpEF (Pulmonary Hypertension Patients with Heart Failure and Preserved Left Ventricular Ejection Fraction) in a human subject exhibiting edema and limited exercise capacity with success by improving the human subject’s six-minute walk distance to 16 meters.
Acknowledgement is made of the receipt and entry of Applicant’s argument filed on November 03, 2025.
Applicant’s argument
Applicant argues that it is settled law that prima facie obviousness of a method of treatment claim requires evidence showing that a person of ordinary skill in the art (POSA) had a reasonable expectation that the method would be successful. In multiple cases with facts analogous to those of the present case, the U.S. Court of Appeals for the Federal Circuit has consistently held that claims to a method of treating a disease are not obvious from a published clinical trial protocol because a protocol represents a hope that a disease might be successfully treated, but does not provide a reasonable expectation that the disease would be successfully treated. Indeed, as detailed below, most clinical trials fail.
Examiner’s response
In response, Applicant’s argument is not persuasive. It may well be true that the U.S. Court of Appeals for the Federal Circuit has consistently held that claims to a method of treating a disease are not obvious from a published clinical trial protocol because a protocol represents a hope that a disease might be successfully treated, but does not provide a reasonable expectation that the disease would be successfully treated. However, the Examiner contends the rejection as necessitated by the claim amendment is no longer an obviousness rejection, but rather an animation rejection. A prior art reference provides an enabling disclosure and thus anticipates a claimed invention if the reference describes the claimed invention in sufficient detail to enable a person of ordinary skill in the art to carry out the claimed invention; “proof of efficacy is not required for a prior art reference to be enabling for purposes of anticipation.” Impax Labs. Inc. v. Aventis Pharm.Inc., 468 F.3d 1366, 1383, 81 USPQ2d 1001, 1013 (Fed. Cir. 2006) (citing Rasmusson v. SmithKline Beecham Corp., 413 F.3d 1318, 1326, 75 USPQ2d 1297, 1302 (Fed. Cir. 2005)). In the present case, the clinical trial protocol needs not disclose proof of efficacy to anticipate the claim. The clinical trial protocol does indeed satisfy the enablement requirement of 102 merely by showing that a skilled artisan could practice the method disclosed in the prior art. For the obviousness rejection the examiner notes that MPEP 2143.02 (I) states “conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019).” MPEP 2143.02 (II) states “obviousness does not require absolute predictability, but at least some degree of predictability is required. Evidence showing there was no reasonable expectation of success may support a conclusion of nonobviousness. In re Rinehart, 531 F.2d 1048, 189 USPQ 143 (CCPA 1976).”
Applicant’s argument
Applicant argues that the secondary references cited cannot and do not cure the deficiencies of the clinical trial protocol. Levosimendan's efficacy in treating heart failure could not have been predictive of efficacy in treating a subject exhibiting a left ventricular ejection fraction of at least 40% because all previously approved drugs to treat heart failure had
failed to show any therapeutic benefit in such patients. Prior to Applicant's clinical results reported for the first time in the referenced application, there was no reasonable expectation that a subject as claimed could be successfully treated with levosimendan at all. On the contrary, several publications discussed herein establish that a POSA would not have had a reasonable expectation of treating a heart condition in a human subject exhibiting a left ventricular ejection fraction of at least 40% and limited exercise capacity by administering to the human subject levosimendan, its metabolites OR-1896 or OR-1855, or a combination thereof, as claimed.
Examiner’s response
In response, Applicant’s argument is not persuasive. Again, contrary to Applicant’s assertion that prior to Applicant's clinical results reported for the first time in the referenced application, there was no reasonable expectation that a subject as claimed could be successfully treated with levosimendan at all. NCT03541603 clearly teaches a method of treating PH-HFpEF (Pulmonary Hypertension Patients with Heart Failure and Preserved Left Ventricular Ejection Fraction) patient with limited exercise capacity and has a left ventricular ejection fraction of at least 40%, the method comprising administering levosimendan to a human subject and the human subject as the ability to walk at least 50 meters, but not more than 550 meters, in a six-minute walk test. Therefore, prior to Applicant’s invention, levosimendan was known to treat PH-HFpEF (Pulmonary Hypertension Patients with Heart Failure and Preserved Left Ventricular Ejection Fraction) patient with limited exercise capacity and has a left ventricular ejection fraction of at least 40%, Again, reasonable expecdtation is a standard for obviousness rejection, and not a standard for anticipation rejection which forms the basis for the new rejection.
Applicant’s argument
Applicant argues that the clinical classification of the many distinct forms of such heart
condition is especially relevant because every drug that had ever been attempted to treat a subject exhibiting a left ventricular ejection fraction of at least 40% failed despite having success in treating other forms of pulmonary hypertension. Furthermore, prior to the surprising success demonstrated by Applicant, the use of levosimendan to treat such patients (e.g., PH-HFpEF patients in particular was considered counter intuitive because it was an inotrope. As stated at paragraph [0006] of the specification as published: Levosimendan has been studied exclusively in heart failure patients with reduced ejection fraction (HFrEF). In fact, with the single exception of the Hemodynamic Evaluation of Levosimendan in PH-HFpEF (HELP) Study (Borlaug 2020, Burkhoff 2020) that this invention is based upon, all of the many prior multi-center randomized placebo-controlled trials of levosimendan in heart failure patients have specifically excluded heart failure patients with preserved ejection fraction (HFpEF). The complete lack of clinical research evaluating levosimendan in HFpEF and PH-HFpEF patients is consistent with the historical treatment paradigm that levosimendan should be used to treat HFrEF patients. The HELP Study represents a major departure from this traditional
mindset and as a result the findings from this novel clinical trial represent significant and surprising discoveries regarding the benefits of levosimendan in PH- HFpEF patients. A further discussion of the many failed attempts to treat heart conditions is provided at paragraphs [0015] - [0026] of the specification as published. Simply put, nothing in the cited art, alone or in combination, could have provided a POSA with a reasonable expectation that levosimendan
would be effective to treat a subject exhibiting a left ventricular ejection fraction of at least 40% in any way.
Examiner’s response
In response, Applicant’s argument is not persuasive. Just because Levosimendan has been studied exclusively in heart failure patients with reduced ejection fraction (HFrEF) and just because a few references have not tested or indicated or suggested the use of Levosimendan in heart failure patients with reduced ejection fraction (HFrEF) does not Levosimendan cannot be used to treat heart failure patients with reduced ejection fraction (HFrEF). In fact, again, NCT03541603 teaches a method of treating PH-HFpEF (Pulmonary Hypertension Patients with Heart Failure and Preserved Left Ventricular Ejection Fraction) patient with limited exercise capacity and has a left ventricular ejection fraction of at least 40%, the method comprising administering levosimendan to a human subject and the human subject as the ability to walk at least 50 meters, but not more than 550 meters, in a six-minute walk test. (See Study Design Section, and Arms and Interventions and Inclusion Criteria Sections.)
Double Patenting
The non-statutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A non-statutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on non-statutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-2, 7, 22-27, 29, 31, 57-59, and 62 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of prior U.S. Patent No. US11,969,424 B2 in view of Rosenkranz et al (International Journal of Cardiology, Volume 272, Supplement, 1 December 2018, Pages 53-62), Kundra et al (Annals of Cardiac Anaesthesia 21(3): p 328-332, Jul–Sep 2018), and Valjakka-Koskela et al (European Journal of Pharmaceutical Sciences 11 (2000) 343–350).
The U.S. patent claims teach a method for improving exercise capacity as measured by an at least 5 meter increase in the six (6) minute walk distance in a human subject afflicted with Pulmonary Hypertension Heart Failure with preserved Ejection Fraction (PH-HFpEF) comprising intravenously, orally, or subcutaneously administering to the human subject an amount of levosimendan, its metabolites OR-1896 or OR-1855, or a combination thereof, so as to improve the human subject's exercise capacity by an at least 5 meter increase in the six (6) minute walk distance. (See claim 1.)
The U.S. patent claims do not teach the human subject exhibits edema. Moreover, the U.S. patent claims do not teach transdermal and inhaled administrations.
Rosenkranz teaches factors which suggest the presence of pulmonary hypertension due to left heart disease (PH-LHD), e.g., HFpEF in patients with suspected pulmonary hypertension include, but no limited to pulmonary edema. (See Table 3.and “Introduction section.)
Kundra teaches inhaled levosimendan may act as selective pulmonary vasodilator and avoid systemic side effects of intravenous levosimendan, which include decrease in systemic vascular resistance (SVR) and systemic hypotension, but with same beneficial effect on pulmonary artery pressure (PAP) and right ventricular (RV) function. Inhaled levosimendan is a selective pulmonary vasodilator. It causes decrease in PAP and improvement in RV function, without having a significant effect on SVR. (See Abstract).
Valjakka-Koskela teaches therapeutic concentrations of levosimendan in plasma are achieved with intravenous infusion at doses of 0.05–0.2 μg/kg/min. The clearance of levosimendan is 300–360 ml/min and it seems to be mainly eliminated by metabolism. Continuous, controlled, and non-invasive delivery of levosimendan via a transdermal route might provide convenient administration with long duration of activity and less risk of excessive drug concentrations.
It would have been prima facie obvious for a person of ordinary skill in the art at the time of the invention was filed to substitute the administration taught by the U.S. patent claims with the inhaled administration taught by Kundra and/or the transdermal administration taught by Valjakka-Koskela. One would have been motivated to do so, Rosenkranz teaches the presence of pulmonary edema in HFpEF patients and because Kundra teaches the inhaled administration of levosimendan has the same beneficial effect on pulmonary artery pressure (PAP) and right ventricular (RV) function, but avoids the systemic side effects associated with intravenous levosimendan, and also because Valjakka-Koskela teaches transdermal route might provide convenient administration with long duration of activity and less risk of excessive drug concentrations as compared to the intravenous administration. One would be expected the substitution to effectively treat PH-HFpEF (Pulmonary Hypertension Patients with Heart Failure and Preserved Left Ventricular Ejection Fraction) in a human subject exhibiting edema and limited exercise capacity with success by improving the human subject’s six-minute walk distance to 16 meters.
Accordingly, a person of ordinary skill in the art can infer that the claimed limitation “wherein no rest, atrial or ventricular, are observed when comparing baseline electrocardiographic monitoring with 72-hour monitoring after 5 weeks of treatment and/or wherein treating presents no more statistically significant adverse events than the matching placebo” is a test simply that expresses the intended outcomes of the method step positively recited. Since the prior art teaches the same compound as claimed and the obvious patient population claimed, the intended outcomes would necessarily present. In the absence of evidence to the contrary, the burden is on the applicant to prove that the claimed method is different from that taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
Claims 1-2, 7, 22-27, 29, 31, 57-59, and 62 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of prior U.S. Patent No. US11,607,412 B2 in view of Rosenkranz et al (International Journal of Cardiology, Volume 272, Supplement, 1 December 2018, Pages 53-62), Kundra et al (Annals of Cardiac Anaesthesia 21(3): p 328-332, Jul–Sep 2018), and Valjakka-Koskela et al (European Journal of Pharmaceutical Sciences 11 (2000) 343–350).
The U.S. patent claims teach a method for improving exercise capacity as measured by an at least 10 meter increase in the six (6) minute walk distance in a human subject afflicted with Pulmonary Hypertension with Heart Failure with preserved Ejection Fraction (PH-HFpEF) comprising intravenously administering using a peripherally inserted central catheter (PICC) or a port-a-cath to the human subject an amount of levosimendan, its metabolites OR-1896 or OR-1855, or a combination thereof, that is effective to improve the human subject's exercise capacity by an at least 10 meter increase in the six (6) minute walk distance,
wherein the subject is initially intravenously administered 0.075 μg levosimendan/kg subject/minute for 24 hours once weekly, and after three weeks of treatment the subject is
a) intravenously administered an escalated dose of 0.1 μg levosimendan/kg subject/minute for 24 hours; or
b) intravenously administered a lowered dose of 0.5 μg levosimendan/kg subject/minute for 24 hours if a meaningful change in blood pressure or heart rate occurs or an adverse event is detected in the subject. (See claim 1.)
The U.S. patent claims do not teach the human subject exhibits edema and a left ventricular ejection fraction of at least 40. Moreover, the U.S. patent claims do not teach transdermal and inhaled administrations.
Rosenkranz teaches factors which suggest the presence of pulmonary hypertension due to left heart disease (PH-LHD), e.g., HFpEF in patients with suspected pulmonary hypertension include, but no limited to pulmonary edema. (See Table 3.and “Introduction section.)
Kundra teaches inhaled levosimendan may act as selective pulmonary vasodilator and avoid systemic side effects of intravenous levosimendan, which include decrease in systemic vascular resistance (SVR) and systemic hypotension, but with same beneficial effect on pulmonary artery pressure (PAP) and right ventricular (RV) function. Inhaled levosimendan is a selective pulmonary vasodilator. It causes decrease in PAP and improvement in RV function, without having a significant effect on SVR. (See Abstract).
Valjakka-Koskela teaches therapeutic concentrations of levosimendan in plasma are achieved with intravenous infusion at doses of 0.05–0.2 μg/kg/min. The clearance of levosimendan is 300–360 ml/min and it seems to be mainly eliminated by metabolism. Continuous, controlled, and non-invasive delivery of levosimendan via a transdermal route might provide convenient administration with long duration of activity and less risk of excessive drug concentrations.
It would have been prima facie obvious for a person of ordinary skill in the art at the time of the invention was filed to substitute the administration taught by the U.S. patent claims with the inhaled administration taught by Kundra and/or the transdermal administration taught by Valjakka-Koskela. One would have been motivated to do so, Rosenkranz teaches the presence of pulmonary edema in HFpEF patients and because Kundra teaches the inhaled administration of levosimendan has the same beneficial effect on pulmonary artery pressure (PAP) and right ventricular (RV) function, but avoids the systemic side effects associated with intravenous levosimendan, and also because Valjakka-Koskela teaches transdermal route might provide convenient administration with long duration of activity and less risk of excessive drug concentrations as compared to the intravenous administration. One would be expected the substitution to effectively treat PH-HFpEF (Pulmonary Hypertension Patients with Heart Failure and Preserved Left Ventricular Ejection Fraction) in a human subject exhibiting edema and limited exercise capacity with success by improving the human subject’s six-minute walk distance to 16 meters.
Accordingly, a person of ordinary skill in the art can infer that the claimed limitation “wherein no rest, atrial or ventricular, are observed when comparing baseline electrocardiographic monitoring with 72-hour monitoring after 5 weeks of treatment and/or wherein treating presents no more statistically significant adverse events than the matching placebo” is a test simply that expresses the intended outcomes of the method step positively recited. Since the prior art teaches the same compound as claimed and the obvious patient population claimed, the intended outcomes would necessarily present. In the absence of evidence to the contrary, the burden is on the applicant to prove that the claimed method is different from that taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
Claims 1-2, 7, 22-27, 29, 31, 57-59, and 62 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of prior U.S. Patent No. US11,701,355 B2 in view of Rosenkranz et al (International Journal of Cardiology, Volume 272, Supplement, 1 December 2018, Pages 53-62), Kundra et al (Annals of Cardiac Anaesthesia 21(3): p 328-332, Jul–Sep 2018), and Valjakka-Koskela et al (European Journal of Pharmaceutical Sciences 11 (2000) 343–350). This is a statutory double patenting rejection.
The U.S. patent claims teach a method for improving exercise capacity as measured by an at least 5 meter increase in the six (6) minute walk distance in a human subject afflicted with Pulmonary Hypertension with Heart Failure with preserved Ejection Fraction (PH-HFpEF) comprising orally administering to the human subject from 1 mg to 4 mg per day of levosimendan, its metabolites OR-1896 or OR-1855, or a combination thereof, so as to improve the human subject's exercise capacity by an at least 5 meter increase in the six (6) minute walk distance. (See claim 1.)
The U.S. patent claims do not teach the human subject exhibits edema and a left ventricular ejection fraction of at least 40%. Moreover, the U.S. patent claims do not teach transdermal and inhaled administrations.
Rosenkranz teaches factors which suggest the presence of pulmonary hypertension due to left heart disease (PH-LHD), e.g., HFpEF in patients with suspected pulmonary hypertension include, but no limited to pulmonary edema. (See Table 3.and “Introduction section.)
Kundra teaches inhaled levosimendan may act as selective pulmonary vasodilator and avoid systemic side effects of intravenous levosimendan, which include decrease in systemic vascular resistance (SVR) and systemic hypotension, but with same beneficial effect on pulmonary artery pressure (PAP) and right ventricular (RV) function. Inhaled levosimendan is a selective pulmonary vasodilator. It causes decrease in PAP and improvement in RV function, without having a significant effect on SVR. (See Abstract).
Valjakka-Koskela teaches therapeutic concentrations of levosimendan in plasma are achieved with intravenous infusion at doses of 0.05–0.2 μg/kg/min. The clearance of levosimendan is 300–360 ml/min and it seems to be mainly eliminated by metabolism. Continuous, controlled, and non-invasive delivery of levosimendan via a transdermal route might provide convenient administration with long duration of activity and less risk of excessive drug concentrations.
It would have been prima facie obvious for a person of ordinary skill in the art at the time of the invention was filed to substitute the administration taught by the U.S. patent claims with the inhaled administration taught by Kundra and/or the transdermal administration taught by Valjakka-Koskela. One would have been motivated to do so, Rosenkranz teaches the presence of pulmonary edema in HFpEF patients and because Kundra teaches the inhaled administration of levosimendan has the same beneficial effect on pulmonary artery pressure (PAP) and right ventricular (RV) function, but avoids the systemic side effects associated with intravenous levosimendan, and also because Valjakka-Koskela teaches transdermal route might provide convenient administration with long duration of activity and less risk of excessive drug concentrations as compared to the intravenous administration. One would be expected the substitution to effectively treat PH-HFpEF (Pulmonary Hypertension Patients with Heart Failure and Preserved Left Ventricular Ejection Fraction) in a human subject exhibiting edema and limited exercise capacity with success by improving the human subject’s six-minute walk distance to 16 meters.
Accordingly, a person of ordinary skill in the art can infer that the claimed limitation “wherein no rest, atrial or ventricular, are observed when comparing baseline electrocardiographic monitoring with 72-hour monitoring after 5 weeks of treatment and/or wherein treating presents no more statistically significant adverse events than the matching placebo” is a test simply that expresses the intended outcomes of the method step positively recited. Since the prior art teaches the same compound as claimed and the obvious patient population claimed, the intended outcomes would necessarily present. In the absence of evidence to the contrary, the burden is on the applicant to prove that the claimed method is different from that taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
Claims 1-2, 7, 22-27, 29, 31, 57-59, and 62 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5, 11, 20, 24-25, 28, 30, 32, 41, 43, 45, and 49 of copending Application No 18/725,602 in view of Rosenkranz et al (International Journal of Cardiology, Volume 272, Supplement, 1 December 2018, Pages 53-62), Kundra et al (Annals of Cardiac Anaesthesia 21(3): p 328-332, Jul–Sep 2018), and Valjakka-Koskela et al (European Journal of Pharmaceutical Sciences 11 (2000) 343–350).
The copending claims teach a method for treating Pulmonary Hypertension Heart Failure with preserved ejection fraction (PH-HFpEF) in a human subject afflicted with PH-HFpEF comprising orally administering to the human subject an amount of levosimendan, its metabolites OR-1896 or OR-1855, or a combination thereof, that is effective to treat the PH-HFpEF in the human subject wherein the treating comprises a reduction in the human subject's serum brain natriuretic peptide (BNP) level and/or N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels;an improvement in quality of life as assessed by Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TS), clinical summary score (KCCQ-CS), and/or overall summary score (KCCQ-OS); and/or a change in resting heart rate of about 5 beats/minute or less and/or a change in systolic arterial blood pressure of about 4 mmHg or less. (See claim 1.) Moreover, the copending claims teach has the ability to walk at least 50 meters in a six-minute walk test, does not have the ability to walk more than 550 meters in a six-minute walk test and has a left ventricular ejection fraction of at least 40%; b) has a baseline pulmonary arterial pressure of at least 35. (See claim 2 and claim 5.)
The copending claims do not teach the human subject exhibits edema. Moreover, the U.S. patent claims do not teach transdermal and inhaled administrations.
Rosenkranz teaches factors which suggest the presence of pulmonary hypertension due to left heart disease (PH-LHD), e.g., HFpEF in patients with suspected pulmonary hypertension include, but no limited to pulmonary edema. (See Table 3.and “Introduction section.)
Kundra teaches inhaled levosimendan may act as selective pulmonary vasodilator and avoid systemic side effects of intravenous levosimendan, which include decrease in systemic vascular resistance (SVR) and systemic hypotension, but with same beneficial effect on pulmonary artery pressure (PAP) and right ventricular (RV) function. Inhaled levosimendan is a selective pulmonary vasodilator. It causes decrease in PAP and improvement in RV function, without having a significant effect on SVR. (See Abstract).
Valjakka-Koskela teaches therapeutic concentrations of levosimendan in plasma are achieved with intravenous infusion at doses of 0.05–0.2 μg/kg/min. The clearance of levosimendan is 300–360 ml/min and it seems to be mainly eliminated by metabolism. Continuous, controlled, and non-invasive delivery of levosimendan via a transdermal route might provide convenient administration with long duration of activity and less risk of excessive drug concentrations.
It would have been prima facie obvious for a person of ordinary skill in the art at the time of the invention was filed to substitute the administration taught by the copending claims with the inhaled administration taught by Kundra and/or the transdermal administration taught by Valjakka-Koskela. One would have been motivated to do so, Rosenkranz teaches the presence of pulmonary edema in HFpEF patients and because Kundra teaches the inhaled administration of levosimendan has the same beneficial effect on pulmonary artery pressure (PAP) and right ventricular (RV) function, but avoids the systemic side effects associated with intravenous levosimendan, and also because Valjakka-Koskela teaches transdermal route might provide convenient administration with long duration of activity and less risk of excessive drug concentrations as compared to the intravenous administration. One would be expected the substitution to effectively treat PH-HFpEF (Pulmonary Hypertension Patients with Heart Failure and Preserved Left Ventricular Ejection Fraction) in a human subject exhibiting edema and limited exercise capacity with success by improving the human subject’s six-minute walk distance to 16 meters.
Accordingly, a person of ordinary skill in the art can infer that the claimed limitation “wherein no rest, atrial or ventricular, are observed when comparing baseline electrocardiographic monitoring with 72-hour monitoring after 5 weeks of treatment and/or wherein treating presents no more statistically significant adverse events than the matching placebo” is a test simply that expresses the intended outcomes of the method step positively recited. Since the prior art teaches the same compound as claimed and the obvious patient population claimed, the intended outcomes would necessarily present. In the absence of evidence to the contrary, the burden is on the applicant to prove that the claimed method is different from that taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
This is a provisional nonstatutory double patenting rejection.
Claims 1-2, 7, 22-27, 29, 31, 57-59, and 62 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 5, 7, 9, 11-12, 18-26, 28-30, and 32 of copending Application No 18/714,318 in view of Rosenkranz et al (International Journal of Cardiology, Volume 272, Supplement, 1 December 2018, Pages 53-62), Kundra et al (Annals of Cardiac Anaesthesia 21(3): p 328-332, Jul–Sep 2018), and Valjakka-Koskela et al (European Journal of Pharmaceutical Sciences 11 (2000) 343–350).
The copending claims teach a method of treating heart failure in a human subject comprising administering to the human subject an effective amount of a combination therapy comprising a) an amount of levosimendan, its metabolites OR-1896 or OR-1855, or a combination thereof; and b) an amount of a sodium-glucose cotransporter-2 (SGLT-2) inhibitor. (See claim 1.) Moreover, the copending claims teach has the ability to walk at least 50 meters in a six-minute walk test, does not have the ability to walk more than 550 meters in a six-minute walk test and has a left ventricular ejection fraction of at least 40%; b) has a baseline pulmonary arterial pressure of at least 35. (See claim 2 and claim 5.) The improvement in the subject's exercise capacity is an increase of at least 10, 20, 30, 40, 50, 60, 70, 80, or 100 meters in a 6- minute walk distance. (See claim 26.)
The copending claims do not teach the human subject exhibits edema and limited exercise capacity. Moreover, the U.S. patent claims do not teach transdermal and inhaled administrations.
Rosenkranz teaches factors which suggest the presence of pulmonary hypertension due to left heart disease (PH-LHD), e.g., HFpEF in patients with suspected pulmonary hypertension include, but no limited to pulmonary edema. (See Table 3.and “Introduction section.)
Kundra teaches inhaled levosimendan may act as selective pulmonary vasodilator and avoid systemic side effects of intravenous levosimendan, which include decrease in systemic vascular resistance (SVR) and systemic hypotension, but with same beneficial effect on pulmonary artery pressure (PAP) and right ventricular (RV) function. Inhaled levosimendan is a selective pulmonary vasodilator. It causes decrease in PAP and improvement in RV function, without having a significant effect on SVR. (See Abstract).
Valjakka-Koskela teaches therapeutic concentrations of levosimendan in plasma are achieved with intravenous infusion at doses of 0.05–0.2 μg/kg/min. The clearance of levosimendan is 300–360 ml/min and it seems to be mainly eliminated by metabolism. Continuous, controlled, and non-invasive delivery of levosimendan via a transdermal route might provide convenient administration with long duration of activity and less risk of excessive drug concentrations.
It would have been prima facie obvious for a person of ordinary skill in the art at the time of the invention was filed to substitute the administration taught by the copending claims with the inhaled administration taught by Kundra and/or the transdermal administration taught by Valjakka-Koskela in a subject with edema and limited exercise capacity. One would have been motivated to do so, not only the copending claims teach the method can improve the subject’s exercise capacity in an increase of at least 10-100 meters in a six-minute walt test, but also because Rosenkranz teaches the presence of pulmonary edema in HFpEF patients and because Kundra teaches the inhaled administration of levosimendan has the same beneficial effect on pulmonary artery pressure (PAP) and right ventricular (RV) function, but avoids the systemic side effects associated with intravenous levosimendan, and also because Valjakka-Koskela teaches transdermal route might provide convenient administration with long duration of activity and less risk of excessive drug concentrations as compared to the intravenous administration. One would be expected the substitution to effectively treat PH-HFpEF (Pulmonary Hypertension Patients with Heart Failure and Preserved Left Ventricular Ejection Fraction) in a human subject exhibiting edema and limited exercise capacity with success by improving the human subject’s six-minute walk distance to 16 meters.
This is a provisional nonstatutory double patenting rejection.
Applicant requests that this ground of rejection be held in abeyance until allowable claims have been identified.
In response, since no allowable claims have been identified and since no terminal disclaimer has been filed, the double patenting rejections are maintained.
Conclusion
Claims 1-2, 7, 22-27, 29, 31, 57-59, and 62 are not allowed.
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.
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/JEAN P CORNET/Primary Examiner, Art Unit 1628