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 .
Status of Claims
The claim amendments filed 18 November 2025 amended claims 1, 11-12, 14-16, 19-24, 26-27, 29,32-33, 36-41 and 45; canceled claims 2-10, 18, 28, 30, 34-35 and 46-48.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1, 11-17, 19-27, 29, 31-33, 36-41 and 45, in the reply filed on 18 November 2025 is acknowledged. Applicant further elected atrial cardiomyopathy as the specific atrial dysfunction, a reduction in atrial fibrillation recurrence as the treatment for atrial fibrillation, systolic dysfunction as what the patient exhibits and/or has been treated with, heart failure with reduced ejection fraction (HFrEF) as the specific systolic dysfunction and specific heart failure, AF burden of <2% or >70% as what the patient does not have, a beta blocker as the specific active further administered to the patient, and reduced risk of urgent outpatient intervention for atrial dysfunction, systolic dysfunction, or both as the results from the method.
Claims 13-14 are 24-27 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 18 November 2025.
Claims 1, 11-12, 15-17, 19-23, 29, 31-33, 36-41 and 45 are examined herein to the extent that atrial cardiomyopathy is the specific atrial dysfunction, a reduction in atrial fibrillation recurrence is the treatment for atrial fibrillation, systolic dysfunction is what the patient exhibits and/or has been treated with, heart failure with reduced ejection fraction (HFrEF) as the specific systolic dysfunction and specific heart failure, AF burden of <2% or >70% as what the patient does not have, a beta blocker as the specific active further administered to the patient, and reduced risk of urgent outpatient intervention for atrial dysfunction, systolic dysfunction, or both as the results from the method, e.g., applicant's elected species.
Information Disclosure Statement
The information disclosure statement (IDS) filed 03/09/2023 has been considered by the Examiner. A signed and initialed copy of the IDS is included with the instant Office Action.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 19-20 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.
Claim 19 recites the limitation "the tachyarrhythmia or atrial fibrillation" in line 2. There is insufficient antecedent basis for this limitation in the claim.
Claim 20 recites the limitation "the atrial fibrillation" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim.
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 1, 11-12, 15-16, 23, 33, 36, 38, 41 and 45 are rejected under 35 U.S.C. 103 as being unpatentable over OSLOB (WO 2016/118774 A1, cited in IDS filed 03/09/2023) in view of MELENOVSKY (“Left Atrial Remodeling and Function in Advanced Heart Failure With Preserved or Reduced Ejection Fraction”, Circ Heart Fail, pages 295-303, March 2015).
Oslob is primarily directed towards compounds that are useful for treatment of dilated cardiomyopathy and conditions associated with left and/or right ventricular systolic dysfunction or systolic reserve (abstract).
Regarding claims 1, 11, 16, 33 and 45, Oslob discloses series of 4-methylsulfonyl-substituted piperidine ureas and pharmaceutically acceptable salts thereof that increase contractility by enhancing phosphate release from myosin without prolonging systole or shortening diastole (paragraph [0013]). Oslob discloses that the compounds can be used to treat cardiac disorders characterized by diminished cardiac output (paragraph [0013]). Oslob discloses that the compounds that increase systolic function hold promise of treating a wide spectrum of disorders in which symptoms and/or clinical outcomes are attributable to systolic dysfunction (left or right sided heart failure) (paragraph [0059]). Oslob discloses that the compounds can confer benefit to patients suffering from heart failure with reduced ejection fraction (e.g., systolic dysfunction/HFrEF) (paragraph [0061]). Oslob discloses that reducing or eliminating functional mitral regurgitation and/or lowering left atrial pressures may reduce the risk of paroxysmal or permanent atrial fibrillation (paragraph [0061]). Oslob discloses that dosage level of the compound particularly includes 75 mg and may be administered once per day (paragraph [0062]). The amount of 75 mg lies inside the range of “10-350 mg” recited in claim 33. Thus, 33 is rendered prima facie obvious. See In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). See also MPEP 2144.05. Oslob discloses that the compounds include compound 20 which is (R)-4-(l-((3-(Difluoromethyl)-l-methyl-lH-pyrazol-4-yl)sulfonyl)-l-fluoroethyl)-N-(isoxazol-3-yl)piperidine-l-carboxamide (paragraph [0180]).
Regarding claim 13, Oslob discloses that implantable cardioverter defibrillators for patients with left ventricular ejection fraction of less than 30% can reduce sudden arrhythmic death (paragraph [0006]).
Regarding claim 36, Oslob discloses that the compounds can be administered by oral (paragraph [0062]).
Regarding claim 38, Oslob discloses that compositions can be dose units to be imbibed directly or they can be mixed with food prior to ingestion (paragraph [00110]).
Regarding claim 41, Oslob discloses that co-administration of cardiovascular agents including beta blockers (paragraphs [0029-0030]).
Oslob does not specifically teach treating atrial cardiomyopathy in a patient. The deficiency is made up for by the teachings of Melenovsky.
Melenovsky is primarily directed towards the differences in left atrial properties between heart failure with preserved (HFpEF) and reduced ejection fraction (HFrEF) (abstract).
Regarding claims 1 and 27, Melenovsky teaches that patients with including HFrEF displayed including LA dilatation (e.g., atrial cardiomyopathy/myopathy) (page 298, second column, last paragraph). Melenovsky teaches that HFrEF patients displayed more eccentric LA remodeling (e.g., atrial cardiomyopathy/myopathy) (paragraph bridging pages 298 and 299). Melenovsky teaches that loss of normal atrial electric activity in HF patients with AF is associated with including systolic dysfunction (page 301, first column, second paragraph).
Regarding claim 15, Melenovsky teaches both HF groups were highly symptomatic with NYHA III-IV (page 298 second column, second paragraph).
Regarding claim 23, Melenovsky teaches LV ejection fraction % for HFrEF of 24±9.7 (Table 2).
It would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to treat a patient with heart failure with reduced ejection fraction (e.g., systolic dysfunction/HFrEF) which display left atrial dilatation and eccentric left atrial remodeling (e.g., atrial cardiomyopathy/myopathy), by administering a composition comprising a compound including (R)-4-(l-((3-(Difluoromethyl)-l-methyl-lH-pyrazol-4-yl)sulfonyl)-l-fluoroethyl)-N-(isoxazol-3-yl)piperidine-l-carboxamide; wherein the compound present as a dosage of including 75 mg and the compositions is administered including once a day. The person of ordinary skill in the art would have been motivated to administer the compound to patients with heart failure with reduced ejection fraction (e.g., systolic dysfunction/HFrEF) because patients with HFrEF displays including LA dilatation and more eccentric LA remodeling (e.g., atrial cardiomyopathy/myopathy), as taught by Melenovsky. The person of ordinary skill in the art would have reasonably expected patients with including heart failure with reduced ejection fraction (e.g., systolic dysfunction/HFrEF) that display left atrial dilatation and eccentric left atrial remodeling (e.g., atrial cardiomyopathy) would benefit from administration of the composition of Oslob because Oslob discloses series of 4-methylsulfonyl-substituted piperidine ureas and pharmaceutically acceptable salts thereof that increase contractility by enhancing phosphate release from myosin without prolonging systole or shortening diastole (paragraph [0013]). Oslob discloses that the compounds can be used to treat cardiac disorders characterized by diminished cardiac output (paragraph [0013]). Oslob discloses that the compounds that increase systolic function hold promise of treating a wide spectrum of disorders in which symptoms and/or clinical outcomes are attributable to systolic dysfunction (left or right sided heart failure) (paragraph [0059]). Oslob discloses that the compounds can confer benefit to patients suffering from heart failure with reduced ejection fraction (e.g., systolic dysfunction/HFrEF) (paragraph [0061]). Oslob discloses that reducing or eliminating functional mitral regurgitation and/or lowering left atrial pressures may reduce the risk of paroxysmal or permanent atrial fibrillation (paragraph [0061]). Melenovsky teaches that patients with including HFrEF displayed including LA dilatation (e.g., atrial cardiomyopathy) (page 298, second column, last paragraph). Melenovsky teaches that HFrEF patients displayed more eccentric LA remodeling (e.g., atrial cardiomyopathy) (paragraph bridging pages 298 and 299).
Claims 17 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Oslob in view of Melenovsky as applied to claims 1, 11-12, 15-16, 23, 33, 36, 38, 41 and 45 above, and further in view of SANTHANAKRISHNAN (“Atrial Fibrillation Begets Heart Failure and Vice Versa Temporal Associations and Differences in Preserved Versus Reduced Ejection Fraction”, Circulation, pages 484-492, 02 February 2016).
Regarding claim 17, the method of claim 16 is described above in section 10.
Regarding claim 19, the method of claim 1 is described above in section 10.
Oslob and Melenovsky do not specifically teach that the patient exhibits atrial fibrillation. The deficiency is made up for by the teachings of Santhanakrishnan.
Santhanakrishnan is primarily directed towards differences in temporal association of AF (atrial fibrillation) with HF (heart failure) with preserved versus reduced ejection fraction (abstract).
Regarding claim 17, Santhanakrishnan teaches that more than half of participants with HF had AF at some point, with AF more likely to antedate than to follow HF. Santhanakrishnan teaches that more than one third or participants with AF had HF, with most developing HF onset after AF rather than beforehand (page 488, second column, second paragraph). Santhanakrishnan teaches that AF and HF conjointly portend a poor prognosis, with higher risk among those with HFrEF (page 490, second column, third paragraph).
Regarding claim 19, Santhanakrishnan teaches that concurrent AF and HF is defined as the diagnosis of including new AF within 30 days of HF (page 485, second column, second paragraph).
It would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to treat a patient with atrial fibrillation and has heart failure with reduced ejection fraction (e.g., systolic dysfunction/HFrEF) which display left atrial dilatation and eccentric left atrial remodeling (e.g., atrial cardiomyopathy/myopathy), by administering a composition comprising a compound including (R)-4-(l-((3-(Difluoromethyl)-l-methyl-lH-pyrazol-4-yl)sulfonyl)-l-fluoroethyl)-N-(isoxazol-3-yl)piperidine-l-carboxamide; wherein the compound present as a dosage of including 75 mg and the compositions is administered including once a day. The person of ordinary skill in the art would have been motivated administer the compound to patients with including atrial fibrillation because half of patients with heart failure including HFrEF have atrial fibrillation, as taught Santhanakrishnan. The person of ordinary skill in the art would have reasonably expected patients with including atrial fibrillation would benefit from the composition of Oslob because Oslob discloses that the compounds can confer benefit to patients suffering from heart failure with reduced ejection fraction (e.g., systolic dysfunction/HFrEF) (paragraph [0061]). Oslob discloses that reducing or eliminating functional mitral regurgitation and/or lowering left atrial pressures may reduce the risk of paroxysmal or permanent atrial fibrillation (paragraph [0061]). Melenovsky teaches that patients with including HFrEF displayed including LA dilatation (e.g., atrial cardiomyopathy/myopathy) (page 298, second column, last paragraph). Melenovsky teaches that HFrEF patients displayed more eccentric LA remodeling (e.g., atrial cardiomyopathy/myopathy) (paragraph bridging pages 298 and 299). Santhanakrishnan teaches that more than half of participants with HF had AF at some point, with AF more likely to antedate than to follow HF. Santhanakrishnan teaches that more than one third or participants with AF had HF, with most developing HF onset after AF rather than beforehand (page 488, second column, second paragraph).
Regarding recitation of “reduces atrial fibrillation recurrence” in claim 17, although the combination of Oslob, Melenovsky and Santhanakrishnan do not specifically teach reducing atrial fibrillation recurrence, the claimed method of administration of to a patient in need of treating atrial dysfunction, exhibits systolic dysfunction and atrial fibrillation, a composition comprising a therapeutically effective amount of (R)-4-(l-((3-(Difluoromethyl)-l-methyl-lH-pyrazol-4-yl)sulfonyl)-l-fluoroethyl)-N-(isoxazol-3-yl)piperidine-l-carboxamide (paragraphs [0059] and [0061-0062] of Oslob; page 298, second column, last paragraph, and paragraph bridging pages 298 and 299 of Melenovsky; page 488, second column, second paragraph of Santhanakrishnan) appears to be the same as the prior art, absent a showing of unobvious differences. The office does not have the facilities and resources to provide the factual evidence needed in order to establish that the composition of the prior art does not possess the same material, structural and steps-like characteristics of the claimed composition. In the absence of evidence to the contrary, the burden is on Applicant to prove that the claimed composition 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 2nd 1992 (PTO Bd. Pat. App. & Int. 1989).
Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). Therefore, the prima facie case can be rebutted by evidence showing that the prior art products do not necessarily possess the characteristics of the claimed product. In re Best, 562 F.2d at 1255, 195 USPQ at 433. See also Titanium Metals Corp. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985) (Claims were directed to a titanium alloy containing 0.2-0.4% Mo and 0.6-0.9% Ni having corrosion resistance. A Russian article disclosed a titanium alloy containing 0.25% Mo and 0.75% Ni but was silent as to corrosion resistance. The Federal Circuit held that the claim was anticipated because the percentages of Mo and Ni were squarely within the claimed ranges. The court went on to say that it was immaterial what properties the alloys had or who discovered the properties because the composition is the same and thus must necessarily exhibit the properties.). MPEP 2112.01 (I).
Claims 20-21, 29 and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Oslob in view of Melenovsky as applied to claims 1, 11-12, 15-16, 23, 33, 36, 38, 41 and 45 above, and further in view of SANTHANAKRISHNAN (“Atrial Fibrillation Begets Heart Failure and Vice Versa Temporal Associations and Differences in Preserved Versus Reduced Ejection Fraction”, Circulation, pages 484-492, 02 February 2016) and GO (“Association of Burden of Atrial Fibrillation With Risk of Ischemic Stroke in Adults With Paroxysmal Atrial Fibrillation”, JAMA Cardiol, 7, pages 601-608, published 16 May 2018).
Regarding claims 20-21 and 32, the method of claim 1 is described above in section 10.
Oslob and Melenovsky do not specifically teach that the patient has paroxysmal or persistent atrial fibrillation (e.g., claim 20). Oslob and Melenovsky do not specifically teach that the patient has atrial fibrillation burden of 2-70% or not have AF burden of <2% or >70% (e.g., claims 21 and 32). The deficiencies are made up for by the teachings of Santhanakrishnan and Go.
Santhanakrishnan is primarily directed towards differences in temporal association of AF (atrial fibrillation) with HF (heart failure) with preserved versus reduced ejection fraction (abstract).
Regarding claims 20-21 and 32, Santhanakrishnan teaches that more than half of participants with HF had AF at some point, with AF more likely to antedate than to follow HF. Santhanakrishnan teaches that more than one third or participants with AF had HF, with most developing HF onset after AF rather than beforehand (page 488, second column, second paragraph). Santhanakrishnan teaches that AF and HF conjointly portend a poor prognosis, with higher risk among those with HFrEF (page 490, second column, third paragraph).
Go is primarily directed towards association of burden of atrial fibrillation with risk of ischemic stroke in adults with paroxysmal atrial fibrillations (abstract).
Regarding claims 20-21 and 32, Go teaches that burden of atrial fibrillation is the amount of time spent in atrial fibrillation (page 602, first column, second paragraph). Go teaches that burden of atrial fibrillation of including 2.05%-11.28% and 11.36-99.99% which had higher heart failure than burden of atrial fibrillation of 0.01%-2.03% (Table).
Regarding claim 29, Go teaches that adults with atrial fibrillation include with prior ablation and cardioversion (Table).
It would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to treat a patient with atrial fibrillation and has heart failure with reduced ejection fraction (e.g., systolic dysfunction/HFrEF) which display left atrial dilatation and eccentric left atrial remodeling (e.g., atrial cardiomyopathy/myopathy), by administering a composition comprising a compound including (R)-4-(l-((3-(Difluoromethyl)-l-methyl-lH-pyrazol-4-yl)sulfonyl)-l-fluoroethyl)-N-(isoxazol-3-yl)piperidine-l-carboxamide; wherein the compound present as a dosage of including 75 mg and the compositions is administered including once a day; wherein the patient has atrial fibrillation with a burden of atrial fibrillation of including 2.05%-11.28%. The person of ordinary skill in the art would have been motivated administer the compound to patients with including atrial fibrillation because half of patients with heart failure including HFrEF have atrial fibrillation, as taught Santhanakrishnan, and specifically to patients with paroxysmal atrial fibrillation with a burden of atrial fibrillation of including 2.05%-11.28% which experiences higher heart failure with increasing burden, as taught by Go. The person of ordinary skill in the art would have reasonably expected patients with including atrial fibrillation would benefit from the composition of Oslob because Oslob discloses that the compounds can confer benefit to patients suffering from heart failure with reduced ejection fraction (e.g., systolic dysfunction/HFrEF) (paragraph [0061]). Oslob discloses that reducing or eliminating functional mitral regurgitation and/or lowering left atrial pressures may reduce the risk of paroxysmal or permanent atrial fibrillation (paragraph [0061]). Melenovsky teaches that patients with including HFrEF displayed including LA dilatation (e.g., atrial cardiomyopathy/myopathy) (page 298, second column, last paragraph). Melenovsky teaches that HFrEF patients displayed more eccentric LA remodeling (e.g., atrial cardiomyopathy/myopathy) (paragraph bridging pages 298 and 299). Santhanakrishnan teaches that more than half of participants with HF had AF at some point, with AF more likely to antedate than to follow HF. Santhanakrishnan teaches that more than one third or participants with AF had HF, with most developing HF onset after AF rather than beforehand (page 488, second column, second paragraph). Go teaches that burden of atrial fibrillation is the amount of time spent in atrial fibrillation (page 602, first column, second paragraph). Go teaches that burden of atrial fibrillation of including 2.05%-11.28% and 11.36-99.99% which had higher heart failure than burden of atrial fibrillation of 0.01%-2.03% (Table).
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Oslob in view of Melenovsky as applied to claims 1, 11-12, 15-16, 23, 33, 36, 38, 41 and 45 above, and further in view of SANTHANAKRISHNAN (“Atrial Fibrillation Begets Heart Failure and Vice Versa Temporal Associations and Differences in Preserved Versus Reduced Ejection Fraction”, Circulation, pages 484-492, 02 February 2016) and ALTURKI (“Major Adverse Cardiovascular Events Associated With Postoperative Atrial Fibrillation After Noncardiac Surgery”, Circulation: Arrhythmia and Electrophysiology, pages 71-80, January 2020).
Regarding claims 22, the method of claim 1 is described above in section 10.
Oslob and Melenovsky do not specifically teach that the patient has postoperative AF. The deficiency is made up for by the teachings of Santhanakrishnan and Alturki.
Santhanakrishnan is primarily directed towards differences in temporal association of AF (atrial fibrillation) with HF (heart failure) with preserved versus reduced ejection fraction (abstract).
Regarding claim 22, Santhanakrishnan teaches that more than half of participants with HF had AF at some point, with AF more likely to antedate than to follow HF. Santhanakrishnan teaches that more than one third or participants with AF had HF, with most developing HF onset after AF rather than beforehand (page 488, second column, second paragraph). Santhanakrishnan teaches that AF and HF conjointly portend a poor prognosis, with higher risk among those with HFrEF (page 490, second column, third paragraph).
Alturki is primarily directed towards risk of stroke, myocardial infarction and death associated with postoperative atrial fibrillation following noncardiac surgery (abstract).
Regarding claim 22, Alturki teaches that postoperative atrial fibrillation was associated with a marked increase in the risk of stroke, myocardial infarction and death following noncardiac surgery (page 78, paragraph in second column).
It would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to treat a patient with atrial fibrillation and has heart failure with reduced ejection fraction (e.g., systolic dysfunction/HFrEF) which display left atrial dilatation and eccentric left atrial remodeling (e.g., atrial cardiomyopathy/myopathy), by administering a composition comprising a compound including (R)-4-(l-((3-(Difluoromethyl)-l-methyl-lH-pyrazol-4-yl)sulfonyl)-l-fluoroethyl)-N-(isoxazol-3-yl)piperidine-l-carboxamide; wherein the compound present as a dosage of including 75 mg and the compositions is administered including once a day; wherein the atrial fibrillation includes postoperative atrial fibrillation. The person of ordinary skill in the art would have been motivated administer the compound to patients with including atrial fibrillation because half of patients with heart failure including HFrEF have atrial fibrillation, as taught Santhanakrishnan, and specifically to patients postoperative atrial fibrillation which is associated with a marked increase in the risk of stroke and myocardial infarction, as taught by Alturki. The person of ordinary skill in the art would have reasonably expected patients with including atrial fibrillation would benefit from the composition of Oslob because Oslob discloses that the compounds can confer benefit to patients suffering from heart failure with reduced ejection fraction (e.g., systolic dysfunction/HFrEF) (paragraph [0061]). Oslob discloses that reducing or eliminating functional mitral regurgitation and/or lowering left atrial pressures may reduce the risk of paroxysmal or permanent atrial fibrillation (paragraph [0061]). Oslob discloses that compounds of the invention or their pharmaceutically acceptable salts can also promote salutary ventricular reverse remodeling of left ventricular dysfunction due to ischemia or volume or pressure overload; e.g., myocardial infarctions (paragraph [0061]). Melenovsky teaches that patients with including HFrEF displayed including LA dilatation (e.g., atrial cardiomyopathy/myopathy) (page 298, second column, last paragraph). Melenovsky teaches that HFrEF patients displayed more eccentric LA remodeling (e.g., atrial cardiomyopathy/myopathy) (paragraph bridging pages 298 and 299). Santhanakrishnan teaches that more than half of participants with HF had AF at some point, with AF more likely to antedate than to follow HF. Santhanakrishnan teaches that more than one third or participants with AF had HF, with most developing HF onset after AF rather than beforehand (page 488, second column, second paragraph). Alturki teaches that postoperative atrial fibrillation was associated with a marked increase in the risk of stroke, myocardial infarction and death following noncardiac surgery (page 78, paragraph in second column). Alturki teaches that postoperative atrial fibrillation was associated with a marked increase in the risk of stroke, myocardial infarction and death following noncardiac surgery (page 78, paragraph in second column).
Claim 31 is rejected under 35 U.S.C. 103 as being unpatentable over Oslob in view of Melenovsky as applied to claims 1, 11-12, 15-16, 23, 33, 36, 38, 41 and 45 above, further in view of Santhanakrishnan and Go as applied to claims 20-21, 29 and 32 above, and further in view of NUSAIR (“Electric Cardioversion of Atrial Fibrillation”, Missouri Medicine, 107:1, pages 59-64, January/February 2010).
Regarding claim 31, the method of claim 29 is described above in section 12.
Oslob, Melenovsky, Santhanakrishnan and Go do not specifically teach that the patient has previously been treated with electrical cardioversion. The deficiencies is made up for by the teachings of Nusair.
Nusair is primarily directed towards electric cardioversion of atrial fibrillation (abstract).
Regarding claim 31, Nusair teaches that electrical cardioversion is safe, effective and reliable method of converting AF (page 64, last paragraph).
It would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to treat a patient with atrial fibrillation and has heart failure with reduced ejection fraction (e.g., systolic dysfunction/HFrEF) which display left atrial dilatation and eccentric left atrial remodeling (e.g., atrial cardiomyopathy/myopathy), by administering a composition comprising a compound including (R)-4-(l-((3-(Difluoromethyl)-l-methyl-lH-pyrazol-4-yl)sulfonyl)-l-fluoroethyl)-N-(isoxazol-3-yl)piperidine-l-carboxamide; wherein the compound present as a dosage of including 75 mg and the compositions is administered including once a day; wherein the patient has atrial fibrillation with a burden of atrial fibrillation of including 2.05%-11.28%; wherein the patient has been treated with electrical cardioversion for the atrial fibrillation. The person of ordinary skill in the art would have been motivated administer the compound to patients with including atrial fibrillation because half of patients with heart failure including HFrEF have atrial fibrillation, as taught Santhanakrishnan, and specifically to patients with paroxysmal atrial fibrillation with a burden of atrial fibrillation of including 2.05%-11.28% which experiences higher heart failure with increasing burden, as taught by Go. The person of ordinary skill in the art would have reasonably expected patients with including atrial fibrillation would benefit from the composition of Oslob because Oslob discloses that the compounds can confer benefit to patients suffering from heart failure with reduced ejection fraction (e.g., systolic dysfunction/HFrEF) (paragraph [0061]). Oslob discloses that reducing or eliminating functional mitral regurgitation and/or lowering left atrial pressures may reduce the risk of paroxysmal or permanent atrial fibrillation (paragraph [0061]). Melenovsky teaches that patients with including HFrEF displayed including LA dilatation (e.g., atrial cardiomyopathy/myopathy) (page 298, second column, last paragraph). Melenovsky teaches that HFrEF patients displayed more eccentric LA remodeling (e.g., atrial cardiomyopathy/myopathy) (paragraph bridging pages 298 and 299). Santhanakrishnan teaches that more than half of participants with HF had AF at some point, with AF more likely to antedate than to follow HF. Santhanakrishnan teaches that more than one third or participants with AF had HF, with most developing HF onset after AF rather than beforehand (page 488, second column, second paragraph). Go teaches that burden of atrial fibrillation is the amount of time spent in atrial fibrillation (page 602, first column, second paragraph). Go teaches that burden of atrial fibrillation of including 2.05%-11.28% and 11.36-99.99% which had higher heart failure than burden of atrial fibrillation of 0.01%-2.03% (Table). Nusair teaches that electrical cardioversion is safe, effective and reliable method of converting AF (page 64, last paragraph).
Claims 37 and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Oslob in view of Melenovsky as applied to claims 1, 11-12, 15-16, 23, 33, 36, 38, 41 and 45 above, further in view of SANTHANAKRISHNAN (“Atrial Fibrillation Begets Heart Failure and Vice Versa Temporal Associations and Differences in Preserved Versus Reduced Ejection Fraction”, Circulation, pages 484-492, 02 February 2016) and SHULER (WO 2018/209107 A1, publication date of 15 November 2018).
Regarding claims 37 and 39, the method of claim 1 is described above in section 10.
Oslob and Melenovsky do not specifically teach that administration in a dose resulting in compound I plasma concentrations of 1000 to 8000 ng/mL in the patient. The deficiencies is made up for by the teachings of Shuler.
Santhanakrishnan is primarily directed towards differences in temporal association of AF (atrial fibrillation) with HF (heart failure) with preserved versus reduced ejection fraction (abstract).
Regarding claims 37 and 39, Santhanakrishnan teaches that more than half of participants with HF had AF at some point, with AF more likely to antedate than to follow HF. Santhanakrishnan teaches that more than one third or participants with AF had HF, with most developing HF onset after AF rather than beforehand (page 488, second column, second paragraph). Santhanakrishnan teaches that AF and HF conjointly portend a poor prognosis, with higher risk among those with HFrEF (page 490, second column, third paragraph).
Shuler is primarily directed towards a method of treating a heart condition comprising administration by inhalation (abstract).
Regarding claims 37 and 39, Shuler teaches aerosol comprising particles having a mass medium aerodynamic diameter less than 10 µm (paragraph [0209]). Shuler teaches rapid acting inhaled product with a fast onset of action compared to oral medicine (paragraph [0213]). Shuler teaches that the Cmax (e.g., plasma concentration) of the pharmaceutical agent administered via inhalation can be from 10 ng/mL to about 5000 ng/mL (paragraph [0371]).
It would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to treat a patient with heart failure with reduced ejection fraction (e.g., systolic dysfunction/HFrEF) which display left atrial dilatation and eccentric left atrial remodeling (e.g., atrial cardiomyopathy/myopathy), by administering by inhalation a composition in the form of particles comprising a compound including (R)-4-(l-((3-(Difluoromethyl)-l-methyl-lH-pyrazol-4-yl)sulfonyl)-l-fluoroethyl)-N-(isoxazol-3-yl)piperidine-l-carboxamide; wherein the compound present as a dosage of including 75 mg; wherein the particles have a mass medium aerodynamic diameter less than 10 µm; and wherein the Cmax (e.g., plasma concentration) of the compound administered via inhalation is from 10 ng/mL to about 5000 ng/mL. The person of ordinary skill in the art would have been motivated to administer the compound by inhalation in form of particles with a mass medium aerodynamic diameter less than 10 µm and provides Cmax (e.g., plasma concentration) of the compound administered via inhalation of from 10 ng/mL to about 5000 ng/mL, in order to obtain rapid acting and fast onset of action compared to oral medicine. The person of ordinary skill in the art would have reasonably expected patients with including heart failure with reduced ejection fraction (e.g., systolic dysfunction/HFrEF) that display left atrial dilatation and eccentric left atrial remodeling (e.g., atrial cardiomyopathy) would benefit from administration of the composition of Oslob because Oslob discloses series of 4-methylsulfonyl-substituted piperidine ureas and pharmaceutically acceptable salts thereof that increase contractility by enhancing phosphate release from myosin without prolonging systole or shortening diastole (paragraph [0013]). Oslob discloses that the compounds can be used to treat cardiac disorders characterized by diminished cardiac output (paragraph [0013]). Oslob discloses that the compounds that increase systolic function hold promise of treating a wide spectrum of disorders in which symptoms and/or clinical outcomes are attributable to systolic dysfunction (left or right sided heart failure) (paragraph [0059]). Oslob discloses that the compounds can confer benefit to patients suffering from heart failure with reduced ejection fraction (e.g., systolic dysfunction/HFrEF) (paragraph [0061]). Oslob discloses that reducing or eliminating functional mitral regurgitation and/or lowering left atrial pressures may reduce the risk of paroxysmal or permanent atrial fibrillation (paragraph [0061]). Shuler teaches treating a heart condition using administration of a formulation by inhalation (paragraph [0025]). Shuler teaches aerosol comprising particles having a mass medium aerodynamic diameter less than 10 µm (paragraph [0209]). Shuler teaches rapid acting inhaled product with a fast onset of action compared to oral medicine (paragraph [0213]). Shuler teaches that the Cmax (e.g., plasma concentration) of the pharmaceutical agent administered via inhalation can be from 10 ng/mL to about 5000 ng/mL (paragraph [0371]).
Claim 40 is rejected under 35 U.S.C. 103 as being unpatentable over Oslob in view of Melenovsky as applied to claims 1, 11-12, 15-16, 23, 33, 36, 38, 41 and 45 above, further in view of SANTHANAKRISHNAN (“Atrial Fibrillation Begets Heart Failure and Vice Versa Temporal Associations and Differences in Preserved Versus Reduced Ejection Fraction”, Circulation, pages 484-492, 02 February 2016) and NUSAIR (“Electric Cardioversion of Atrial Fibrillation”, Missouri Medicine, 107:1, pages 59-64, January/February 2010).
Regarding claims 40, the method of claim 1 is described above in section 10.
Oslob and Melenovsky do not specifically teach that the patient has undergone an electrical cardioversion. The deficiencies is made up for by the teachings of Santhanakrishnan and Nusair.
Santhanakrishnan is primarily directed towards differences in temporal association of AF (atrial fibrillation) with HF (heart failure) with preserved versus reduced ejection fraction (abstract).
Regarding claim 40, Santhanakrishnan teaches that more than half of participants with HF had AF at some point, with AF more likely to antedate than to follow HF. Santhanakrishnan teaches that more than one third or participants with AF had HF, with most developing HF onset after AF rather than beforehand (page 488, second column, second paragraph). Santhanakrishnan teaches that AF and HF conjointly portend a poor prognosis, with higher risk among those with HFrEF (page 490, second column, third paragraph).
Oslob, Melenovsky, Santhanakrishnan and Go do not specifically teach the patient has previously been treated with electrical cardioversion. The deficiencies is made up for by the teachings of Nusair.
Santhanakrishnan is primarily directed towards differences in temporal association of AF (atrial fibrillation) with HF (heart failure) with preserved versus reduced ejection fraction (abstract).
Regarding claim 40, Santhanakrishnan teaches that more than half of participants with HF had AF at some point, with AF more likely to antedate than to follow HF. Santhanakrishnan teaches that more than one third or participants with AF had HF, with most developing HF onset after AF rather than beforehand (page 488, second column, second paragraph). Santhanakrishnan teaches that AF and HF conjointly portend a poor prognosis, with higher risk among those with HFrEF (page 490, second column, third paragraph).
Nusair is primarily directed towards electric cardioversion of atrial fibrillation (abstract).
Regarding claim 40, Nusair teaches that electrical cardioversion is safe, effective and reliable method of converting AF (page 64, last paragraph).
It would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to treat a patient with atrial fibrillation and has heart failure with reduced ejection fraction (e.g., systolic dysfunction/HFrEF) which display left atrial dilatation and eccentric left atrial remodeling (e.g., atrial cardiomyopathy/myopathy), by administering a composition comprising a compound including (R)-4-(l-((3-(Difluoromethyl)-l-methyl-lH-pyrazol-4-yl)sulfonyl)-l-fluoroethyl)-N-(isoxazol-3-yl)piperidine-l-carboxamide; wherein the compound present as a dosage of including 75 mg and the compositions is administered including once a day; wherein the patient has been treated with electrical cardioversion for the atrial fibrillation. The person of ordinary skill in the art would have been motivated administer the compound to patients with including atrial fibrillation and have been treated with electrical cardioversion. The person of ordinary skill in the art would have reasonably expected success because Oslob discloses that the compounds can confer benefit to patients suffering from heart failure with reduced ejection fraction (e.g., systolic dysfunction/HFrEF) (paragraph [0061]). Oslob discloses that reducing or eliminating functional mitral regurgitation and/or lowering left atrial pressures may reduce the risk of paroxysmal or permanent atrial fibrillation (paragraph [0061]). Melenovsky teaches that patients with including HFrEF displayed including LA dilatation (e.g., atrial cardiomyopathy/myopathy) (page 298, second column, last paragraph). Melenovsky teaches that HFrEF patients displayed more eccentric LA remodeling (e.g., atrial cardiomyopathy/myopathy) (paragraph bridging pages 298 and 299). Santhanakrishnan teaches that more than half of participants with HF had AF at some point, with AF more likely to antedate than to follow HF. Santhanakrishnan teaches that more than one third or participants with AF had HF, with most developing HF onset after AF rather than beforehand (page 488, second column, second paragraph). Nusair teaches that electrical cardioversion is safe, effective and reliable method of converting AF (page 64, last paragraph).
Double Patenting
The nonstatutory 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 nonstatutory 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 nonstatutory 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, 11-12, 15, 16, 23, 27 and 41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 33 of U.S. Patent No. 10,758,525 (date of patent of 1 September 2020; hereafter ‘525) in view of MELENOVSKY (“Left Atrial Remodeling and Function in Advanced Heart Failure With Preserved or Reduced Ejection Fraction”, Circ Heart Fail, pages 295-303, March 2015).
Regarding instant claims 1, 11-12, 16 and 45, claim 1 of ‘525 recites a method of treating heart failure with reduced ejection fraction (e.g., systolic adj dysfunction/HFrEF), comprising administering to a subject in need thereof an effective amount of a compound. Claim 32 of “525 recites that the compound is
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or a pharmaceutically acceptable salt thereof.
Regarding instant claim 41, claim 33 of ‘525 recites further comprising administering to the subject an agent including a β-blocker.
The claims of ‘525 do not specifically recite a patient in need of treating atrial cardiomyopathy (e.g., elected species). The deficiency is made up for by the teachings of Melenovsky.
Melenovsky is primarily directed towards the differences in left atrial properties between heart failure with preserved (HFpEF) and reduced ejection fraction (HFrEF) (abstract).
Regarding claims 1 and 27, Melenovsky teaches that patients with including HFrEF displayed including LA dilatation (e.g., atrial cardiomyopathy/myopathy) (page 298, second column, last paragraph). Melenovsky teaches that HFrEF patients displayed more eccentric LA remodeling (e.g., atrial cardiomyopathy/myopathy) (paragraph bridging pages 298 and 299). Melenovsky teaches that loss of normal atrial electric activity in HF patients with AF is associated with including systolic dysfunction (page 301, first column, second paragraph).
Regarding claim 15, Melenovsky teaches both HF groups were highly symptomatic with NYHA III-IV (page 298 second column, second paragraph).
Regarding claim 23, Melenovsky teaches LV ejection fraction % for HFrEF of 24±9.7 (Table 2).
It would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to treat a patient with heart failure with reduced ejection fraction (e.g., systolic dysfunction/HFrEF) which display left atrial dilatation and eccentric left atrial remodeling (e.g., atrial cardiomyopathy/myopathy), by administering a composition comprising an effective amount of a compound including
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(e.g., (R)-4-(l-((3-(Difluoromethyl)-l-methyl-lH-pyrazol-4-yl)sulfonyl)-l-fluoroethyl)-N-(isoxazol-3-yl)piperidine-l-carboxamide. The person of ordinary skill in the art would have been motivated to administer the compound to patients with heart failure with reduced ejection fraction (e.g., systolic dysfunction/HFrEF) because patients with HFrEF displays including LA dilatation and more eccentric LA remodeling (e.g., atrial cardiomyopathy/myopathy), as taught by Melenovsky. The person of ordinary skill in the art would have reasonably expected success because claim 1 of ‘525 recites a method of treating heart failure with reduced ejection fraction (HFrEF), comprising administering to a subject in need thereof an effective amount of a compound. Claim 32 of “525 recites that the compound is
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or a pharmaceutically acceptable salt thereof. Melenovsky teaches that patients with including HFrEF displayed including LA dilatation (e.g., atrial cardiomyopathy) (page 298, second column, last paragraph). Melenovsky teaches that HFrEF patients displayed more eccentric LA remodeling (e.g., atrial cardiomyopathy) (paragraph bridging pages 298 and 299).
Claims 17 and 19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 33 of U.S. Patent No. 10,758,525 (date of patent of 1 September 2020; hereafter ‘525) in view of Melenovsky as applied to claims 1, 11-12, 15, 16, 23, 27 and 41 above, and further in view of SANTHANAKRISHNAN (“Atrial Fibrillation Begets Heart Failure and Vice Versa Temporal Associations and Differences in Preserved Versus Reduced Ejection Fraction”, Circulation, pages 484-492, 02 February 2016).
Regarding claim 17, the method of claim 16 is described above in section 18.
Regarding claim 19, the method of claim 1 is described above in section 18.
The claims of ‘525 do not recite and Melenovsky does not specifically teach that the patient exhibits atrial fibrillation. The deficiency is made up for by the teachings of Santhanakrishnan.
Santhanakrishnan is primarily directed towards differences in temporal association of AF (atrial fibrillation) with HF (heart failure) with preserved versus reduced ejection fraction (abstract).
Regarding claim 17, Santhanakrishnan teaches that more than half of participants with HF had AF at some point, with AF more likely to antedate than to follow HF. Santhanakrishnan teaches that more than one third or participants with AF had HF, with most developing HF onset after AF rather than beforehand (page 488, second column, second paragraph). Santhanakrishnan teaches that AF and HF conjointly portend a poor prognosis, with higher risk among those with HFrEF (page 490, second column, third paragraph).
Regarding claim 19, Santhanakrishnan teaches that concurrent AF and HF is defined as the diagnosis of including new AF within 30 days of HF (page 485, second column, second paragraph).
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It would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to treat a patient with atrial fibrillation and has heart failure with reduced ejection fraction (e.g., systolic dysfunction/HFrEF) which display left atrial dilatation and eccentric left atrial remodeling (e.g., atrial cardiomyopathy/myopathy), by administering a composition comprising a compound including
(e.g., (R)-4-(l-((3-(Difluoromethyl)-l-methyl-lH-pyrazol-4-yl)sulfonyl)-l-fluoroethyl)-N-(isoxazol-3-yl)piperidine-l-carboxamide. The person of ordinary skill in the art would have been motivated administer the compound to patients with including atrial fibrillation because half of patients with heart failure including HFrEF have atrial fibrillation, as taught Santhanakrishnan. The person of ordinary skill in the art would have reasonably expected success because claim 1 of ‘525 recites a method of treating heart failure with reduced ejection fraction (HFrEF), comprising administering to a subject in need thereof an effective amount of a compound. Melenovsky teaches that patients with including HFrEF displayed including LA dilatation (e.g., atrial cardiomyopathy/myopathy) (page 298, second column, last paragraph). Melenovsky teaches that HFrEF patients displayed more eccentric LA remodeling (e.g., atrial cardiomyopathy/myopathy) (paragraph bridging pages 298 and 299). Santhanakrishnan teaches that more than half of participants with HF had AF at some point, with AF more likely to antedate than to follow HF. Santhanakrishnan teaches that more than one third or participants with AF had HF, with most developing HF onset after AF rather than beforehand (page 488, second column, second paragraph).
Regarding recitation of “reduces atrial fibrillation recurrence” in claim 17, although the combination of the claims of ‘525, Melenovsky and Santhanakrishnan do not specifically teach reducing atrial fibrillation recurrence, the claimed method of administration of to a patient in need of treating atrial dysfunction, exhibits systolic dysfunction and atrial fibrillation, a composition comprising a therapeutically effective amount of (R)-4-(l-((3-(Difluoromethyl)-l-methyl-lH-pyrazol-4-yl)sulfonyl)-l-fluoroethyl)-N-(isoxazol-3-yl)piperidine-l-carboxamide (claims 1 and 32 of ‘525; page 298, second column, last paragraph, and paragraph bridging pages 298 and 299 of Melenovsky; page 488, second column, second paragraph of Santhanakrishnan) appears to be the same as the prior art, absent a showing of unobvious differences. The office does not have the facilities and resources to provide the factual evidence needed in order to establish that the composition of the prior art does not possess the same material, structural and steps-like characteristics of the claimed composition. In the absence of evidence to the contrary, the burden is on Applicant to prove that the claimed composition 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 2nd 1992 (PTO Bd. Pat. App. & Int. 1989).
Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). Therefore, the prima facie case can be rebutted by evidence showing that the prior art products do not necessarily possess the characteristics of the claimed product. In re Best, 562 F.2d at 1255, 195 USPQ at 433. See also Titanium Metals Corp. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985) (Claims were directed to a titanium alloy containing 0.2-0.4% Mo and 0.6-0.9% Ni having corrosion resistance. A Russian article disclosed a titanium alloy containing 0.25% Mo and 0.75% Ni but was silent as to corrosion resistance. The Federal Circuit held that the claim was anticipated because the percentages of Mo and Ni were squarely within the claimed ranges. The court went on to say that it was immaterial what properties the alloys had or who discovered the properties because the composition is the same and thus must necessarily exhibit the properties.). MPEP 2112.01 (I).
Claims 20-21, 29 and 32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 33 of U.S. Patent No. 10,758,525 (date of patent of 1 September 2020; hereafter ‘525) in view of Melenovsky as applied to claims 1, 11-12, 15, 16, 23, 27 and 41 above, and further in view of SANTHANAKRISHNAN (“Atrial Fibrillation Begets Heart Failure and Vice Versa Temporal Associations and Differences in Preserved Versus Reduced Ejection Fraction”, Circulation, pages 484-492, 02 February 2016) and GO (“Association of Burden of Atrial Fibrillation With Risk of Ischemic Stroke in Adults With Paroxysmal Atrial Fibrillation”, JAMA Cardiol, 7, pages 601-608, published 16 May 2018).
Regarding claims 20-21 and 32, the method of claim 1 is described above in section 18.
The claims of ‘525 do not recite and Melenovsky does not specifically teach that the patient has paroxysmal or persistent atrial fibrillation (e.g., claim 20). The claims of ‘525 do not recite and Melenovsky does not specifically teach that the patient has atrial fibrillation burden of 2-70% or not have AF burden of <2% or >70% (e.g., claims 21 and 32). The deficiencies are made up for by the teachings of Santhanakrishnan and Go.
Santhanakrishnan is primarily directed towards differences in temporal association of AF (atrial fibrillation) with HF (heart failure) with preserved versus reduced ejection fraction (abstract).
Regarding claims 20-21 and 32, Santhanakrishnan teaches that more than half of participants with HF had AF at some point, with AF more likely to antedate than to follow HF. Santhanakrishnan teaches that more than one third or participants with AF had HF, with most developing HF onset after AF rather than beforehand (page 488, second column, second paragraph). Santhanakrishnan teaches that AF and HF conjointly portend a poor prognosis, with higher risk among those with HFrEF (page 490, second column, third paragraph).
Go is primarily directed towards association of burden of atrial fibrillation with risk of ischemic stroke in adults with paroxysmal atrial fibrillations (abstract).
Regarding claims 20-21 and 32, Go teaches that burden of atrial fibrillation is the amount of time spent in atrial fibrillation (page 602, first column, second paragraph). Go teaches that burden of atrial fibrillation of including 2.05%-11.28% and 11.36-99.99% which had higher heart failure than burden of atrial fibrillation of 0.01%-2.03% (Table).
Regarding claim 29, Go teaches that adults with atrial fibrillation include with prior ablation and cardioversion (Table).
It would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to treat a patient with atrial fibrillation and has heart failure with reduced ejection fraction (e.g., systolic dysfunction/HFrEF) which display left atrial dilatation and eccentric left atrial remodeling (e.g., atrial cardiomyopathy/myopathy), by administering a composition comprising a compound including
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(e.g., (R)-4-(l-((3-(Difluoromethyl)-l-methyl-lH-pyrazol-4-yl)sulfonyl)-l-fluoroethyl)-N-(isoxazol-3-yl)piperidine-l-carboxamide; wherein the patient has atrial fibrillation with a burden of atrial fibrillation of including 2.05%-11.28%. The person of ordinary skill in the art would have been motivated administer the compound to patients with including atrial fibrillation because half of patients with heart failure including HFrEF have atrial fibrillation, as taught Santhanakrishnan, and specifically to patients with paroxysmal atrial fibrillation with a burden of atrial fibrillation of including 2.05%-11.28% which experiences higher heart failure with increasing burden, as taught by Go. The person of ordinary skill in the art would have reasonably expected success because claim 1 of ‘525 recites a method of treating heart failure with reduced ejection fraction (HFrEF), comprising administering to a subject in need thereof an effective amount of a compound. Melenovsky teaches that patients with including HFrEF displayed including LA dilatation (e.g., atrial cardiomyopathy/myopathy) (page 298, second column, last paragraph). Melenovsky teaches that HFrEF patients displayed more eccentric LA remodeling (e.g., atrial cardiomyopathy/myopathy) (paragraph bridging pages 298 and 299). Santhanakrishnan teaches that more than half of participants with HF had AF at some point, with AF more likely to antedate than to follow HF. Santhanakrishnan teaches that more than one third or participants with AF had HF, with most developing HF onset after AF rather than beforehand (page 488, second column, second paragraph). Go teaches that burden of atrial fibrillation is the amount of time spent in atrial fibrillation (page 602, first column, second paragraph). Go teaches that burden of atrial fibrillation of including 2.05%-11.28% and 11.36-99.99% which had higher heart failure than burden of atrial fibrillation of 0.01%-2.03% (Table).
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Oslob in view of Melenovsky as applied to claims 1, 11-12, 15-16, 23, 33, 36, 38, 41 and 45 above, and further in view of SANTHANAKRISHNAN (“Atrial Fibrillation Begets Heart Failure and Vice Versa Temporal Associations and Differences in Preserved Versus Reduced Ejection Fraction”, Circulation, pages 484-492, 02 February 2016) and ALTURKI (“Major Adverse Cardiovascular Events Associated With Postoperative Atrial Fibrillation After Noncardiac Surgery”, Circulation: Arrhythmia and Electrophysiology, pages 71-80, January 2020).
Regarding claims 22, the method of claim 1 is described above in section 18.
The claims of ‘525 do not recite and Melenovsky do not specifically teach that the patient has postoperative AF. The deficiency is made up for by the teachings of Santhanakrishnan and Alturki.
Santhanakrishnan is primarily directed towards differences in temporal association of AF (atrial fibrillation) with HF (heart failure) with preserved versus reduced ejection fraction (abstract).
Regarding claim 22, Santhanakrishnan teaches that more than half of participants with HF had AF at some point, with AF more likely to antedate than to follow HF. Santhanakrishnan teaches that more than one third or participants with AF had HF, with most developing HF onset after AF rather than beforehand (page 488, second column, second paragraph). Santhanakrishnan teaches that AF and HF conjointly portend a poor prognosis, with higher risk among those with HFrEF (page 490, second column, third paragraph).
Alturki is primarily directed towards risk of stroke, myocardial infarction and death associated with postoperative atrial fibrillation following noncardiac surgery (abstract).
Regarding claim 22, Alturki teaches that postoperative atrial fibrillation was associated with a marked increase in the risk of stroke, myocardial infarction and death following noncardiac surgery (page 78, paragraph in second column).
It would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to treat a patient with atrial fibrillation and has heart failure with reduced ejection fraction (e.g., systolic dysfunction/HFrEF) which display left atrial dilatation and eccentric left atrial remodeling (e.g., atrial cardiomyopathy/myopathy), by administering a composition comprising a compound including
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(e.g., (R)-4-(l-((3-(Difluoromethyl)-l-methyl-lH-pyrazol-4-yl)sulfonyl)-l-fluoroethyl)-N-(isoxazol-3-yl)piperidine-l-carboxamide; wherein the atrial fibrillation includes postoperative atrial fibrillation. The person of ordinary skill in the art would have been motivated administer the compound to patients with including atrial fibrillation because half of patients with heart failure including HFrEF have atrial fibrillation, as taught Santhanakrishnan, and specifically to patients postoperative atrial fibrillation which is associated with a marked increase in the risk of stroke and myocardial infarction, as taught by Alturki. The person of ordinary skill in the art would have reasonably expected success because claim 1 of ‘525 recites a method of treating heart failure with reduced ejection fraction (HFrEF), comprising administering to a subject in need thereof an effective amount of a compound. Melenovsky teaches that patients with including HFrEF displayed including LA dilatation (e.g., atrial cardiomyopathy/myopathy) (page 298, second column, last paragraph). Melenovsky teaches that HFrEF patients displayed more eccentric LA remodeling (e.g., atrial cardiomyopathy/myopathy) (paragraph bridging pages 298 and 299). Santhanakrishnan teaches that more than half of participants with HF had AF at some point, with AF more likely to antedate than to follow HF. Santhanakrishnan teaches that more than one third or participants with AF had HF, with most developing HF onset after AF rather than beforehand (page 488, second column, second paragraph). Alturki teaches that postoperative atrial fibrillation was associated with a marked increase in the risk of stroke, myocardial infarction and death following noncardiac surgery (page 78, paragraph in second column). Alturki teaches that postoperative atrial fibrillation was associated with a marked increase in the risk of stroke, myocardial infarction and death following noncardiac surgery (page 78, paragraph in second column).
Claim 31 is rejected under 35 U.S.C. 103 as being unpatentable over Oslob in view of Melenovsky as applied to claims 1, 11-12, 15-16, 23, 33, 36, 38, 41 and 45 above, further in view of Santhanakrishnan and Go as applied to claims 20-21, 29 and 32 above, and further in view of NUSAIR (“Electric Cardioversion of Atrial Fibrillation”, Missouri Medicine, 107:1, pages 59-64, January/February 2010).
Regarding claim 31, the method of claim 29 is described above in section 20.
The claims of ‘525 do not recite and Melenovsky, Santhanakrishnan and Go do not specifically teach that the patient has previously been treated with electrical cardioversion. The deficiencies is made up for by the teachings of Nusair.
Nusair is primarily directed towards electric cardioversion of atrial fibrillation (abstract).
Regarding claim 31, Nusair teaches that electrical cardioversion is safe, effective and reliable method of converting AF (page 64, last paragraph).
It would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to treat a patient with atrial fibrillation and has heart failure with reduced ejection fraction (e.g., systolic dysfunction/HFrEF) which display left atrial dilatation and eccentric left atrial remodeling (e.g., atrial cardiomyopathy/myopathy), by administering a composition comprising a compound including
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(e.g., (R)-4-(l-((3-(Difluoromethyl)-l-methyl-lH-pyrazol-4-yl)sulfonyl)-l-fluoroethyl)-N-(isoxazol-3-yl)piperidine-l-carboxamide; wherein the patient has atrial fibrillation with a burden of atrial fibrillation of including 2.05%-11.28%; and wherein the patient has been treated with electrical cardioversion for the atrial fibrillation. The person of ordinary skill in the art would have been motivated administer the compound to patients with including atrial fibrillation including patients with atrial fibrillation have been treated with electrical cardioversion which is safe and effective for converting AF. The person of ordinary skill in the art would have reasonably expected success because claim 1 of ‘525 recites a method of treating heart failure with reduced ejection fraction (HFrEF), comprising administering to a subject in need thereof an effective amount of a compound. Melenovsky teaches that patients with including HFrEF displayed including LA dilatation (e.g., atrial cardiomyopathy/myopathy) (page 298, second column, last paragraph). Melenovsky teaches that HFrEF patients displayed more eccentric LA remodeling (e.g., atrial cardiomyopathy/myopathy) (paragraph bridging pages 298 and 299). Santhanakrishnan teaches that more than half of participants with HF had AF at some point, with AF more likely to antedate than to follow HF. Santhanakrishnan teaches that more than one third or participants with AF had HF, with most developing HF onset after AF rather than beforehand (page 488, second column, second paragraph). Go teaches that burden of atrial fibrillation is the amount of time spent in atrial fibrillation (page 602, first column, second paragraph). Go teaches that burden of atrial fibrillation of including 2.05%-11.28% and 11.36-99.99% which had higher heart failure than burden of atrial fibrillation of 0.01%-2.03% (Table). Nusair teaches that electrical cardioversion is safe, effective and reliable method of converting AF (page 64, last paragraph).
Claims 37 and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Oslob in view of Melenovsky as applied to claims 1, 11-12, 15-16, 23, 33, 36, 38, 41 and 45 above, further in view of SANTHANAKRISHNAN (“Atrial Fibrillation Begets Heart Failure and Vice Versa Temporal Associations and Differences in Preserved Versus Reduced Ejection Fraction”, Circulation, pages 484-492, 02 February 2016) and SHULER (WO 2018/209107 A1, publication date of 15 November 2018).
Regarding claims 37 and 39, the method of claim 1 is described above in section 18.
The claims of ‘525 do not recite and Melenovsky do not specifically teach that administration in a dose resulting in compound I plasma concentrations of 1000 to 8000 ng/mL in the patient. The deficiencies is made up for by the teachings of Shuler.
Santhanakrishnan is primarily directed towards differences in temporal association of AF (atrial fibrillation) with HF (heart failure) with preserved versus reduced ejection fraction (abstract).
Regarding claims 37 and 39, Santhanakrishnan teaches that more than half of participants with HF had AF at some point, with AF more likely to antedate than to follow HF. Santhanakrishnan teaches that more than one third or participants with AF had HF, with most developing HF onset after AF rather than beforehand (page 488, second column, second paragraph). Santhanakrishnan teaches that AF and HF conjointly portend a poor prognosis, with higher risk among those with HFrEF (page 490, second column, third paragraph).
Shuler is primarily directed towards a method of treating a heart condition comprising administration by inhalation (abstract).
Regarding claims 37 and 39, Shuler teaches aerosol comprising particles having a mass medium aerodynamic diameter less than 10 µm (paragraph [0209]). Shuler teaches rapid acting inhaled product with a fast onset of action compared to oral medicine (paragraph [0213]). Shuler teaches that the Cmax (e.g., plasma concentration) of the pharmaceutical agent administered via inhalation can be from 10 ng/mL to about 5000 ng/mL (paragraph [0371]).
It would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to treat a patient with heart failure with reduced ejection fraction (e.g., systolic dysfunction/HFrEF) which display left atrial dilatation and eccentric left atrial remodeling (e.g., atrial cardiomyopathy/myopathy), by administering by inhalation a composition in the form of particles comprising a compound including
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(e.g., (R)-4-(l-((3-(Difluoromethyl)-l-methyl-lH-pyrazol-4-yl)sulfonyl)-l-fluoroethyl)-N-(isoxazol-3-yl)piperidine-l-carboxamide; wherein the particles have a mass medium aerodynamic diameter less than 10 µm; and wherein the Cmax (e.g., plasma concentration) of the compound administered via inhalation is from 10 ng/mL to about 5000 ng/mL. The person of ordinary skill in the art would have been motivated to administer the compound by inhalation in form of particles with a mass medium aerodynamic diameter less than 10 µm and provides Cmax (e.g., plasma concentration) of the compound administered via inhalation of from 10 ng/mL to about 5000 ng/mL, in order to obtain rapid acting and fast onset of action compared to oral medicine. The person of ordinary skill in the art would have reasonably expected success because claim 1 of ‘525 recites a method of treating heart failure with reduced ejection fraction (HFrEF), comprising administering to a subject in need thereof an effective amount of a compound. Shuler teaches treating a heart condition using administration of a formulation by inhalation (paragraph [0025]). Shuler teaches aerosol comprising particles having a mass medium aerodynamic diameter less than 10 µm (paragraph [0209]). Shuler teaches rapid acting inhaled product with a fast onset of action compared to oral medicine (paragraph [0213]). Shuler teaches that the Cmax (e.g., plasma concentration) of the pharmaceutical agent administered via inhalation can be from 10 ng/mL to about 5000 ng/mL (paragraph [0371]).
Claim 40 is rejected under 35 U.S.C. 103 as being unpatentable over Oslob in view of Melenovsky as applied to claims 1, 11-12, 15-16, 23, 33, 36, 38, 41 and 45 above, further in view of SANTHANAKRISHNAN (“Atrial Fibrillation Begets Heart Failure and Vice Versa Temporal Associations and Differences in Preserved Versus Reduced Ejection Fraction”, Circulation, pages 484-492, 02 February 2016) and NUSAIR (“Electric Cardioversion of Atrial Fibrillation”, Missouri Medicine, 107:1, pages 59-64, January/February 2010).
Regarding claims 40, the method of claim 1 is described above in section 18.
The claims of ‘525 do not recite and Melenovsky do not specifically teach that the patient has undergone an electrical cardioversion. The deficiencies is made up for by the teachings of Santhanakrishnan and Nusair.
Santhanakrishnan is primarily directed towards differences in temporal association of AF (atrial fibrillation) with HF (heart failure) with preserved versus reduced ejection fraction (abstract).
Regarding claim 40, Santhanakrishnan teaches that more than half of participants with HF had AF at some point, with AF more likely to antedate than to follow HF. Santhanakrishnan teaches that more than one third or participants with AF had HF, with most developing HF onset after AF rather than beforehand (page 488, second column, second paragraph). Santhanakrishnan teaches that AF and HF conjointly portend a poor prognosis, with higher risk among those with HFrEF (page 490, second column, third paragraph).
Oslob, Melenovsky, Santhanakrishnan and Go do not specifically teach the patient has previously been treated with electrical cardioversion. The deficiencies is made up for by the teachings of Nusair.
Nusair is primarily directed towards electric cardioversion of atrial fibrillation (abstract).
Regarding claim 40, Nusair teaches that electrical cardioversion is safe, effective and reliable method of converting AF (page 64, last paragraph).
It would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to treat a patient with atrial fibrillation and has heart failure with reduced ejection fraction (e.g., systolic dysfunction/HFrEF) which display left atrial dilatation and eccentric left atrial remodeling (e.g., atrial cardiomyopathy/myopathy), by administering a composition comprising a compound including
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(e.g., (R)-4-(l-((3-(Difluoromethyl)-l-methyl-lH-pyrazol-4-yl)sulfonyl)-l-fluoroethyl)-N-(isoxazol-3-yl)piperidine-l-carboxamide; wherein the patient has been treated with electrical cardioversion for the atrial fibrillation. The person of ordinary skill in the art would have been motivated administer the compound to patients with including atrial fibrillation and have been treated with electrical cardioversion. The person of ordinary skill in the art would have reasonably expected success because claim 1 of ‘525 recites a method of treating heart failure with reduced ejection fraction (HFrEF), comprising administering to a subject in need thereof an effective amount of a compound. Melenovsky teaches that patients with including HFrEF displayed including LA dilatation (e.g., atrial cardiomyopathy/myopathy) (page 298, second column, last paragraph). Melenovsky teaches that HFrEF patients displayed more eccentric LA remodeling (e.g., atrial cardiomyopathy/myopathy) (paragraph bridging pages 298 and 299). Santhanakrishnan teaches that more than half of participants with HF had AF at some point, with AF more likely to antedate than to follow HF. Santhanakrishnan teaches that more than one third or participants with AF had HF, with most developing HF onset after AF rather than beforehand (page 488, second column, second paragraph). Nusair teaches that electrical cardioversion is safe, effective and reliable method of converting AF (page 64, last paragraph).
Conclusion and Correspondence
No claims are found allowable.
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/John P Nguyen/
Examiner, Art Unit 1619
/ANNA R FALKOWITZ/Primary Examiner, Art Unit 1600