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 .
Priority
This application is a CIP of U.S. Application No. 16/726,857 filed on 12/25/2019, now U.S. Patent No. 11,446,282, which is a CIP of U.S. Application No. 16/227,440 filed on 12/20/2018 now abandoned which claims benefit of U.S. Provisional Application No. 62/609,048, filed on December 21, 2017.
Response to Amendment
Applicant’s preliminary amendment filed December 5, 2022 canceling claims 1-20 and adding new claims 21-40 has been entered. Claims 21-40 are currently pending and presented for examination.
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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 21-40 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims of U.S. Patent No. 11,446,282. Although the claims at issue are not identical, they are not patentably distinct from each other because the cited claims of the instant application and the cited claims of ‘282 claim a method for treating dyslipidemia including hypertriglyceridemia in a renally impaired patient comprising the administration of 0.4 mg/day of pemafibrate.
Thus the cited claims of the instant application would be anticipated over the cited claims of ‘282. Therefore, the cited claims of the instant application are not patentably distinct over the cited claims of ‘282.
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 21 and 23-32 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Arai et al. (Atherosclerosis, Vol. 261, pages 144-152, March 24, 2017 Provided on IDS).
Claims 21 and 23-32 of the instant application claim a method of treating moderate hypertriglyceridemia (serum TG > 200 mg/dL and < 500 mg/dL) or severe hypertriglyceridemia (serum TG ≥ about 500 mg/dL) as well as treating dyslipidemia in renally impaired patients including patients with severe renal impairment as well as mild to moderate renal impairment comprising administering a therapeutically effective amount of pemafibrate which is 0.4 mg/day. As detailed on page 9 of the instant specification, the term “mild renal impairment” refers to an eGFR less than 90mL/min/1.73m2 and greater than or equal to 60 mL/min/1.73m2 (60 < eGFR < 90) qualifies as mild renal impairment. The term “moderate renal impairment” refers to an eGFR less than 60 mL/min/1.73m2 and greater than or equal to 30 mL/min/1.73m2 (30 < eGFR < 60) qualifies as moderate renal impairment. The term “mild or moderate renal impairment” refers to an eGFR less than 90 mL/min/1.73m2 and greater than or equal to 30 mL/min/1.73m2 (30 < eGFR < 90) qualifies as mild or moderate renal impairment. The term “severe renal impairment” refers to an eGFR less than 30 mL/min/1.73m2 (eGFR < 30) qualifies as severe renal impairment.
Arai et al. teaches the treatment of dyslipidemic patients under statin administration and having increased triglyceride levels comprising the administration of pemafibrate at a dosage of 0.2 mg twice per day for a total of 0.4 mg/day (page 145). Arai et al. teaches that the patients treated had residual dyslipidemia with a mean fasting TG ranging from 347 to 382 mg/dL or 325 to 333 mg/dL and despite pitavastatin treatment, elevated levels of LDL-C from 116 to 125 mg/dL (pages 145 and 146). Arai et al. further teaches that the patients treated have low baseline levels HDL-C of 1.2 ± 0.3 mmol/L which is between about 34.8 and 58 mg/dL (Table 1 page 146). Arai et al. teaches that TG levels were significantly reduced by approximately 50% (page 145). Arai et al. further teaches that reductions in remnant lipoprotein cholesterol (RemL-C), apolipoprotein B48 (ApoB48), and ApoCIII and increases in HDL were achieved (page 145). Arai et al. specifically demonstrates that pemafibrate treatment in combination with statin decreased small and very small LDL-C and increased medium, small and very small HDL-C (Figure 2 page 148). Arai et al. further demonstrates that the combination of statin and pemafibrate did not adversely affect kidney function as serum creatinine did not increase and eGFR did not decrease with treatment (page 149 Figure 3).
Arai et al. specifically teaches treating patients with 0.2 mg twice per day (0.4 mg daily) for the treatment of dyslipidemia wherein the patient has an initial eGFR of less than 90 mL/min/1.73 m2 and the eGFR does not further decrease throughout the duration of treatment (see page 149 Figure 3). The patients treated had a baseline eGFR between 77 and 82 (see page 149 Figure 3 and supplementary table 3). Thus Arai et al. specifically teaches treating patients having mild or moderate renal impairment with an eGFR less than 90 mL/min/1.73m2 and greater than or equal to 30 mL/min/1.73m2 (30 < eGFR < 90).
Thus the cited claims of the instant application are anticipated since Arai specifically demonstrates treating dyslipidemia and hypertriglyceridemia in patients having mild or moderate renal impairment with an eGFR less than 90 mL/min/1.73m2 and greater than or equal to 30 mL/min/1.73m2 (30 < eGFR < 90), comprising administering to the patient about 0.4 mg/day (0.2 mg twice daily) of pemafibrate.
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.
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 21-40 are rejected under 35 U.S.C. 103 as being unpatentable over Kastelein et al. (2015, European Heart Journal, 36 Abstract Supplement, 1048, P5983) (Provided on IDS) in view of Harper et al. (2008, Journal of the American College of Cardiology, Volume 51 No. 25, pages 2375-2384 Provided on IDS), and Blair (Drugs, 2017, Volume 77, pages 1805-1810 Provided on IDS).
Claims 21-40 of the instant application claim a method of treating moderate hypertriglyceridemia (serum TG > 200 mg/dL and < 500 mg/dL) or severe hypertriglyceridemia (serum TG ≥ about 500 mg/dL) as well as treating dyslipidemia in renally impaired patients including patients with severe renal impairment as well as mild to moderate renal impairment comprising administering a therapeutically effective amount of pemafibrate which is 0.4 mg/day. As detailed on page 9 of the instant specification, the term “mild renal impairment” refers to an eGFR less than 90mL/min/1.73m2 and greater than or equal to 60 mL/min/1.73m2 (60 < eGFR < 90) qualifies as mild renal impairment. The term “moderate renal impairment” refers to an eGFR less than 60 mL/min/1.73m2 and greater than or equal to 30 mL/min/1.73m2 (30 < eGFR < 60) qualifies as moderate renal impairment. The term “mild or moderate renal impairment” refers to an eGFR less than 90 mL/min/1.73m2 and greater than or equal to 30 mL/min/1.73m2 (30 < eGFR < 90) qualifies as mild or moderate renal impairment. The term “severe renal impairment” refers to an eGFR less than 30 mL/min/1.73m2 (eGFR < 30) qualifies as severe renal impairment.
Kastelein et al. teaches that patients treated with statins, particularly those with elevated triglyceride levels and reduced HDL-C levels, are still at risk for cardiovascular disease (CVD) even when LDL-C levels are controlled (background). Kastelein et al. teaches combining statins with the selective PPAR modulator, K-877 (pemafibrate) in patients whose LDL-C levels are adequately controlled with statins (title, background and purpose).
Kastelein et al. teaches that the patients treated were taking atorvastatin, rosuvastatin, or simvastatin with significant residual dyslipidemia having TG levels from 175-500 mg/dL (1.9-5.7 mmol/L) and HDL-C levels of 50 mg/dL (1.3 mmol/L) or less in men and 55 mg/dL (1.4 mmol/L) or less in women (methods). The patients were treated with 0.2 mg of pemafibrate twice a day (results). Pemafibrate significantly reduced TG levels, non-HDL-C levels, and remnant cholesterol, and significantly increased HDL-C levels.
Kastelein et al. further teaches that overall, the median TG level was high (245.3 mg/dL) and mean levels of HDL-C were low (39.2 mg/dL) and mean levels of LDL-C were also low (88.4 mg/dL) (results poster). Overall 31.9% had a history of coronary heart disease (CHD), 37.8% had type 2 diabetes mellitus, 46.3% of the patients were on high intensity statin treatment, and 48.1% of the patients were on moderate statin treatment (poster results section).
Thus Kastelein et al. specifically teaches a method for treating dyslipidemia and hypertriglyceridemia comprising the administration of pemafibrate.
Kastelein et al. does not specifically teach treating a patient having mild, moderate or severe renal impairment.
However Kastelein et al. specifically teaches that pemafibrate does not increase serum creatinine levels and thus does not affect kidney function.
Accordingly, prior to the effective filing date of the instant application, it would have been obvious to a person of ordinary skill in the art to treat patients in need of treatment for hypertriglyceridemia and dyslipidemia and also having impaired kidney function comprising the administration of pemafibrate since Kastelein et al. teaches that pemafibrate does not have adverse events on the kidney and thus does not decrease kidney function. Therefore, an ordinary skilled artisan would have been motivated to treat patients with impaired kidney function with pemafibrate with a reasonable expectation that pemafibrate would not further decrease kidney function and thus would not be contraindicated.
Furthermore, Harper et al. teaches patients with chronic kidney disease frequently have mixed dyslipidemia, and high-risk patients may need treatment with a statin and a fibric acid derivative (page 2380). Harper et al. teaches that the National Lipid Association (NLA) recommends not using the maximum dose of a statin in combination with a fibrate (page 2380). Harper et al. further teaches that fibrates are known to increase serum creatinine (page 2379). Harper et al. also teaches that fibrates may accumulate in patients with chronic kidney disease due to a reduced rate of excretion (page 2379). However, despite these pharmacokinetic characteristics, the National Kidney foundation (NKF) and the NLA recommends the use of fibrates in patients with chronic kidney disease with caution (page 2379). Harper et al. teaches that the NKF and the NLA recommend reducing the dosage of certain fibrates in patients with GFR of 15 to 59 ml/min/1.73 m2 while certain other fibrates can be used in patients with chronic kidney disease with no dose adjustments (page 2380).
Blair teaches that following administration of pemafibrate, 14.5% is recovered in urine and 73.3% is recovered in feces (page 1807). Blair teaches that exposure to pemafibrate increased in subjects with mild, moderate or high-grade renal dysfunction or end-stage renal failure, however, this increase was not dependent on the extent of renal dysfunction (page 1807). Blair further teaches that pemafibrate does not increase plasma creatinine levels (page 1809). Blair teaches that clinical data from two studies suggest that pemafibrate is also generally well tolerated when administered as add-on therapy to a statin (page 1809).
Accordingly, prior to the effective filing date of the instant application, it would have been obvious to a person of ordinary skill in the art to combine the teachings of Kastelein et al. which teaches treating patients in need of treatment for hypertriglyceridemia and dyslipidemia comprising the administration of pemafibrate in combination with a statin wherein said combination does not increase serum creatinine with the teachings of Harper et al. which teaches patients with chronic kidney disease frequently have mixed dyslipidemia, and high-risk patients may need treatment with a statin and a fibric acid derivative. Therefore since Kastelein et al. teaches that the combination of pemafibrate and a statin does not increase serum creatinine, Kastelein et al. teaches that the combination does not have adverse effects on the kidney and thus does not decrease kidney function. Therefore, an ordinary skilled artisan would have been motivated to treat patients with impaired kidney function with pemafibrate and a statin with a reasonable expectation that pemafibrate combined with a statin would not further decrease kidney function and thus would not be contraindicated. In addition, Harper et al. teaches that the dosage of certain fibrates may need to be adjusted in patients with chronic kidney disease, and Blair teaches that exposure to pemafibrate increased in subjects with mild, moderate or high-grade renal dysfunction or end-stage renal failure, however, this increase was not dependent on the extent of renal dysfunction (page 1807). Thus a person of ordinary skill in the art would have been motivated to optimize the dosage of pemafibrate suitable for patients with chronic kidney disease such that optimal results are achieved with minimal effects on the kidney. In addition, since the increase in exposure was not due to the extent of renal dysfunction, it would have been obvious that the same dosage determined to be optimal for a patient with mild chronic kidney disease would be appropriate for patients with moderate, severe and end-stage renal disease. Thus the treatment of patients with mild, moderate, severe and end-stage renal disease comprising the administration of pemafibrate is rendered obvious in view of the cited prior art teachings.
Thus the cited claims of the instant application are rendered obvious in view of the cited prior art teachings.
Claims 22 and 35-40 are rejected under 35 U.S.C. 103 as being unpatentable over Arai et al. (Atherosclerosis, Vol. 261, pages 144-152, March 24, 2017 Provided on IDS) as applied to claims 20-34 above and further in view of Harper et al. (2008, Journal of the American College of Cardiology, Volume 51 No. 25, pages 2375-2384 Provided on IDS), and Blair (Drugs, 2017, Volume 77, pages 1805-1810 Provided on IDS).
Claim 22 of the instant application claims treating a subject with severe hypertriglyceridemia (serum TG ≥ about 500 mg/dL). Claims 35-40 of the instant application claim a treating renally impaired patients having an estimated glomerular filtration rate (eGFR) of less than 60 or 30 ml/min/1.73 m2 or having end stage renal disease.
Arai et al. teaches the treatment of dyslipidemic patients under statin administration and having increased triglyceride levels comprising the administration of pemafibrate at a dosage of 0.1, 0.2 and 0.4 mg/day (page 145). Arai et al. teaches that the patients treated had residual dyslipidemia with a mean fasting TG ranging from 347 to 382 mg/dL or 325 to 333 mg/dL (pages 145 and 146). Arai et al. further teaches that the patients treated have a baseline HDL-C of 1.2 ± 0.3 mmol/L which is between about 34.8 and 58 mg/dL (Table 1 page 146). Arai et al. teaches that TG levels were significantly reduced by approximately 50% (page 145). Arai et al. further teaches that reductions in remnant lipoprotein cholesterol (RemL-C), apolipoprotein B48 (ApoB48), and ApoCIII and increases in HDL were achieved (page 145). Arai et al. specifically demonstrates that pemafibrate treatment in combination with statin decreased small and very small LDL-C and increased medium, small and very small HDL-C (Figure 2 page 148). Arai et al. further demonstrates that the combination of statin and pemafibrate did not adversely affect kidney function as serum creatinine did not increase and eGFR did not decrease with treatment (page 149 Figure 3).
Arai et al. does not specifically teach treating a patient having severe hypertriglyceridemia. Arai et al. does not specifically teach treating a patient having an estimated glomerular filtration rate (eGFR) of less than 60 or 30 ml/min/1.73 m2 or having end stage renal disease.
However, Arai et al. specifically teaches that TG levels were significantly reduced by approximately 50% by pemafibrate administration (page 145).
Accordingly, prior to the effective filing date of the instant claims, based on the teaching of Arai et al. which specifically demonstrates that pemafibrate administration significantly reduced TG levels by approximately 50%, it would have been obvious to a person of ordinary skill in the art to treat patients with severe hypertriglyceridemia with a reasonable expectation that administration of pemafibrate will also significantly reduce triglyceride levels in said patients. Thus claim 22 is rendered obvious in view of the teachings of Arai et al.
Moreover, Arai et al. specifically demonstrates that pemafibrate combined with statin does not increase serum creatinine levels and does not decrease eGFR and thus does not affect kidney function (Figure 3 page 149).
Furthermore, Harper et al. teaches patients with chronic kidney disease frequently have mixed dyslipidemia, and high-risk patients may need treatment with a statin and a fibric acid derivative (page 2380). Harper et al. teaches that the National Lipid Association (NLA) recommends not using the maximum dose of a statin in combination with a fibrate (page 2380). Harper et al. further teaches that fibrates are known to increase serum creatinine (page 2379). Harper et al. also teaches that fibrates may accumulate in patients with chronic kidney disease due to a reduced rate of excretion (page 2379). However, despite these pharmacokinetic characteristics, the National Kidney foundation (NKF) and the NLA recommends the use of fibrates in patients with chronic kidney disease with caution (page 2379). Harper et al. teaches that the NKF and the NLA recommend reducing the dosage of certain fibrates in patients with GFR of 15 to 59 ml/min/1.73 m2 while certain other fibrates can be used in patients with chronic kidney disease with no dose adjustments (page 2380).
Blair teaches that following administration of pemafibrate, 14.5% is recovered in urine and 73.3% is recovered in feces (page 1807). Blair teaches that exposure to pemafibrate increased in subjects with mild, moderate or high-grade renal dysfunction or end-stage renal failure, however, this increase was not dependent on the extent of renal dysfunction (page 1807). Blair further teaches that pemafibrate does not increase plasma creatinine levels (page 1809). Blair teaches that clinical data from two studies suggest that pemafibrate is also generally well tolerated when administered as add-on therapy to a statin (page 1809).
Accordingly, prior to the effective filing date of the instant application, it would have been obvious to a person of ordinary skill in the art to combine the teachings of Arai et al. which teaches treating dyslipidemia comprising the administration of pemafibrate in combination with a statin wherein said combination does not increase serum creatinine or decrease eGFR with the teachings of Harper et al. which teaches patients with chronic kidney disease frequently have mixed dyslipidemia, and high-risk patients may need treatment with a statin and a fibric acid derivative. Therefore since Arai et al. teaches that the combination of pemafibrate and a statin does not increase serum creatinine or decrease eGFR, Arai et al. teaches that the combination does not have adverse effects on the kidney and thus does not decrease kidney function. Therefore, an ordinary skilled artisan would have been motivated to treat patients with impaired kidney function with pemafibrate and a statin with a reasonable expectation that pemafibrate combined with a statin would not further decrease kidney function and thus would not be contraindicated. In addition, Harper et al. teaches that the dosage of certain fibrates may need to be adjusted in patients with chronic kidney disease, and Blair teaches that exposure to pemafibrate increased in subjects with mild, moderate or high-grade renal dysfunction or end-stage renal failure, however, this increase was not dependent on the extent of renal dysfunction (page 1807). Thus a person of ordinary skill in the art would have been motivated to optimize the dosage of pemafibrate suitable for patients with chronic kidney disease such that optimal results are achieved with minimal effects on the kidney. In addition, since the increase in exposure was not due to the extent of renal dysfunction, it would have been obvious that the same dosage determined to be optimal for a patient with mild chronic kidney disease (0.4 mg/day as taught by Arai et al.) would also be appropriate for patients with moderate, severe and end-stage renal disease. Thus the treatment of patients with mild, moderate, severe and end-stage renal disease comprising the administration of pemafibrate and moderate to high intensity statin therapy is rendered obvious in view of the cited prior art teachings.
Thus the cited claims of the instant application are rendered obvious in view of the cited prior art teachings.
Conclusion
Claims 21-40 are rejected. Claims 1-20 are canceled. No claims are allowed.
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/KARA R. MCMILLIAN/Primary Examiner, Art Unit 1623
KRM