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
Claims 1 and 3-23 are pending and under examination.
Priority
Acknowledgment is made of applicant's claim for foreign priority based on an application filed in Europe on July 26, 2021. It is noted, however, that applicant has not filed a certified copy of the European Application No. EP21187721 as required by 37 CFR 1.55.
Response to arguments
Response to arguments
Applicant’s arguments have been considered but are not persuasive. Applicant appears to argue that the cited art does not expressly disclose treating a HIS hyporesponder, defined as failing to achieve at least a 35% LDL-C reduction after at least one month of HIS therapy, while continuing HIS therapy and administering obicetrapib. However, the rejection is based on the combined teachings of the references, not Hovingh alone. Hovingh teaches obicetrapib/TA-8995 as a CETP inhibitor useful for lowering LDL-C and further teaches obicetrapib in combination with statin therapy. Stone teaches the use of HIS therapy in patients having or at risk of ASCVD and recognizes that some patients have a less-than-expected LDL-C response despite HIS therapy and may receive added nonstatin cholesterol-lowering therapy. Thus, Stone teaches the patient population and clinical reason for adding nonstatin therapy, while Hovingh provides obicetrapib as an effective nonstatin lipid-lowering agent suitable for combination with statin therapy.
Applicant relies on Stone’s disclosure of reemphasizing adherence and lifestyle before adding nonstatin therapy. However, that disclosure does not teach away from the claimed method. Rather, it discloses ordinary clinical management before adding a further lipid-lowering agent. Once a patient has received HIS therapy and failed to achieve the expected LDL-C reduction, Stone supports consideration of added nonstatin therapy. The claim itself requires prior HIS therapy and inadequate LDL-C response, which is consistent with, not contrary to, Stone’s clinical teachings.
Applicant’s argument that Stone lacks clinical trial evidence for routine nonstatin therapy to reduce ASCVD events. The rejection does not rely on Stone alone to show obicetrapib efficacy. Hovingh teaches the LDL-C lowering effect and tolerability of obicetrapib, including with statin therapy. Therefore, a person of ordinary skill in the art would have had a reasonable expectation that adding obicetrapib to continued HIS therapy in a patient with inadequate LDL-C response would further reduce LDL-C and thereby treat or reduce risk associated with CVD.
Regarding claim 23, limiting the pretreatment LDL-C level to less than 190 mg/dL does not render the claim patentable. The cited art is not limited to severe hypercholesterolemia patients having LDL-C ≥190 mg/dL, and the claimed threshold merely selects a patient population still within the ordinary dyslipidemia/CVD-risk treatment context addressed by Hovingh and Stone.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or non-obviousness.
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.
A. Claims 1, 3-17, 22, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Hovingh et al. (Lancet 2015 Aug 1; 386 (9992):452-60. doi: 10.1016/S0140-6736(15)60158-1. Epub 2015 Jun 2. PMID: 26047975) in view of Stone et al. (Circulation; Volume 129, Number 25_suppl_2; https://doi.org/10.1161/01.cir.0000437738.63853.7a.)
Claimed invention
A method for the prophylactic and/or therapeutic treatment of a subject suffering from or at risk of suffering from cardiovascular disease (CVD), said method comprising:
administering to the subject a pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt, hydrate or solvate thereof,
wherein the subject is a hypo-responder to high-intensity statin (HIS) therapy,
wherein hyporesponsiveness to HIS therapy is defined as failing to achieve at least a 35% reduction in LDL-C after at least one month of HIS therapy; and
wherein the subject is further receiving concomitant HIS therapy.
Prior art
Recognizing 1) dyslipidemia as a significant risk factor for cardiovascular disease and 2) reducing the concentration of LDL cholesterol significantly reduces the risk of having a major cardiovascular event, Hovingh acknowledges that additional lipid-modifying treatments are warranted to further decrease the cardiovascular disease burden. (See Summary and ‘Introduction’ section.) Hovingh assessed the safety, tolerability and efficacy of a novel cholesterol esterase transfer protein (CETP) inhibitor TA-8995 (i.e., obicetrapib - “OBT”) in patients with dyslipidemia. (See abstract.) Hovingh reported treatment of patients with dyslipidemia with 1.0, 2.5, 5.0 and 10 mg/day of OBT lowered LDL-C by ~45% from baseline. The LDL-C was lowered by ~63% and ~68% from baseline when obicetrapib is used in combination with statin therapy – particularly, rosuvastatin and atorvastatin, respectively.
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(See p. 458; see also Table 2.) The treatment was safe and well tolerated. (See p. 458, right column.) Hovingh’s findings show that OBT, a CETP inhibitor, provided beneficial effect on lipids and lipoproteins. (See excerpt on right side of p. 459.)
While Hovingh teaches combination therapy against CVD comprising OBT and statins (particularly, atorvastatin and rosuvastatin) is efficacious in lowering LDL-C from baseline, Hovingh does not expressly teach 1) high intensity statin (HIS) therapy or 2) treatment of those who are hyporesponders to HIS.
However, Stone teaches HIS therapy is expected to benefit those having or at risk of having atherosclerotic cardiovascular disease (ASCVD). An extensive body of evidence demonstrates that high-intensity statin therapy reduces ASCVD events more than moderate-intensity statin therapy in individuals with clinical ASCVD. (See Stone, section 4.3; see also Table 4.) HIS includes atorvastatin 40 mg-80 mg or rosuvastatin at 20 mg or 40 mg daily. See Table 5. It is disclosed that high-intensity statins – atorvastatin 80 mg and rosuvastatin 20 mg daily – reduce LDL-C ≥50% on average and have been shown to reduce ASCVD events in randomized clinical trials (RCTs). (See section 4.3.) However, some individuals (e.g., HIS hyporesponders) maintain a higher than expected level of LDL-C even when on HIS therapy and may be further provided the addition of non-statin drug therapy. (See section 6.3.2.; see also Table 5.)
A person of ordinary skill in the art (POSA) would have found it obvious to treat a patient having or at risk of having atherosclerotic cardiovascular disease (ASCVD) with a combination of high intensity statins (HIS) therapy and obicetrapib because: 1) Hovingh teaches OBT and statin combination therapy is effective for lowering the levels of LDL-C, a known risk factor of atherogenic CVD issues, and 2) Stone teaches individuals that maintain a higher than expected level of LDL-C when on HIS therapy (e.g., HIS hyporesponders) may be further provided the addition of non-statin drug therapy. Given the recognized clinical need for added non-statin drugs those hyporesponsive to HIS therapy (Stone) and the efficacy of the combination of OBT and statins (e.g., atorvastatin and rosuvastatin) (Hovingh), a POSA would have had a reasonable expectation of success that OBT and statin combination would provide efficacy for ASCVD patients.
Therefore, the claimed invention as a whole would have been prima facie obvious at the time the invention application was filed.
Claims 3-10 – daily dosages of statins
Claim 3 limits claim 1, wherein the concomitant statin therapy is an administration of atorvastatin in a daily dosage of 30-90 mg. Claim 4 limits claim 3, wherein the concomitant statin therapy is the administration of atorvastatin in a daily dosage of 40-80 mg. Claim 5 limits claim 4, wherein the concomitant statin therapy is the administration of atorvastatin in a daily dosage of 40 mg. Claim 6 limits claim 4, wherein the concomitant statin therapy is the administration of atorvastatin in a daily dosage of 80 mg. Claim 7 limits claim 1, wherein the concomitant statin therapy is an administration of rosuvastatin in a daily dosage of 15-50 mg. Claim 8 limits claim 7, wherein the concomitant statin therapy is an administration of rosuvastatin in a daily dosage of 20-40 mg. Claim 9 limits claim 8, wherein the concomitant statin therapy is an administration of rosuvastatin in a daily dosage of 20 mg. Claim 10 limits claim 8, wherein the concomitant statin therapy is an administration of rosuvastatin in a daily dosage of 40 mg.
As outlined above, the combination of Hovingh and Stone suggests the prevention or treatment of ASCVD in HIS hyporesponders with OBT+HIS combination therapy. Also outlined above is that Stone teaches HIS therapy constitutes atorvastatin 40mg-80mg (specifically emphasizing administration of 40 mg atorvastatin if 80mg of same is intolerable – see Table 5) or rosuvastatin at 20 mg or 40 mg daily. See Table 5. Stone further teaches individuals who merit guideline-recommended statin therapy should be treated with the maximum-appropriate intensity of a statin that does not cause adverse effects. (See section 6.2. at p. S21) Regarding the daily dosages of atorvastatin and rosuvastatin, a person of ordinary skill in the art (POSA) would have found it obvious to use the dosage amounts disclosed for HIS therapy (i.e., 40 mg or 80 mg atorvastatin or 20 mg or 40 mg rosuvastatin) when treating the patient with the combination of OBT and HIS therapy because those are the amounts explicitly described for HIS therapy. Further given that Stone teaches individuals who merit guideline-recommended statin therapy should be treated with the maximum-appropriate intensity of a statin that does not cause adverse effects, the POSA would have found it obvious to optimize the disease of the statin drug within the disclosed ranges provided.
Claim 11 limits claim 1, wherein the cardiovascular disease (CVD) is atherosclerotic cardiovascular disease (ASCVD). As outlined above, Hovingh and Stone suggests the prevention or treatment of ASCVD in HIS hyporesponders with OBT+HIS combination therapy.
Claim 12 limits claim 1, wherein obicetrapib or a pharmaceutically acceptable salt, hydrate or solvate thereof, is administered by oral administration. Hovingh strongly infers oral administration because it teaches OBT was taken with food in the form of capsules. See p. 453; see also top of p. 454.
Claims 13-16
Claim 13 limits claim 1, wherein obicetrapib or a pharmaceutically acceptable salt, hydrate or solvate thereof, is administered at a dose of 4-25 mg. Claim 14 limits claim 13, wherein obicetrapib or a pharmaceutically acceptable salt, hydrate or solvate thereof, is administered at a dose of 5 mg or 10 mg. Claim 15 limits claim 14, wherein obicetrapib or a pharmaceutically acceptable salt, hydrate or solvate thereof, is administered at a dose of 10 mg. Claim 16 limits claim 1, wherein obicetrapib or a pharmaceutically acceptable salt, hydrate or solvate thereof, is administered once daily. Hovingh teaches 5 mg and 10 mg administration of OBT daily. See p. 454.
Claim 17 limits claim 1, wherein the method comprises the repeated administration of the composition containing obicetrapib or a salt, hydrate or solvate thereof, during a period of at least six months. Stone teaches CETP inhibitors are lipophilic by nature and it has been reported that another CETP inhibitor, anacetrapib, is retained in adipose tissue and might remain detectable in serum years after discontinuation of dosing. However, by contrast, TA-8995 is not retained in adipose tissue and is rapidly eliminated after discontinuation of dosing. Furthermore, TA-8995 was not detected in fat or liver tissue after 9 months chronic dosing of cynomolgus monkeys at a supratherapeutic dose. (See p. 460.) Thus, given the disclosed safety and tolerability profile of OBT (as outlined above) and the disclosure that OBT is not detected in fat or liver tissue after chronic (9 month) supratherapeutic doses, a POSA would have found it obvious to treat a patient with or at risk having CVD with repeated doses of OBT for as long as possible (e.g., greater than 6 months) in order to minimize a potential adverse event due to the chronic CVD.
Claim 22 limits claim 1, wherein the subject has diabetes, hypertension, hypercholesterolemia, overweight/obesity and/or metabolic syndrome. While the presence of diabetes was generally an exclusionary criterium, one of the subject treated in the Hovingh reference had diabetes. See Hovingh, Table 1. Additionally, Stone teaches, while statins modestly increase the excess risk of type 2 diabetes in some individuals, the potential for an ASCVD risk-reduction benefit outweighs the excess risk of diabetes. See Stone, S21, left column.
Claim 23 limits claim 22, wherein the LDL-C level of the subject prior to the first administration of the pharmaceutical composition comprising obicetrapib or a pharmaceutically acceptable salt, hydrate or solvate thereof is less than 190 mg/dL. However, limiting the pretreatment LDL-C level to less than 190 mg/dL does not render the claim patentable. The cited art is not limited to severe hypercholesterolemia patients having LDL-C ≥190 mg/dL, and the claimed threshold merely selects a patient population still within the ordinary dyslipidemia/CVD-risk treatment context disclosed by Hovingh and Stone.
B. Claims 18-21 are rejected under 35 U.S.C. 103 as being unpatentable over Hovingh et al. (Lancet. 2015 Aug 1;386(9992):452-60. doi: 10.1016/S0140-6736(15)60158-1. Epub 2015 Jun 2. PMID: 26047975) in view of Stone et al. (Circulation; Volume 129, Number 25_suppl_2; https://doi.org/10.1161/01.cir.0000437738.63853.7a) as applied to Claims 1, 3-17 and 22-23, taken further in view of Grundy et al. (Circulation. 2019;139:e1082–e1143. DOI: 10.1161/CIR.0000000000000625.)
Claim invention
Claim 18 limits claim 1, wherein the subject has a plasma level of LDL-C of at least 70 mg/dL, as measured with the Friedewald formula, after at least 3 months of continuous HIS therapy and prior to commencement of obicetrapib administration. Claim 19 limits claim 18, wherein the method reduces LDL-C plasma level by at least 25 mg/dL, as measured with the Friedewald formula, from baseline, wherein baseline is defined as start of the treatment with obicetrapib as an add-on to HIS therapy.
Claim 20 limits claim 1, wherein the subject has a plasma level of ApoB of at least 70 mg/dL, after at least 3 months of continuous HIS therapy and prior to commencement of obicetrapib administration. Claim 21 limits claim 20, wherein the method reduces ApoB plasma level by at least 25 mg/dL, from baseline, wherein baseline is defined as start of the treatment with obicetrapib as an add-on to HIS therapy.
Prior art
While Hovingh and Stone teaches prophylactic/therapeutic treatment of cardiovascular disease (CVD) by administering obicetrapib and statin therapy in a subject who is a hyporesponder to HIS therapy, the combination of Hovingh and Stone does not expressly teach:
1) the LDL-C level was determined using the Friedewald formula (Claims 18) or
2) the plasma level of ApoB of at least 70 mg/dL, after at least 3 months of continuous HIS therapy and prior to commencement of obicetrapib administration (Claim 20).
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However, it was known that statin therapy was monitored and included an initial fasting lipid panel (total cholesterol, triglycerides, HDL-C and calculated LD-C) followed by a second lipid panel 4-12 weeks after initiation of statin therapy to monitor adherence and to determine therapeutic response (See Stone, 6.1. at p. S21; see also Figure 5 at p. S23).
However, patients with LDL-C levels >=190 mg/dL require substantial reduction in LDL-C levels and intensive management and it is reasonable to use HIS therapy to achieve at least a 50% reduction. (See Stones, 4.4. at p. S14.) Thus, if initial HIS therapy in a patient with a baseline LDL-C of >= 190 mg/dL has not obtained a reduction of the expected 50% after 3-12 weeks on HIS therapy (i.e., at least 70 mg/dL after 3 months on the high end of HIS treatment), then the artisan would seek to add non-statin drug therapy such as OBT administration as described in the obvious rejection above.
Regarding 1) the LDL-C level was determined using the Friedewald formula (Claims 18):
Like Stone, Grundy also teaches treatment of CVD by lowering LDL-C using statin therapy. LDL-C levels are determined in plasma. (See 2.2.) Grundy also teaches that Friedewald formula is the standard for calculating LDL-C levels. (See Grundy, p. e1089, left column.) The POSA would have found it obvious to use the Friedewald formula to calculate the LDL-C because Stone teaches the LDL-C levels are calculated while Grundy teaches the Friedewald formula is the standard formula that can be used to calculate LDL-C levels. The POSA would reasonably believe the Friedewald formula would be suitable to use for successful calculation of the LDL-C levels disclosed in Stone.
Regarding 2) the plasma level of ApoB of at least 70 mg/dL, after 3 months of continuous HIS therapy and prior to commencement of obicetrapib administration (Claim 20):
Grundy further teaches apoB is the major lipoprotein in LDL and VLDL and has been strongly associated with ASCVD. It’s a stronger indicator of atherogenicity and its measurement may provide advantages. (See 2.2.1. and 2.3.) A level of apoB >130 mg/dL corresponds to an LDL-C level ≥160 mg/dL and constitutes a risk-enhancing factor. Thus, a POSA would have found it obvious to determine the apoB level after 3-12 weeks along with LDL-C levels as disclosed by Stone because Stone teaches the LDL-C levels are determine 3-12 weeks after initiating statin treatment to monitor adherence and therapeutic effect while Grundy teaches apoB levels can provide relatively stronger atherogenicity evidence wherein a level of apoB >130 mg/dL corresponds to an LDL-C level ≥160 mg/dL and constitutes a risk-enhancing factor.
Therefore, a POSA would have sought to combine a non-statin drug such as OBT (as outlined above) after 12 weeks of initiating HIS therapy but still maintaining a high level of ≥130 mg/dL apoB.
Claim 19 limits claim 18, wherein the method reduces LDL-C plasma level by at least 25 mg/dL, as measured with the Friedewald formula, from baseline, wherein baseline is defined as start of the treatment with obicetrapib as an add-on to HIS therapy. Claim 21 limits claim 20, wherein the method reduces ApoB plasma level by at least 25 mg/dL, from baseline, wherein baseline is defined as start of the treatment with obicetrapib as an add-on to HIS therapy. Claim 19 and Claim 21 recite the limitations “wherein the method reduces LDL-C plasma level by at least 25 mg/dL…” and “wherein the method reduces ApoB plasma level by at least 25 mg/dL…”, respectively. These limitations are considered to be intended outcomes that do not give further meaning and purpose to the manipulative steps of administering the therapeutic agents for the treatment of the patient. Therefore, the limitations in the "wherein" clauses are not given patentable weight because they simply express the intended result of the process steps positively recited.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRIS E SIMMONS whose telephone number is (571)272-9065. The examiner can normally be reached M-F: 9:30-6:00p.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James H. Alstrum-Acevedo can be reached at (571) 272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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CHRIS E. SIMMONS
Examiner
Art Unit 1622
/CHRIS E SIMMONS/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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