DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 06/29/2026 has been entered.
Applicant’s amendment, filed 06/29/2026, has been entered.
Claims 19, 34, 36-40 are pending and currently under examination as they read on a method of reducing a risk of a cardiovascular event comprising administering an anti-PCSK9 antibody.
The previous rejection under 35 USC 102(a)(1) as being anticipated by Chan et al. has been withdrawn in view of Applicant’s remarks, filed 06/29/2026.
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.
Claims 19 and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Chan et al. (US 2013/0064825 A1; reference of record) in view of Sabatine et al. (N. Engl. J. Med. 372:1500–1509, (2015)).
Regarding claim 19, Chan teaches a method of reducing the risk of cardiovascular events by administering an anti-PCSK9 antibody, including 21B12 (evolocumab), to subjects having elevated LDL-C, including subjects having fasting LDL-C ≥85 mg/dL (see, e.g., Example 25). Chan teaches that administration of the antibody reduces LDL-C and expressly contemplates reductions of up to at least about 90% relative to predose LDL-C (see [0038]). Chan further teaches that the magnitude and duration of LDL-C reduction are dose dependent and that repeated administration provides maintenance of LDL-C reduction (see Example 20, Examples 22–25/Fig. 24). Thus, Chan teaches administration of evolocumab in amounts and frequencies capable of reducing LDL-C to less than 40 mg/dL in subjects having baseline LDL-C greater than 70 mg/dL.
Chan does not expressly teach maintaining LDL-C at less than 40 mg/dL for at least one year. Sabatine, however, teaches administration of evolocumab 140 mg every two weeks or 420 mg monthly during approximately one year of therapy and reports persistent LDL-C reduction and a reduction in cardiovascular events during the one-year treatment period (see Abstract, Methods and Results; Results—Lipid Changes and Cardiovascular Events; Figs. 1 and 2).
It would have been obvious to one of ordinary skill in the art to continue administering evolocumab according to Chan for at least one year, as taught by Sabatine, at an amount and frequency sufficient to maintain LDL-C below 40 mg/dL in order to provide sustained LDL-C lowering and reduce cardiovascular risk. The amount and frequency of evolocumab administration were known result-effective variables with respect to the magnitude and duration of LDL-C reduction, as Chan expressly teaches that these effects are dose dependent and that repeated administration maintains LDL-C reduction. Accordingly, optimization of the amount and frequency to achieve and maintain the desired LDL-C level would have amounted to routine optimization of known result-effective variables, with a reasonable expectation of success in view of Chan’s substantial LDL-C reductions and Sabatine’s demonstration of sustained LDL-C lowering during long-term evolocumab treatment.
Regarding claim 40, Chan further teaches administration of 21B12/evolocumab in combination with an HMG-CoA reductase inhibitor (statin), including subjects maintained on stable statin therapy, with or without ezetimibe (see Example 25). Therefore, Chan teaches the additional limitation of claim 40.
Therefore, the invention, as a whole, was prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 34 and 36–39 are rejected under 35 U.S.C. 103 as being unpatentable over Puri et al. (Am. Heart J. 176:83–92 (2016)) in view of Leeper et al. (Circulation 116(6):613-618 (2007)).
Regarding claim 34, Puri teaches a method of treating subjects having atherosclerotic cardiovascular disease, specifically coronary artery disease, by administering evolocumab to subjects receiving maximally tolerated statin therapy for the purpose of reducing coronary atheroma burden. Puri teaches evaluating the effect of evolocumab on coronary atherosclerosis by measuring percent atheroma volume (PAV) and total atheroma volume (TAV) using intravascular ultrasound (Puri, pp. 83, 85–86, Aims; Methods; Study rationale and objectives).
Puri teaches that aggressive LDL-C lowering results in plaque regression, with plaque regression evident in patients achieving LDL-C levels <70 mg/dL, and further teaches that PCSK9 inhibitors permit an additional 54–75% reduction in LDL-C in statin-treated patients (Puri, p. 83, Background). Puri specifically identifies that “[t]he impact of achieving very low LDL-C levels with PCSK9 inhibitors on coronary atherosclerosis has not been investigated” and expressly tests the hypothesis that incremental LDL-C lowering with evolocumab will result in a significantly greater change in coronary atheroma volume (Puri, p. 83, Background; Aims).
Puri further teaches an established relationship between progressively lower achieved LDL-C and greater coronary plaque regression. Puri reports that ASTEROID achieved an LDL-C of 61 mg/dL with a PAV reduction of approximately 0.98%, and that SATURN achieved LDL-C of 63 mg/dL with a PAV reduction of 1.22% in the rosuvastatin group (Puri, p. 84, Insights from serial coronary intravascular ultrasonography; Fig. 1). Puri further predicts that lowering LDL-C to approximately 40 mg/dL with evolocumab would result in still further degrees of atheroma regression (Puri, p. 89, Discussion; Fig. 1).
Puri differs from claim 34 in that Puri’s GLAGOV inclusion criteria require LDL-C ≥80 mg/dL, or LDL-C ≥60 but <80 mg/dL in subjects having specified additional risk factors, and therefore does not expressly administer evolocumab to a subject having an LDL-C level <60 mg/dL (Puri, p. 86, Table I).
Leeper, however, teaches treatment of cardiovascular patients having very low LDL-C levels, including patients having LDL-C <60 mg/dL, and teaches that continued lipid-lowering statin therapy in such patients is associated with clinical benefit, including benefit in patients having LDL-C levels <40 mg/dL (see, e.g., Discussion).
It would have been obvious to one of ordinary skill in the art to administer evolocumab as taught by Puri to an atherosclerotic cardiovascular disease patient having an LDL-C level below 60 mg/dL, as taught by Leeper, in order to further lower LDL-C and reduce coronary atheroma burden. Puri itself provides the motivation for doing so by teaching that aggressive LDL-C lowering produces plaque regression, that evolocumab provides substantial additional LDL-C lowering in statin-treated cardiovascular patients, and that incremental LDL-C lowering with evolocumab was expected to produce greater coronary atheroma regression. Leeper further establishes that an already-low LDL-C level would not have discouraged continued lipid-lowering treatment. Accordingly, one of ordinary skill would have had a reasonable expectation that further LDL-C lowering with evolocumab in such patients would provide further regression of coronary atherosclerosis.
Regarding claim 36, Puri expressly teaches administering evolocumab 420 mg subcutaneously monthly, which falls within the claimed amount of 300–450 mg about every four weeks (Puri, pp. 83, 85, 87; Methods; Fig. 2).
Regarding claim 37, Puri expressly teaches that phase II dose-ranging studies identified 140 mg evolocumab every two weeks or 420 mg monthly as optimal dosing regimens to maximally reduce LDL-C (Puri, p. 85, Clinical development of evolocumab). Thus, Puri teaches the claimed administration of 75–150 mg about every two weeks.
Regarding claims 38 and 39, Puri does not expressly report the ultimately observed quantitative degree of PAV and TAV regression because Puri reports the rationale and design of GLAGOV rather than the subsequently determined study results. However, the recited reductions in PAV and TAV are considered to be inherent results of performing the method rendered obvious by Puri in view of Leeper. The applied references render obvious administration of the same therapeutic agent, evolocumab, according to the same treatment regimen to the same type of patient for the same purpose of producing coronary plaque regression. Puri further provides a sound factual basis for the expected result by establishing a relationship between lower achieved LDL-C and greater plaque regression and predicting still further atheroma regression upon lowering LDL-C to approximately 40 mg/dL (Puri, pp. 84, 89; Fig. 1; Discussion).
Accordingly, when the substantially identical treatment method is performed, the resulting reduction in PAV by at least 1% as recited in claim 38 and TAV by at least 2% as recited in claim 39 would necessarily flow from performance of the method. Where the prior art teaches substantially the same method and treatment conditions, a property or result necessarily resulting from performance of that method is inherent notwithstanding that the prior art did not expressly recognize or quantify the result. See MPEP § 2112; In re Best, 562 F.2d 1252, 1254–55 (CCPA 1977).
Therefore, the invention, as a whole, was prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention as evidenced by the references, especially in the absence of evidence to the contrary.
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 claims at issue 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); and 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 a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form 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 http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 19 and 40 are rejected on the ground of nonstatutory double patenting as being unpatentable over the following in view of Chan et al. (US 2013/0064825 A1) and Sabatine et al. (N. Engl. J. Med. 372:1500–1509, 2015).
US Patent (cited in IDS)
Claims
US 11464857 B2
1-12
US 8168762 B2
1-22
US 8829165 B2
1-29
US 8871913 B2
1-25
US 8883983 B2
1-30
US 8981064 B2
1-29
US 9056915 B2
1-23
US 9920134 B2
1-17
US 9994923 B2
1-19
US 8030457 B2
1-27
US 8563698 B2
1-6
US 8859741 B2
1-24
US 8871914 B2
1-25
US 8889834 B2
1-20
US 9045547 B2
1-66
US 9493576 B2
1-43
US 10611850 B2
1-33
Although the claims at issue are not identical, they are not patentably distinct from each other because the patent claims are directed to an anti-PCSK9 antibody known for lowering cholesterol and/or a method of lowering cholesterol comprising administering the same anti-PCSK9 antibody. Given the teaching by Chan et al. and Sabatine et al. as discussed above in 103, one of ordinary skill in the art would have arrived at the present claims of combined treatment of a PCSK9 antibody and statin for reducing a risk of a cardiovascular event. Therefore, the patent claims would render obvious of the present claims in view of Chan et al. and Sabatine et al.
Claims 34 and 36-39 are rejected on the ground of nonstatutory double patenting as being unpatentable over the following in view of Puri et al. (Am. Heart J. 176:83–92 (2016)) and Leeper et al. (Circulation 116(6):613-618 (2007)).
US Patent (cited in IDS)
Claims
US 11464857 B2
1-12
US 8168762 B2
1-22
US 8829165 B2
1-29
US 8871913 B2
1-25
US 8883983 B2
1-30
US 8981064 B2
1-29
US 9056915 B2
1-23
US 9920134 B2
1-17
US 9994923 B2
1-19
US 8030457 B2
1-27
US 8563698 B2
1-6
US 8859741 B2
1-24
US 8871914 B2
1-25
US 8889834 B2
1-20
US 9045547 B2
1-66
US 9493576 B2
1-43
US 10611850 B2
1-33
Although the claims at issue are not identical, they are not patentably distinct from each other because the patent claims are directed to an anti-PCSK9 antibody known for lowering cholesterol and/or a method of lowering cholesterol comprising administering the same anti-PCSK9 antibody. Given the teaching by Puri and Leeper as discussed above in 103, one of ordinary skill in the art would have arrived at the present claims of combined treatment of a PCSK9 antibody for reducing PAV and/or TAV. Therefore, the patent claims would render obvious of the present claims in view of Puri and Leeper.
Claim 19 and 40 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of copending Application No. 14/316,587; claims 39-59, 86-91,94-98, 100, 102-105, 107-118 of copending Application No. 13/469,032; claims 1-21, 29-30, 33-46 of copending Application USSN 13931716; claims 2-30 of copending application USSN 17011433; claims 1-42, 44, 46-50, 52, 54-56, 60-85, 87-88, 90-91, 94-98, 100, 102-105 and 107-138 of copending application USSN 13469032; claims 118-121, 125-127, 157-164 and 170-197 of copending application USSN 13886180; claims 16-17, 20, 22-88 of copending application USSN 14562546 in view of Chan et al. (US 2013/0064825 A1) and Sabatine et al. (N. Engl. J. Med. 372:1500–1509, 2015). Although the claims at issue are not identical, they are not patentably distinct from each other because the co-pending claims disclosed the same anti-PCSK9 antibody and/or are directed to methods of lowering cholesterol comprising administering the same anti-PCSK9 antibody. Given the teaching by Chan and Sabatine as discussed above in 103, one of ordinary skill in the art would have arrived at the present claims upon reading Chan’s disclosure of combined treatment of a PCSK9 antibody and statin for reducing a risk of a cardiovascular event. Therefore, the co-pending claims would render obvious of the present claims in view of Chan and Sabatine.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 34 and 36-39 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of copending Application No. 14/316,587; claims 39-59, 86-91,94-98, 100, 102-105, 107-118 of copending Application No. 13/469,032; claims 1-21, 29-30, 33-46 of copending Application USSN 13931716; claims 2-30 of copending application USSN 17011433; claims 1-42, 44, 46-50, 52, 54-56, 60-85, 87-88, 90-91, 94-98, 100, 102-105 and 107-138 of copending application USSN 13469032; claims 118-121, 125-127, 157-164 and 170-197 of copending application USSN 13886180; claims 16-17, 20, 22-88 of copending application USSN 14562546 in view of Puri et al. (Am. Heart J. 176:83–92 (2016)) and Leeper et al. (Circulation 116(6):613-618 (2007)). Although the claims at issue are not identical, they are not patentably distinct from each other because the co-pending claims disclosed the same anti-PCSK9 antibody and/or are directed to methods of lowering cholesterol comprising administering the same anti-PCSK9 antibody. Given the teaching by Chan and Sabatine as discussed above in 103, one of ordinary skill in the art would have arrived at the present claims upon reading Chan’s disclosure of combined treatment of a PCSK9 antibody for reducing PAV and/or TAV. Therefore, the co-pending claims would render obvious of the present claims in view of Puri and Leeper.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is allowed.
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/SHARON X WEN/Primary Examiner, Art Unit 1641
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