DETAILED ACTION
The present application is being examined under the pre-AIA first to invent provisions.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 05/11/2026 has been entered.
Applicant’s amendment, filed on 05/11/2025 has been entered.
Claims 1-3, 10-11, 13, 16, 19, 22-34, 37, 41, 46-49 have been canceled.
Claims 55-61 have been added.
Claims 4-9, 12, 14-15, 17-18, 20-21, 35-36, 38-40, 42-45, 50-61 are pending and currently under examination as they read on a method of lowering serum LDL cholesterol in an adult human patient comprising administering an anti-PCSK9 antibody.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
Claims 4-9, 12, 14-15, 17-18, 20-21, 35-36, 38-40, 42-45, 50-61 are rejected under pre-AIA 35 U.S.C. 103(a) as being obvious over Jackson et al. (US 2009/0142352 A1, cited on IDS).
Jackson teaches antigen-binding proteins directed against PCSK9, including antibody 21B12, for lowering serum cholesterol and treating or preventing cholesterol-related disorders. In particular, Jackson teaches that neutralizing antigen-binding proteins to PCSK9 may be used to treat, prevent, and/or reduce the risk of disorders related to elevated serum cholesterol, including hypercholesterolemia, coronary heart disease, cardiovascular disease, and other dyslipidemias (paragraphs [0375]-[0378]). Jackson further teaches administering a therapeutically effective amount of PCSK9 antibody, including 21B12, to a human patient having a cholesterol-related disorder or hypercholesterolemia and monitoring the patient for reduction in serum cholesterol (Examples 19-20). Jackson additionally expressly teaches identifying a human patient at risk of developing coronary heart disease and administering a therapeutically effective amount of 21B12 or another disclosed PCSK9 antibody to the patient to reduce serum cholesterol and thereby reduce the patient’s risk of coronary heart disease (Example 21).
Jackson expressly identifies the light- and heavy-chain variable regions of antibody 21B12 as SEQ ID NOs: 23 and 49, respectively (Table 2), and teaches antibodies comprising the CDR1, CDR2, and CDR3 sequences contained within these variable regions. Accordingly, Jackson teaches the antibody structural limitations recited in the claims, including the six CDRs of SEQ ID NOs: 23 and 49 and the recited variable-region sequences and sequence identities.
Jackson further demonstrates that 21B12 is a neutralizing anti-PCSK9 antibody that interferes with the PCSK9/LDLR interaction and lowers LDL cholesterol in vivo. Example 26 teaches administration of 21B12 at 10 or 30 mg/kg and reports significant LDL-cholesterol lowering through the final 48-hour measurement. Jackson further teaches that 21B12 binds human PCSK9 with high affinity and inhibits the interaction of PCSK9 with LDLR.
Jackson teaches that appropriate dosage levels depend upon, inter alia, the molecule delivered, indication, route of administration, patient characteristics, and desired therapeutic effect, and discloses a broad dosage range extending up to about 100 mg/kg or more. Jackson expressly instructs that a clinician may titrate the dosage to obtain the optimal therapeutic effect, that dosing frequency is selected taking into account pharmacokinetic parameters, that administration continues until a dosage achieving the desired effect is reached, and that further refinement of dosage is routinely performed by those of ordinary skill. Jackson additionally teaches that appropriate dosages may be ascertained using dose-response data and that both the amount and frequency of administration may take into account the desired cholesterol level and the patient’s existing cholesterol and LDL levels (paragraphs [0405]-[0406]). Jackson also expressly teaches subcutaneous administration (paragraphs [0407]).
Jackson does not expressly exemplify the particular fixed human dosage/frequency combinations of about 105-450 mg administered once every two to four weeks recited in the claims. However, in view of Jackson’s express teachings regarding administration of the same 21B12 antibody to human patients for the same cholesterol-lowering purpose, its broad dosage teachings, and its express direction to determine and refine dosage and dosing frequency using pharmacokinetic and dose-response information to obtain a desired cholesterol level, it would have been obvious to one of ordinary skill in the art at the time the invention was made to optimize the amount and frequency of 21B12 administration, including amounts falling within about 105-450 mg and frequencies of once every two to four weeks, through routine dose-ranging and pharmacokinetic studies to obtain and maintain a therapeutically desired reduction in serum LDL cholesterol.
Dose and dosing interval are result-effective variables expressly identified by Jackson as parameters to be adjusted in accordance with pharmacokinetics, dose-response data, and the desired cholesterol-lowering effect. Optimization of such variables would have involved no more than routine experimentation. See In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980); In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); and Merck & Co. v. Biocraft Labs., Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989).
The resulting lowering of serum LDL cholesterol by at least the recited amount and for the recited duration would have been the expected result of administering an effective amount of the same LDL-lowering antibody according to the optimized dosage regimen. Jackson expressly directs the artisan to adjust dosage and frequency based upon the desired cholesterol level and the patient’s present LDL level. Thus, achievement and maintenance of a desired LDL reduction would have constituted the result used by the skilled artisan in determining an appropriate dose and dosing interval rather than an unrelated property discovered only after selection of the claimed regimen.
Accordingly, one of ordinary skill would have had reason to optimize the disclosed 21B12 dosage and frequency within Jackson’s teachings, with a reasonable expectation of obtaining a therapeutically effective and sustained reduction in LDL cholesterol. The claimed dosage and frequency therefore represent optimization of result-effective variables in Jackson’s known method of using the same antibody for the same therapeutic purpose.
For claims 55-61, Jackson additionally expressly teaches administering 21B12 to a human patient at risk of developing coronary heart disease to reduce serum cholesterol and thereby reduce the patient’s risk of coronary heart disease (Example 21, paragraph [0498]).
Therefore, the invention, as a whole, was prima facie obvious to one of ordinary skill in the art, at the time the invention was made as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Applicant’s argument
Applicant’s arguments filed 05/11/2026 have been fully considered but are not persuasive.
Applicant argues that Jackson fails to provide a reasonable expectation of success in modifying the disclosed methods to administer the recited anti-PCSK9 antibody at a dose of about 105 mg to about 450 mg once every 2 to 4 weeks, thereby lowering serum LDL cholesterol by at least 15% for at least two weeks. In particular, Applicant relies on Example 26 and Figures 14A and 14B of Jackson and argues that, because the LDL-C-lowering effect of 21B12 observed in the mouse model had substantially returned to baseline by 48 hours, one of ordinary skill would not have reasonably expected 21B12 to produce the recited LDL-C reduction for at least two weeks in a human patient.
The Examiner acknowledges that Figures 14A and 14B show that, following administration of 21B12 at 10 mg/kg or 30 mg/kg in the mouse model of Example 26, LDL-C was reduced at 24 hours but had returned to or approximately to baseline by the 48-hour measurement. However, Applicant’s argument is not persuasive because it improperly treats the duration of LDL-C lowering observed in the particular experimental mouse model of Example 26 as predictive of the duration that would have been expected upon administration of 21B12 to a human patient.
Jackson expressly explains that the mouse model of Example 26 contained supraphysiologically high levels of circulating human PCSK9 (paragraph 0515). Human PCSK9 was introduced into the mice by AAV-mediated expression, and Jackson explains that the circulating concentration of human PCSK9 in the model was approximately 75-fold higher than the average concentration in human serum. Jackson further explains that PCSK9 expressed in this manner was not subject to normal physiological regulation. Jackson therefore expressly recognizes that the experimental conditions in Example 26 differ substantially from the physiological conditions that would be encountered in a human patient and concludes that the disclosed PCSK9 antigen-binding proteins “should be even more effective in humans” (paragraph 0515).
Accordingly, one of ordinary skill would not have understood the return of LDL-C toward baseline by 48 hours in Example 26 as establishing that 21B12 would necessarily have an approximately 48-hour duration of action in humans. To the contrary, Jackson itself cautions against such an inference by explaining the unusually high PCSK9 burden imposed by the animal model and expressly predicting greater effectiveness under human physiological conditions.
Applicant additionally extrapolates from the 48-hour mouse data that LDL-C would have returned to baseline by approximately 72 hours and argues that the skilled artisan therefore would have expected that a two-week LDL-C reduction could not be achieved. However, Jackson does not report a 72-hour measurement. More importantly, even accepting Applicant’s observation that the effect in the mouse model had substantially disappeared by 48 hours, Jackson expressly attributes the experimental context to a model having circulating human PCSK9 concentrations far exceeding normal human concentrations. Thus, the duration observed in that model does not establish the duration that one of ordinary skill would have expected in a human patient.
Moreover, Jackson’s teachings are not limited to the mouse experiment of Example 26. Jackson expressly contemplates the therapeutic administration of its PCSK9 antigen-binding proteins, including 21B12, to human patients for reducing serum cholesterol and treating or preventing cholesterol-related disorders. Jackson teaches treatment of hyperlipidemia and cardiovascular disease and further teaches administration of a PCSK9 antigen-binding protein to a human patient at risk of developing coronary heart disease.
Significantly, Jackson also provides express guidance regarding determination of an appropriate human dosage and dosing frequency. Jackson teaches that dosing frequency may take into account the pharmacokinetic parameters of the PCSK9 antigen-binding protein; that a clinician may administer the composition until a dosage that achieves the desired effect is reached; and that further refinement of an appropriate dosage is routinely performed by those of ordinary skill. Jackson further teaches that appropriate dosages may be ascertained using dose-response data and that the amount and frequency of administration may take into account the desired cholesterol level and the patient’s present cholesterol level, LDL level, and/or LDLR levels (See paragraphs [0405]-[0406]).
Thus, Jackson does not direct the skilled artisan to use the duration observed in the Example 26 mouse experiment as the human dosing interval. Rather, Jackson expressly directs the skilled artisan to determine and optimize the dosage and frequency of administration based upon pharmacokinetics, dose-response data, and the desired cholesterol-lowering effect in the subject.
The Examiner therefore maintains that dosage and dosing frequency constitute result-effective variables expressly recognized by Jackson. Jackson teaches the same 21B12 antibody for the same purpose of lowering cholesterol, provides dosage ranges encompassing the presently claimed amounts, and expressly instructs the artisan to adjust dosage and frequency to achieve a desired cholesterol level. Determination of an optimum or workable range of a recognized result-effective variable ordinarily constitutes routine optimization. See In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980); In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); and Merck & Co. v. Biocraft Labs., Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989).
The Examiner does not rely upon the proposition that Jackson expressly discloses a ≥15% reduction in LDL-C lasting at least two weeks. Rather, the rejection is based upon Jackson’s teaching of the same antibody for lowering LDL-C in human patients together with its express direction to optimize the amount and frequency of administration to achieve the desired cholesterol-lowering effect. Once the dosage and dosing interval were optimized in accordance with Jackson’s teachings to provide sustained LDL-C lowering, the magnitude and duration of LDL-C reduction resulting from administration of that regimen would flow from practicing the optimized method.
Alleged Unexpected Results
Applicant further argues that the clinical results reported in the present specification rebut any prima facie case of obviousness because the claimed dosage regimens produced clinically significant and unexpectedly superior results. Applicant particularly points to clinical data showing that regimens including 140 mg Q2W and 420 mg Q4W maintained substantial LDL-C lowering for two weeks or longer.
The evidence has been considered but is not sufficient to overcome the prima facie case.
The fact that the claimed regimens successfully produce clinically significant LDL-C lowering does not, by itself, establish an unexpected result. Rather, the relevant consideration is whether the claimed subject matter produces a result that would have been unexpected relative to the closest prior art.
Applicant’s comparison of the human clinical results with the Example 26 mouse results does not establish such unexpected superiority because the two sets of results were obtained under materially different biological conditions. As discussed above, Jackson expressly explains that the Example 26 mice had circulating human PCSK9 concentrations approximately 75-fold greater than average human serum concentrations and expressly predicts that the PCSK9 antigen-binding proteins should be more effective in humans. Thus, greater or more sustained activity in human subjects relative to the Example 26 mouse model is consistent with, rather than contrary to, Jackson’s express teaching.
Moreover, Jackson already establishes that 21B12 possesses LDL-C-lowering activity and directs the skilled artisan to optimize dosage and frequency based upon pharmacokinetic and dose-response information and the desired cholesterol level. The clinical data relied upon by Applicant therefore demonstrate that particular optimized regimens are effective, but the evidence does not establish that the claimed dosage region produces an unexpected result relative to what one of ordinary skill would have reasonably expected in view of Jackson.
Further, the pending claims encompass broad dosage and dosing-frequency ranges. For example, independent claims 40 and 55 encompass doses from about 105 mg to about 450 mg administered at a frequency anywhere from once every two weeks to once every four weeks. Applicant principally relies upon particular clinical regimens within those ranges, including 140 mg Q2W and 420 mg Q4W. Applicant has not established that the asserted unexpected superiority extends throughout the full scope of the claimed dosage and frequency ranges. Accordingly, the evidence is not commensurate in scope with the breadth of the claims.
Therefore, when the evidence of alleged unexpected results is weighed against Jackson’s disclosure as a whole, the evidence is insufficient to outweigh the evidence supporting the prima facie case of obviousness.
New Claims 55–61
Applicant states that new claims 55-61 are allowable for reasons similar to those asserted for the previously pending claims. This argument is not persuasive.
Regarding independent claim 55, Jackson expressly contemplates identifying and treating a human patient at risk of developing coronary heart disease with an anti-PCSK9 antigen-binding protein, including 21B12, for the purpose of reducing serum cholesterol and reducing the risk of coronary heart disease. Thus, the recitation in claim 55 of administering the antibody to an adult human patient at risk for developing CHD does not distinguish the claimed method from Jackson.
The remaining limitations concerning the identity and structure of the antibody, dosage, dosing frequency, LDL-C lowering, and route of administration are taught or rendered obvious by Jackson for the reasons discussed above. Claims 56-61 likewise fail to patentably distinguish the claimed method where they further define the CHD-risk patient population, route and frequency of administration, or structural characteristics of the same 21B12 antibody disclosed by Jackson.
Applicant’s argument has not been found convincing. Therefore, the rejection is maintained as it applies to amended claims.
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 4-9, 12, 14-15, 17-18, 20-21, 35-36, 38-40, 42-45, 50-61 are rejected on the ground of nonstatutory double patenting as being unpatentable over the following in view of Jackson et al. (US 2009/0142352 A1, cited on IDS):
U.S. Patent
Claims
11,464,857
1-12
10,611,850
1-33
8,030,457
1-27
8,168,762
1-22
8,871,914
1-25
8,981,064
1-29
9,045,547
1-66
9,920,134
1-17
8,563,698
1-6
8,829,165
1-29
8,859,741
1-24
8,871,913
1-29
8,883,983
1-30
8,889,834
1-20
9,056,915
1-23
9,493,576
1-43
The above listed patent claims disclosed either the same anti-PCSK9 antibody or a method of using the antibody for lowering cholesterol. Therefore, it would have been obvious to use the antibody for lowering serum LDL-C at a dose of about 10-3000 mg in view of Jackson et al. for reasons discussed above (see 103).
Applicant’s argument and Examiner’s response are essentially same as above (see 103). In addition, Applicant’s request to hold the rejections in abeyance has been noted. Therefore, the rejection is maintained.
Claim 4-9, 12, 14-15, 17-18, 20-21, 35-36, 38-40, 42-45, 50-61 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 Jackson (US 2009/0142352 A1, cited on IDS).
The co-pending claims disclosed either the same anti-PCSK9 antibody or a method of using the antibody for lowering cholesterol. Therefore, it would have been obvious to use the antibody for lowering serum LDL-C at a dose of about 10-3000 mg in view of Jackson et al. for reasons discussed above (see 103).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Applicant’s argument and Examiner’s response are essentially same as above (see 103). In addition, Applicant’s request to hold the rejections in abeyance has been noted. Therefore, the rejection is maintained.
Conclusion
No claim is allowed.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/SHARON X WEN/ Primary Examiner, Art Unit 1641
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