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 .
Claim Status
Claims 1-30, 35, 38, 40, and 59-61 are cancelled. Claims 31-34, 36-37, 39, and 41-58 are pending and currently under consideration for patentability under 37 CFR 1.104.
Priority
This application is a 371 of PCT/KR2022/009027 (filed on 06/24/2022) which claims benefit of Republic of Korea Application No. KR10-2021-0083100 (filed on 06/25/2021). Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Applicant cannot rely upon the certified copy of the foreign priority application because a translation of said application has not been made of record in accordance with 37 CFR 1.55. When an English language translation of a non-English language foreign application is required, the translation must be that of the certified copy (of the foreign application as filed) submitted together with a statement that the translation of the certified copy is accurate. See MPEP §§ 215 and 216.
Because an English translation of the certified copy of the foreign priority application has not been made of the record, the examiner cannot establish whether or not what is claimed in the instant application was properly disclosed in the foreign priority application. Therefore, the benefit to the foreign priority application date is not granted.
Claims 31-34, 36-37, 39, and 41-58 have an effective filing date of 06/24/2022 corresponding to PCT/KR2022/009027.
Information Disclosure Statement
The information disclosure statements filed on 12/21/2023 and 06/05/2025 have been considered. Signed copies are enclosed.
Notably, the disclosure statements filed on 12/21/2023 and 06/05/2025 list Search Reports. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 31-34, 36-37, 39, and 41-58 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of preventing or reducing the risk of the development of the following outcomes: MACE, coronary revascularization, hospitalization for unstable angina in a patient, myocardial infarction, stroke, new macroalbuminuria, a decrease in eGFR of 40 % or more for 30 days or more, renal replacement therapy for 90 days or more, or eGFR of less than 15 ml/min/1.73 m2 for 30 days or more in a patient with T2DM comprising administering an effective amount of efpeglenatide, does not reasonably provide enablement for a method of preventing or reducing the risk of the development of all cardiovascular diseases or all renal dysfunctions in a patient with any disease profile comprising administering an effective amount of efpeglenatide. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation’.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008). See also In re Cortright, 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorer Inc., 49 USPQ2d 1370.
The factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Among these factors are: (1) the nature or the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. When the above factors are weighed, it is the examiner’s position that one skilled in the art could not practice the invention without undue experimentation. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
(1) The nature or the invention and (2) the state of the prior art
Claim 31 is drawn to “a method of preventing development of cardiovascular disease or renal dysfunction in a patient, or reducing the risk of development thereof, comprising administering an effective amount of efpeglenatide to the patient” (lines 1-4).
In addition, “cardiovascular disease or renal dysfunction may be determined by whether the patient experiences an outcome” (Specification, ¶ 0061). Outcome is not defined.
The field of invention resides in the fields of chemistry and biology, specifically clinical medicine, highly complex and unpredictable arts. Although claim 31 broadly recites a method of preventing or reducing the risk of the development of cardiovascular disease or renal dysfunction in a patient comprising administering an effective amount of efpeglenatide, the dependent claims demonstrate that practicing the claimed invention encompasses numerous variables. For example, dependent claims recite multiple patient populations (including patients with type 2 diabetes mellitus [T2DM], specific cardiovascular diseases such as myocardial infarction, and specific renal dysfunctions such as macroalbuminuria) and the therapeutic outcomes in said patient populations that can be improved upon administering efpeglenatide. Collectively, the dependent claims demonstrate that the invention is directed to the reduction in risk of the development and prevention of cardiovascular diseases and renal dysfunctions, subject matter that is highly complex and unpredictable, wherein therapeutic efficacy depends on the patient population and targeted clinical outcomes.
Glucagon-like peptide 1 receptor agonists (GLP1-RAs)
Prior art teaches that glucagon-like peptide 1 receptor agonists (GLP1-RAs) are useful in treating not only type 2 diabetes mellitus (T2DM) but also cardiovascular (CV) and renal outcomes. Zelniker et al. performed a meta-analysis of GLP1-RA treatment in patients with T2DM, including lixisenatide, liraglutide, semaglutide, exenatide, and albiglutide (IDS filed on 06/05/2025, Cite No. 4; Pg. 2022, Title, ”Effects of Glucagon-Like Peptide Receptor Agonists… for Prevention of Major Adverse Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus”; Pg. 2024, Table 1). Zelniker et al. teach that GLP1-RAs as a class reduce the risk of developing major adverse CV event (MACE) in CV disease and macroalbuminuria in kidney disease when treating patients with T2DM (Pg. 2022, Results, GLP1-RA class reduces the risk of developing MACE in CV disease and macroalbuminuria in kidney disease in patients with T2DM). This teaching indicates GLP1-RAs as a class, applicable to efpeglenatide, can reduce the risk of developing certain outcomes related to cardiovascular diseases and renal dysfunctions.
Uneda et al. (Systematic review and meta-analysis for prevention of cardiovascular complications using GLP-1 receptor agonists and SGLT-2 inhibitors in obese diabetic patients, Sci Rep, 2021) teach “glucagon-like peptide-1 receptor agonists (GLP-1 RAs)… have been shown to prevent [CV disease] in T2DM patients” (Pg. 1, Abstract, lines 2-3), specifically regarding cardiovascular death, myocardial infarction, and stroke (Pg. 5, ¶ 5, lines 2-3, “GLP-1 RAs are superior to placebo for the prevention of MACE in T2DM patients”; Pg. 5, ¶ 6, line 6, “MACE, which comprised cardiovascular death, myocardial infarction, and stroke”). Lee et al. (Cardiorenal Protection in Diabetic Kidney Disease, Endocrinol Metab, 2021) teach “GLP-1 RA use to prevent composite renal outcome” (Pg. 263, Fig. 1, last 2 lines) in people with T2DM and chronic kidney disease (Pg. 260, column 2, ¶ 2, lines 14-15). These teachings indicate GLP1-RAs as a class, applicable to efpeglenatide, can prevent certain outcomes related to cardiovascular diseases and renal dysfunctions.
It is unclear how GLP1-RAs affect cardiovascular disease and renal dysfunction in patients without T2DM.
Gerstein et al. teach “[e]fpeglenatide is a GLP-1 RA that comprises a modified exendin-4 molecule.” As efpeglenatide is a GLP-RA, it is expected to also have cardiovascular and renal protective effects. In addition, Sun et al. and Jia et al. teach exendin-4 molecules specifically are known to be protective against chronic heart disease (Sun et al., Theranostics, 2015, Abstract, exendin-4 analog is a “potent long-acting GLP-1 receptor agonist for the treatment of chronic heart disease”) and diabetic kidney disease (Jia et al., Experimental and Molecular Medicine, 2018, Abstract, “exendin-4 exerts a protective effect against [diabetic kidney disease]”).
Cardiovascular diseases
Cardiovascular disease is not one single disease and it “includes a variety of heart and blood vessel conditions, such as coronary artery disease, peripheral arterial disease, heart attack, stroke, high blood pressure, heart valve disease, vascular disease, aorta disease, heart failure, cardiomyopathy, abnormal heart rhythms, congenital heart disease, and many other heart and blood vessel conditions” (Cardiovascular Disease is NOT Just a Man’s Disease, Cardio-HART by Cardio-Phoenix, 2020, Pg. 2, ¶ 1). Cardiovascular diseases could not be prevented broadly by efpeglenatide. For example, congenital heart disease is a heart abnormality present at birth and treated commonly through surgical interventions (Bouma and Mulder, 2017, Abstract, “Congenital heart disease is the most frequently occurring congenital disorder affecting ≈0.8% of live births” and “solutions were sought in perfection and creation of new surgical techniques”).
Zelniker et al. teach GLP1-RAs are useful for reducing the risk of developing of “myocardial infarction, stroke, and cardiovascular death [MACE]” (Pg. 2025, Fig. 1, Legend). Similarly, Uneda et al. teach GLP1-RAs are useful for preventing cardiovascular death, myocardial infarction, and stroke (Pg. 5, ¶ 5, lines 2-3, “GLP-1 RAs are superior to placebo for the prevention of MACE in T2DM patients”; Pg. 5, ¶ 6, line 6, “MACE, which comprised cardiovascular death, myocardial infarction, and stroke”). These teachings focus on reducing the risk of developing or preventing cardiovascular outcomes instead of specific cardiovascular diseases.
Renal dysfunctions
Similarly, renal dysfunction encompasses a variety of renal diseases, including but not limited to polycystic kidney disease, kidney stones, nephrotic syndrome, and nephritis (Kidney Diseases, Health Central, 2019, Pg. 2-3, Types of Kidney Disease). Renal diseases could not be prevented broadly by efpeglenatide. For example, lupus nephritis is “a form of glomerulonephritis that constitutes one of the most severe organ manifestations of the autoimmune disease systemic lupus erythematosus,” best treated via immune suppressive therapy (Anders et al., 2020, Abstract).
Zelniker et al. teach GLP1-RAs are useful for preventing the progression of kidney disease, reducing the relative risk of a kidney composite outcome; “the relative risk reduction of the kidney composite with GLP1-RA appeared to be mainly driven by a reduction in macroalbuminuria” (Pg. 2026, column 2, ¶ 2, line 7-9). Similarly, Lee et al. teach GLP1-RAs are useful “to prevent composite renal outcome” (Pg. 263, Fig. 1, last 2 lines) in people with T2DM and chronic kidney disease (Pg. 260, column 2, ¶ 2, lines 14-15). These teachings focus on reducing the risk of developing or preventing renal outcomes instead of a specific renal dysfunction or kidney disease.
Consequently, claim 31 is directed to complex and unpredictable fields, where a person having ordinary skill in the art could not readily extrapolate that administering efpeglenatide would successfully prevent or reduce the risk of the development of all cardiovascular diseases or all renal dysfunctions in a patient with any disease profile. As such, claim 31 generally reads on a method of preventing or reducing the risk of the development of all cardiovascular diseases or all renal dysfunctions in a patient with any disease profile comprising administering an effective amount of efpeglenatide, the full scope of which is not enabled by the method as instantly claimed.
(3) The relative skill of those in the art and (4) the predictability or unpredictability of the art,
This invention is in a class of invention which the CAFC has characterized as "the unpredictable arts such as chemistry and biology". Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
While the use of GLP1-RA, specifically efpeglenatide, in reducing the risk of developing and preventing myocardial infarction, stroke, MACE, and macroalbuminuria is known by a person having ordinary skill in the art, i.e. someone with a PhD and/or MD (the relative skill of those in the art), the use of efpeglenatide in reducing the risk of developing all cardiovascular diseases or all renal dysfunctions within the scope of claim 31 is not predictable.
Zelniker et al. teach GLP1-RAs are useful for reducing the risk of developing of “myocardial infarction, stroke, and cardiovascular death [MACE]” (Pg. 2025, Fig. 1, Legend). Similarly, Uneda et al. teach GLP1-RAs are useful for preventing cardiovascular death, myocardial infarction, and stroke (Pg. 5, ¶ 5, lines 2-3, “GLP-1 RAs are superior to placebo for the prevention of MACE in T2DM patients”; Pg. 5, ¶ 6, line 6, “MACE, which comprised cardiovascular death, myocardial infarction, and stroke”). These teachings focus on reducing the risk of developing or preventing cardiovascular outcomes instead of specific cardiovascular diseases.
Zelniker et al. teach GLP1-RAs are useful for preventing the progression of kidney disease, reducing the relative risk of a kidney composite outcome; “the relative risk reduction of the kidney composite with GLP1-RA appeared to be mainly driven by a reduction in macroalbuminuria” (Pg. 2026, column 2, ¶ 2, line 7-9). Similarly, Lee et al. teach GLP1-RAs are useful “to prevent composite renal outcome” (Pg. 263, Fig. 1, last 2 lines) in people with T2DM and chronic kidney disease (Pg. 260, column 2, ¶ 2, lines 14-15). These teachings focus on reducing the risk of developing or preventing renal outcomes instead of a specific renal dysfunction or kidney disease.
It is noted that these studies are metanalyses of cardiovascular and renal studies using a variety of GLP1-RAs, including efpeglenatide, and talk about the effects of GLP1-RAs as a class. As these studies were done in patients with T2DM, It is unclear how GLP1-RAs, including efpeglenatide, would affect cardiovascular disease and renal dysfunction in patients without T2DM.
In addition, these studies focus on reducing the risk of developing or preventing renal and cardiovascular outcomes (e.g. myocardial infarction, stroke, cardiovascular death, MACE, macroalbuminuria) with GLP1-RAs instead of specific cardiovascular diseases and renal dysfunctions. Cardiovascular disease is not one single disease and it “includes a variety of heart and blood vessel conditions, such as coronary artery disease, peripheral arterial disease, heart attack, stroke, high blood pressure, heart valve disease, vascular disease, aorta disease, heart failure, cardiomyopathy, abnormal heart rhythms, congenital heart disease, and many other heart and blood vessel conditions” (Cardiovascular Disease is NOT Just a Man’s Disease, Cardio-HART by Cardio-Phoenix, 2020, Pg. 2, ¶ 1). Cardiovascular diseases could not be prevented broadly by efpeglenatide. Similarly, renal dysfunction encompasses a variety of renal diseases, including but not limited to polycystic kidney disease, kidney stones, nephrotic syndrome, and nephritis (Kidney Diseases, Health Central, 2019, Pg. 2-3, Types of Kidney Disease). Renal diseases could not be prevented broadly by efpeglenatide.
The predictability of applying efpeglenatide in reducing the risk of developing all cardiovascular diseases or all renal dysfunctions in a patient with any disease profile would be low given that 1) there is not a link between GLP1-RAs, including efpeglenatide, and prevention/reduction of risk of all cardiovascular diseases or renal dysfunctions in patients without T2DM as the effects of GLP1-RAs on outcomes related to cardiovascular diseases or renal dysfunctions were studied in patients with T2DM only (see above explanation regarding Zelniker et al., Uneda et al., and Lee et al. and the state of the prior art for further information), 2) cardiovascular diseases and renal dysfunctions are not known to be broadly treated by efpeglenatide as they are varied (see above explanation regarding Cardio-HART by Cardio-Phoenix and Health Central and the state of the prior art for further information), and 3) the instant application fails to demonstrate prevention of all cardiovascular diseases or renal dysfunctions with efpeglenatide in a patient with any disease profile (the predictability or unpredictability of the art).
(6) The amount of direction or guidance presented, (7) the presence or absence of working examples, and (8) the quantity of the experimentation
The specification shows how efpeglenatide reduced the risk of developing MACE, coronary revascularization, or hospitalization for unstable angina (Fig. 1-2) and a composite kidney outcome (Fig. 3; Specification, ¶ 0107, composite kidney outcome “defined as macroalbuminuria; a decrease in eGFR of 40 % or more for 30 days or more; renal replacement therapy for 90 days or more; or eGFR of less than 15 ml/min/1.73 m2 for 30 days or more”) in patients with T2DM. Prior art provides support for reducing the risk of developing myocardial infarction and stroke with a GLP1-RA in patients with T2DM.
Both the instant application and the prior are focus on outcomes related to cardiovascular and renal diseases rather than specific diseases.
The specification does not provide any additional examples or guidance on how to 1) use efpeglenatide to prevent any other cardiovascular or renal outcome outside of those described above nor 2) use efpeglenatide in patients without T2DM as recited in the claim (the amount of direction or guidance presented and the presence or absence of working examples). The instant application is not enabled for preventing all cardiovascular diseases and all renal dysfunctions with efpeglenatide in a patient with any disease profile.
The amount of experimentation would not be reasonable because it would require determining how to use efpeglenatide to prevent various cardiovascular diseases and renal dysfunctions in patients with or without T2DM. Cardiovascular diseases and renal dysfunctions have diverse pathologies with no functional link. In addition, it is unclear if efpeglenatide is effective outside of patients with T2DM. It is not routine to determine how to prevent such a broad range of diseases with efpeglenatide in patients of unknown disease profiles.
Undue experimentation would be required to determine whether efpeglenatide would prevent cardiovascular diseases and renal dysfunctions in patients with any disease profile. (the quantity of the experimentation, see MPEP 2164.06).
(5) The breadth of the claims
The scope of claim 31 is extremely broad; it recites multiple cardiovascular diseases and renal dysfunctions and multiple patient disease profiles that require the specification of the instant application to provide support for the entire scope of the claim. The specification fails to show that a person having ordinary skill in the art could treat all recited diseases in patients having any disease profile without undue experimentation.
Zelniker et al. teach GLP1-RAs are useful for reducing the risk of developing of “myocardial infarction, stroke, and cardiovascular death [MACE]” (Pg. 2025, Fig. 1, Legend). Similarly, Uneda et al. teach GLP1-RAs are useful for preventing cardiovascular death, myocardial infarction, and stroke (Pg. 5, ¶ 5, lines 2-3, “GLP-1 RAs are superior to placebo for the prevention of MACE in T2DM patients”; Pg. 5, ¶ 6, line 6, “MACE, which comprised cardiovascular death, myocardial infarction, and stroke”). These teachings focus on reducing the risk of developing or preventing cardiovascular outcomes instead of specific cardiovascular diseases.
Zelniker et al. teach GLP1-RAs are useful for preventing the progression of kidney disease, reducing the relative risk of a kidney composite outcome; “the relative risk reduction of the kidney composite with GLP1-RA appeared to be mainly driven by a reduction in macroalbuminuria” (Pg. 2026, column 2, ¶ 2, line 7-9). Similarly, Lee et al. teach GLP1-RAs are useful “to prevent composite renal outcome” (Pg. 263, Fig. 1, last 2 lines) in people with T2DM and chronic kidney disease (Pg. 260, column 2, ¶ 2, lines 14-15). These teachings focus on reducing the risk of developing or preventing renal outcomes instead of a specific renal dysfunction or kidney disease.
It is noted that these studies are metanalyses of cardiovascular and renal studies using a variety of GLP1-RAs, including efpeglenatide, and talk about the effects of GLP1-RAs as a class. As these studies were done in patients with T2DM, It is unclear how GLP1-RAs, including efpeglenatide, would affect cardiovascular disease and renal dysfunction in patients without T2DM.
In addition, these studies focus on reducing the risk of developing or preventing renal and cardiovascular outcomes (e.g. myocardial infarction, stroke, cardiovascular death, MACE, macroalbuminuria) with GLP1-RAs instead of specific cardiovascular diseases and renal dysfunctions. Cardiovascular disease is not one single disease and it “includes a variety of heart and blood vessel conditions, such as coronary artery disease, peripheral arterial disease, heart attack, stroke, high blood pressure, heart valve disease, vascular disease, aorta disease, heart failure, cardiomyopathy, abnormal heart rhythms, congenital heart disease, and many other heart and blood vessel conditions” (Cardiovascular Disease is NOT Just a Man’s Disease, Cardio-HART by Cardio-Phoenix, 2020, Pg. 2, ¶ 1). Cardiovascular diseases could not be prevented broadly by efpeglenatide. Similarly, renal dysfunction encompasses a variety of renal diseases, including but not limited to polycystic kidney disease, kidney stones, nephrotic syndrome, and nephritis (Kidney Diseases, Health Central, 2019, Pg. 2-3, Types of Kidney Disease). Renal diseases could not be prevented broadly by efpeglenatide.
Moreover, as described above, the diseases do not share a common mechanism of action nor functional link. The specification shows how efpeglenatide reduced the risk of developing MACE, coronary revascularization, or hospitalization for unstable angina (Fig. 1-2) and a composite kidney outcome (Fig. 3; Specification, ¶ 0107, composite kidney outcome “defined as macroalbuminuria; a decrease in eGFR of 40 % or more for 30 days or more; renal replacement therapy for 90 days or more; or eGFR of less than 15 ml/min/1.73 m2 for 30 days or more”) in patients with T2DM. Prior art provides support for reducing the risk of developing myocardial infarction and stroke with a GLP1-RA in patients with T2DM.
Therefore, a method of preventing or reducing the risk of the development of the following outcomes: MACE, coronary revascularization, hospitalization for unstable angina in a patient, myocardial infarction, stroke, new macroalbuminuria, a decrease in eGFR of 40 % or more for 30 days or more, renal replacement therapy for 90 days or more, or eGFR of less than 15 ml/min/1.73 m2 for 30 days or more in a patient with T2DM comprising administering an effective amount of efpeglenatide is supported. A method of preventing or reducing the risk of the development of all cardiovascular diseases or all renal dysfunctions in a patient with any disease profile comprising administering an effective amount of efpeglenatide is not supported.
Claim 31 is not enabled because a person having ordinary skill in the art as of the effective filing date of the application would not be able to prevent all cardiovascular diseases or all renal dysfunctions in a patient with any disease profile comprising administering an effective amount of efpeglenatide with a predictability of success for the reasons outlined above. Claims 32-34, 36-37, 39, and 41-58are included in this rejection as they depend on and/or incorporate claim 31.
Claim Rejections - 35 USC § 112(b)
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.
Claim 31-34, 36-37, 39, and 41-58 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 31 recites the limitation "the risk" in line 2. There is insufficient antecedent basis for this limitation in the claim. Claims 32-34, 36-37, 39, and 41-58 are included in this rejection as they incorporate and/or depend on claim 31.
Claim 53 recites “the adverse effects associated with renal disease” in lines 1-2. There is insufficient antecedent basis for this limitation in the claim. Claim 54 ais included in this rejection as it incorporates and/or depends on claim 53.
Regarding claim 58, the phrase "optionally" (used twice in lines 3 and 7) renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
For the purposes claim interpretation only, limitations following optionally will not be considered part of the claimed invention.
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 (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 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 nonobviousness.
Claims 31-34, 36-37, 39, 41-51, 53-54, and 56-58 are rejected under 35 U.S.C. 103 as being unpatentable over Gerstein et al. (Design and baseline characteristics of the AMPLITUDE-O cardiovascular outcomes trial of efpeglenatide, a weekly glucagon-like peptide-1 receptor agonist, Diabetes Obes Metab, Epub 2020 Oct 22, 2021 Feb;23:318–32; IDS filed on 12/21/2023, Doc No. AD) in view of Zelniker et al. (Comparison of the Effects of Glucagon-Like Peptide Receptor Agonists and Sodium-Glucose Contransporter 2 Inhibitors for Prevention of Major Adverse Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus: Systematic Review and Meta-Analysis of Cardiovascular Outcomes Trials, Circulation, 2019 Feb 21, 139(17):2022-2031; IDS filed on 06/05/2025, Cite No. 4) as evidenced by LeWine (What is type 2 diabetes?, Harvard Health Publishing, 2024 May 7).
Claims 31-32
Regarding claims 31-32, Gerstein et al. teach the design of a clinical trial to assess the effect of efpeglenatide on reducing the risk of development of cardiovascular disease and renal dysfunction in a patient with type 2 diabetes mellitus (Pg. 318, Abstract, Aim, lines 1-3, “effect of weekly exendin-based glucagon-like peptide-1 receptor agonist efpeglenatide on cardiovascular [CV] outcomes in high-risk patients with type 2 diabetes [T2DM]”; Pg. 318, Abstract, Materials and methods, assessed outcomes such as major adverse CV event [MACE] in CV disease and macroalbuminuria in renal dysfunction).
While Gerstein et al. refers to type 2 diabetes by the abbreviation T2DM, the abbreviation is not defined. However, type 2 diabetes and type 2 diabetes mellitus are interchangeable, referring to the same disease (LeWine, Pg. 1, ¶ 1, “Type 2 diabetes is also called type 2 diabetes mellitus”). T2DM refers to type 2 diabetes mellitus as evidenced by LeWine.
Gerstein et al. do not teach the results of the clinical trial.
Zelniker et al. teach a meta-analysis of glucagon-like peptide 1 receptor agonists (GLP1-RA) treatments, reporting that GLP1-RAs as a class reduce the risk of MACE in CV disease and macroalbuminuria in kidney disease when treating patients with T2DM (Pg. 2022, Title, ”Effects of Glucagon-Like Peptide Receptor Agonists… for Prevention of Major Adverse Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus”; Pg. 2022, Results, GLP1-RA class reduces the risk of MACE in CV disease and macroalbuminuria in kidney disease in patients with T2DM).
Zelniker et al. do not teach the specific GLP1-RA efpeglenatide.
Efpeglenatide and, based on the knowledge of the GLP1-RA class, its use in reducing the risk of development of cardiovascular disease and renal dysfunction in a patient with T2DM were known and used prior to the effective filing date of the application. In addition, both Gerstein et al. and Zelniker et al. are analogous arts (i.e. treatment of patients with T2DM by administering a GLP1-RA). Since Zelniker et al. teach GLP1-RAs as a class reduce the risk of development of cardiovascular and kidney disease when treating patients with T2DM, there is motivation for using the specific GLP1-RA efpeglenatide for the same purpose.
MPEP § 2141(III)(G) states a rationale that may support a conclusion of obviousness includes “[s]ome teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.” MPEP § 2143(I)(G) states this rationale should explain why “[a] person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and whether there would have been a reasonable expectation of success in doing so." DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641, 1645 (Fed. Cir. 2006).
The teaching, suggestion, or motivation in the prior art (i.e. GLP1-RAs as a class reduce the risk of development of cardiovascular and kidney disease when treating patients with T2DM as taught in Zelniker et al.) would have led one of ordinary skill to modify the prior art reference (i.e. determine that a clinical trial design to assess the effect of efpeglenatide on reducing the risk of development of cardiovascular disease and renal dysfunction in a patient with T2DM as taught in Gerstein et al. would produce positive results) to arrive at the claimed invention.
There is a reasonable expectation of success as efpeglenatide is a type of GLP1-RA; the class GPL1-RA was known and used prior to the effective filing date of the application in reducing the risk of development of cardiovascular and kidney disease when treating patients with T2DM. In addition, both Gerstein et al. and Zelniker et al. are in analogous arts (i.e. treatment of patients with T2DM by administering a GLP1-RA).
It would have been obvious to a person having ordinary skill in the art prior to the effective filing date of the instant application to use efpeglenatide as the specific type of GLP1-RA as taught in Gerstein et al. in a method of reducing the risk of development of cardiovascular disease and renal dysfunction in a patient with T2DM by administering a GLP1-RA as taught in Zelniker et al.
Claim 33
Regarding claim 33, Gerstein et al. further teach the patient has an HbA1c of greater than 7% (Pg. 319, Table 1, Inclusion criteria, #1)
Claims 34 and 36-37
Regarding claims 34 and 36-37, Gerstein et al. further teach the T2DM patient is age ≥18 years old with previous CV disease such as coronary artery disease, stroke, and peripheral artery disease (Pg. 319, Table 1, Inclusion criteria, #1 and #2).
Claims 39, 41-42, and 44
Regarding claims 39, 41-42, and 44, Gerstein et al. further teach the T2DM patient is age ≥50 years old for men or age ≥55 years old for women who has 1) an eGFR of 25 to 55.9 ml/min/1.73 m2 and 2) the risk factor of smoking (Pg. 319, Table 1, Inclusion criteria, #1 and #3).
Claim 43
Regarding claim 43, Gerstein et al. further teach the T2DM patient has not used a GLP1-RA or DPP-4 inhibitor in the last 3 months (Pg. 319, Table 1, Exclusion criteria, #5).
Claims 45-49
Regarding claim 45-47, Gerstein et al. further teach efpeglenatide is administered subcutaneously (Pg. 322, Table 5, last column, efpeglen = efpeglenatide and SC = subcutaneous) at 4 mg or 6 mg weekly (Pg. 318, Abstract, Materials and methods, lines 6-7, “weekly injections of efpeglenatide [4 mg or 6 mg]”). Regarding claims 48-49, efpeglenatide is alternatively administered “2 mg/week for 4 weeks, then 4 mg/week for 4 weeks, then 6 mg/week” (Pg. 319, column 2, ¶ 2, lines 4-5).
Claims 50-51
Regarding claims 50-51, Gerstein et al. further teach the CV disease is MACE, wherein MACE is defined as non-fatal myocardial infarction, non-fatal stroke or CV death (Pg. 318, Abstract, Materials and methods, lines 7-9, “primary outcome is a major adverse CV event [MACE] defined as non-fatal myocardial infarction, non-fatal stroke or CV death”).
Claims 53-54
Regarding claims 53-54, Gerstein et al. further teach the renal dysfunction is macroalbuminuria defined as a UACR ≥33.9 mg/mmol and UACR increased ≥30% more from baseline (Pg. 320, Table 2, Secondary outcomes, #2).
Claim 56
Regarding claim 56, Gerstein et al. further teach the CV disease comprises MACE, coronary revascularization, and hospitalization for unstable angina (Pg. 320, Table 2, Secondary outcomes, #1).
Claim 57
Regarding claim 57, Zelniker et al. further GLP1-RAs as a class, applicable to efpeglenatide as delineated in the rejection above of claims 31-32, reduce the risk of developing MACE compared to placebo (Pg. 2023, column 2, Data Search and Study Selection, line 4, all trials were randomized and placebo-controlled; Pg. 2025, column 1, ¶ 2, lines 1-3 “reduced MACE… with GLP1-RA reducing the relative risk by 12%”).
Claim 58
Regarding claim 58, Gerstein et al. further teach efpeglenatide is administered in combination with another therapeutic substance (Pg. 322, Table 4, column 1, second to last line, “Current SGLT2 inhibitor use”) .
Accordingly, claims 31-34, 36-37, 39, 41-51, 53-54, and 56-58 are rendered obvious by Gerstein et al. in view of Zelniker et al. as evidenced by LeWine.
Claims 52 and 55 are rejected under 35 U.S.C. 103 as being unpatentable over Gerstein et al. (Design and baseline characteristics of the AMPLITUDE-O cardiovascular outcomes trial of efpeglenatide, a weekly glucagon-like peptide-1 receptor agonist, Diabetes Obes Metab, Epub 2020 Oct 22, 2021 Feb;23:318–32; IDS filed on 12/21/2023, Doc No. AD) and Zelniker et al. (Comparison of the Effects of Glucagon-Like Peptide Receptor Agonists and Sodium-Glucose Contransporter 2 Inhibitors for Prevention of Major Adverse Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus: Systematic Review and Meta-Analysis of Cardiovascular Outcomes Trials, Circulation, 2019 Feb 21, 139(17):2022-2031; IDS filed on 06/05/2025, Cite No. 4) as evidenced by LeWine (What is type 2 diabetes?, Harvard Health Publishing, 2024 May 7) as applied to claim 31 above, and further in view of Del Prato et al. (Efficacy and safety of once-monthly efpeglenatide in patients with type 2 diabetes: Results of a phase 2 placebo-controlled, 16-week randomized dose-finding study, Diabetes Obes Metab, 2020 Jul;22[7]:1176-1186).
Claims 52 and 55
As described in the previous 103 rejection, regarding claim 31, Gerstein et al. teach the design of a clinical trial to assess the effect of efpeglenatide on reducing the risk of development of cardiovascular disease and renal dysfunction in a patient with T2DM (T2DM refers to type 2 diabetes mellitus as evidenced by LeWine). Zelniker et al. teach a meta-analysis of glucagon-like peptide 1 receptor agonists (GLP1-RA) treatments, reporting that GLP1-RAs as a class reduce the risk of MACE in CV disease and macroalbuminuria in kidney disease when treating patients with T2DM.
Regarding claims 52 and 55, Zelniker et al. further teach GLP1-RAs as a class, applicable to efpeglenatide, reduce the risk of developing MACE by 12% and a composite kidney outcome by 18% compared to placebo (Pg. 2023, column 2, Data Search and Study Selection, line 4, all trials were randomized and placebo-controlled; Pg. 2025, column 1, ¶ 2, lines 1-3 “reduced MACE… with GLP1-RA reducing the relative risk by 12%”; Pg. 2026, column 2, ¶ 2, lines 2-4, “GLP1-RA reduced the relative risk of the broad composite kidney outcome significantly by 18%”).
Neither Gerstein et al. nor Zelniker et al. teach that the specific GLP1-RA efpeglenatide reduces the risk of developing MACE by ≥20% (claim 52) and a composite kidney outcome by ≥30% compared to placebo (claim 55).
Del Prato et al. teach a dose titration of efpeglenatide “[t]o determine the optimal dose(s) of once‐monthly administration of efpeglenatide… in patients with type 2 diabetes (T2D)” (Pg. 1176, Abstract, Aims , lines 1-3; Pg. 1176, Abstract, Materials and Methods, lines 3-4, “16‐week treatment period included a 4‐week titration phase with once‐weekly efpeglenatide 4 mg”). Del Prato et al. further teach “once-monthly efpeglenatide showed significant improvements in glycaemic control” (Pg. 177, column 1, last ¶, lines 6-7). These teachings indicate the dose of efpeglenatide can be titrated to improve a desired outcome.
Del Prato et al. does not teach a method of reducing the risk of development of cardiovascular disease and renal dysfunction in a patient with T2DM comprising administering efpeglenatide.
The use of efpeglenatide in (i) reducing the risk of development of MACE (claim 52) and a composite kidney outcome (claim 55) in a patient with T2DM and (ii) a titration to improve a desired outcome were known and used prior to the effective filing date of the application. In addition, Gerstein et al., Zelniker et al., and Del Prato et al. are analogous arts (i.e. treatment of patients with T2DM by administering a GLP1-RA). Since (i) Zelniker et al. teach GLP1-RAs as a class reduce the risk of development of cardiovascular and kidney disease when treating patients with T2DM, specifically MACE (claim 52) and a composite kidney outcome (claim 55) and (ii) Del Prato et al. teach efpeglenatide can be titrated to improve a desired outcome (indicating the dose of efpeglenatide can adjusted until the desired percent reduction in MACE and a composite kidney outcome risk is reached; claims 52 and 55), there is motivation for using the specific GLP1-RA efpeglenatide for reducing the risk of MACE by ≥20% (claim 52) and a composite kidney outcome by ≥30% compared to placebo (claim 55).
MPEP § 2141(III)(G) states a rationale that may support a conclusion of obviousness includes “[s]ome teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.” MPEP § 2143(I)(G) states this rationale should explain why “[a] person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and whether there would have been a reasonable expectation of success in doing so." DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641, 1645 (Fed. Cir. 2006).
The teaching, suggestion, or motivation in the prior art (i.e. [i] Zelniker et al. teach GLP1-RAs as a class reduce the risk of development of cardiovascular and kidney disease when treating patients with T2DM, specifically MACE [claim 52] and a composite kidney outcome [claim 55] and [ii] Del Prato et al. teach efpeglenatide can be titrated to improve a desired outcome, indicating the dose of efpeglenatide can adjusted until the desired percent reduction in MACE and a composite kidney outcome risk is reached [claims 52 and 55]) would have led one of ordinary skill to modify the prior art reference (i.e. determine that a clinical trial design to assess the effect of efpeglenatide on reducing the risk of development of cardiovascular disease and renal dysfunction in a patient with T2DM as taught in Gerstein et al. would reduce the risk of MACE and a composite kidney outcome as taught in Zelniker et al., with the exact percent reductions reached via a dose titration of efpeglenatide as taught in Del Prato et al.) to arrive at the claimed invention.
There is a reasonable expectation of success as efpeglenatide is a type of GLP1-RA; the class GPL1-RA was known and used prior to the effective filing date of the application in reducing the risk of development of cardiovascular and kidney disease when treating patients with T2DM, specifically regarding MACE and a composite kidney outcome. Furthermore, a dose titration of efpeglenatide can be performed to reach a desired outcome, in the instant case reducing the risk of MACE by ≥20% (claim 52) and a composite kidney outcome by ≥30% compared to placebo (claim 55). In addition, Gerstein et al., Zelniker et al., and Del Prato et al. are in analogous arts (i.e. treatment of patients with T2DM by administering a GLP1-RA).
It would have been obvious to a person having ordinary skill in the art prior to the effective filing date of the instant application to use efpeglenatide as the specific type of GLP1-RA as taught in Gerstein et al. in a method of reducing the risk of development of cardiovascular disease and renal dysfunction in a patient with T2DM (specifically reducing the risk of MACE and a composite kidney outcome) by administering a GLP1-RA as taught in Zelniker et al. wherein reducing the risk of MACE by ≥20% (claim 52) and a composite kidney outcome by ≥30% compared to placebo (claim 55) are reached via a dose titration of efpeglenatide as taught in Del Prato et al.
Accordingly, claims 52 and 55 are rendered obvious by Gerstein et al. in view of Zelniker et al. and Del Prato et al. as evidenced by LeWine.
Conclusion
Claims 31-34, 36-37, 39, and 41-58 are pending. Claims 31-34, 36-37, 39, and 41-58 are rejected. No claims are allowed.
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/J.M.P./Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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