Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The present application claimed priority to the application, CN202410181131.8, with the effective filing date of 18 February 2024.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d)
prior to declaration of an interference, a certified English translation of the foreign application must
be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e). Failure to provide a certified
translation may result in no benefit being accorded for the non-English application.
Claim Status
This Office Action is in response to Applicant’s Amendment, filed 18 September 2024.
Claims 1-6 are pending.
Claim Interpretation
For purposes of clarity, the Examiner interprets a medically acceptable auxiliary material to be a non-active pharmaceutical ingredient (such as a pharmaceutically acceptable salt, excipient, or diluent) or adjuvant.
Additionally, for clarity, the Examiner notes that in all review articles encountered by the Examiner that calcific heart valve disease is referenced as calcific aortic valve disease (CAVD): Driscoll (Circ. Res.¸2021, 128, 1344-1370; abstract), Hwang (Cells, 2026, 15(542), 1-22; abstract), and Yutzey (Anterioscler. Thromb. Vasc. Biol.¸2014, 34, 2387-2393; abstract). Further, the Examiner notes that calcific aortic valve disease is a slowly progressive disorder with a disease continuum that ranges from mild valve thickening without obstruction of blood flow (aortic sclerosis) to severe calcification (aortic stenosis) as evidenced by Freeman (page 1, column 1, paragraph 1; Circulation, 2005, 111, 3316-3326). The Examiner notes that manidipine should be used with caution for patients with severe aortic stenosis as evidenced by Synapse (page 3, paragraph 1; “What is Manidipine Hydrochloride used for?” Synapse by patsnap¸ 14 June 2024, < synapse.patsnap.com/article/what-is-manidipine-hydrochloride-used-for>, accessed 23 July 2026). However, the Examiner notes that calcium channel blockers have been evaluated to be safe for use in severe acute stenosis, because the incidence of syncope or presyncope was extremely low in patients with severe aortic stenosis and hypertension receiving a calcium channel blocker as evidenced by Yamamoto (page 1534, column 2, paragraph 1; Circulation Journal, 2025, 89, 1528-1537).
Claim Suggestion
For purposes of clarity, the Examiner respectfully suggests that claim 3 be amended to recite “the method according to claim 2, wherein the manidipine is the only active ingredient of the product.”
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
1. Claim 2 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 1 recites a product containing manidipine, and claim 2 specifies that the product is a drug. Because manidipine is a third generation dihydropyridine calcium channel blocker and itself is a drug, manidipine is only present in drugs/pharmaceuticals as evidenced by Saiz Satjes (page 5, column 1, paragraph 3; Drugs in Context¸2017, 7(212509), 1-17). Thus, claim 2 does not further limit claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
2. Claim(s) 1-6 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Synapse (“What is Manidipine Hydrochloride used for?” Synapse by patsnap¸ 14 June 2024, < synapse.patsnap.com/article/what-is-manidipine-hydrochloride-used-for>, accessed 23 July 2026) as evidenced by Freeman (Circulation, 2005, 111, 3316-3326), Yamamoto (Circulation Journal, 2025, 89, 1528-1537), and Bastin (ORPD¸2000, 4, 427-435).
The reference, Synapse, is intervening art. Applicant cannot rely upon the certified copy of the foreign priority application to overcome this rejection 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.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d)
prior to declaration of an interference, a certified English translation of the foreign application must
be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e). Failure to provide a certified
translation may result in no benefit being accorded for the non-English application.
Accordingly, priority has not been perfected and claims 1-6 are denied the benefit of the 18 February 2024 effective filing date. Instead, claims 1-6 have the benefit of the 18 September 2024 effective filing date.
Synapse teaches that manidipine should be used with caution in patients with severe aortic stenosis (page 3, paragraph 1), which is a calcific aortic valve disease as evidenced by Freeman (page 1, column 1, paragraph 1). Additionally, calcium channel blockers have been evaluated to be safe for use in severe acute stenosis, because the incidence of syncope or presyncope was extremely low in patients with severe aortic stenosis and hypertension receiving a calcium channel blocker as evidenced by Yamamoto (page 1534, column 2, paragraph 1). Accordingly, Synapse teaches a method of treating a calcific aortic valve disease by manidipine hydrochloride (page 3, paragraph 1).
Regarding claim 1, Synapse teaches a method of treating a calcific aortic valve disease by manidipine hydrochloride (page 3, paragraph 1).
Regarding claim 2, Synapse teaches that manidipine hydrochloride is a medication/drug (page 1, paragraph 1; page 3, paragraph 1).
Regarding claim 3, Synapse teaches a method of treating a calcific aortic valve disease by manidipine hydrochloride, wherein manidipine is the sole active ingredient (page 3, paragraph 1), and hydrochloride is a pharmaceutically acceptable salt as evidenced by Bastin (Table 1, page 428).
Regarding claim 4, Synapse teaches a method of treating a calcific aortic valve disease by manidipine hydrochloride (page 1, paragraph 1; page 3, paragraph 1), and hydrochloride is a pharmaceutically acceptable salt as evidenced by Bastin (abstract; Table 1, page 428).
Regarding claim 5, Synapse teaches a method of treating a calcific aortic valve disease by manidipine hydrochloride as a tablet (page 1, paragraph 1; page 2, paragraph 2; page 3, paragraph 1).
Regarding claim 6, Synapse teaches a method of treating a calcific aortic valve disease by manidipine hydrochloride as a tablet (page 1, paragraph 1; page 2, paragraph 2; page 3, paragraph 1), and hydrochloride is a pharmaceutically acceptable salt as evidenced by Bastin (abstract; Table 1, page 428).
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.
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.
3. Claim(s) 1-3 are rejected under 35 U.S.C. 103 as being unpatentable over Toba (Hyperten. Res.¸2006, 29(2)¸105-116) in view of Driscoll (Circ. Res.¸2021, 128, 1344-1370).
Toba teaches the vasoprotective effects of manidipine (abstract). Toba teaches that rennin-angiotensin system plays a large role in the pathogenesis of numerous cardiovascular diseases, including hypertension, hypercholesterolemia, and diabetes (page 105, column 1, paragraph 1; page 105, column 2, paragraph 1). Toba teaches that angiotensin II (Ang II) is the principle effector of the renin-angiotensin system and is known to a potent vasoconstrictor by itself (page 106, column 1, paragraph 1). Toba teaches that one of the important effects of Ang II is to promote oxidative stress by the enhancement of reactive oxygen species (ROS) such as superoxide through activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, a major source of the production of ROS in vascular cells (page 106, column 1, paragraph 1). Toba teaches that calcium channel blockers ameliorate endothelial dysfunction, decrease proliferation of vascular smooth muscle cells, oxidative stress, and inflammation (page 106, column 1, paragraph 3). Toba also teaches that calcium channel blockers have been shown to limit the progression of atherosclerosis and decrease the incidence of cardiovascular events and investigates the vasoprotective effects beyond the blood pressure-lowering effects of these agents with manidipine (abstract; page 110, column 1, paragraph 3). Toba teaches that manidipine attenuated the increased production of superoxide and the overexpression of NADPH oxidase as well as prevented the Ang II-induced increase in lectin-like oxidized low-density lipoprotein receptor -1 content, thereby restoring control levels (abstract; page 112, column 1, paragraph 2; page 115, column 1, paragraph 1). Toba suggests that the antioxidative and anti-inflammatory effects of calcium channel blockers is due to the inhibition of LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1; a receptor for OxLDL; page 106, column 1, paragraph 2; page 114, column 2, paragraph 2).
Regarding claim 1, Toba fails to teach treating calcific aortic valve disease.
Driscoll teaches calcific aortic valve disease (CAVD) is a complex, multifaceted disease involving widespread inflammation (page 1344, column 1, paragraph 1). Driscoll teaches that CAVD is not merely a pathological occurrence of degradation but a mechanobiological manifestation controlled by key cellular regulators of osteogenesis and inflammatory factors (page 1345, column 2, paragraph 2). Driscoll teaches that CAVD has a high global prevalence, that there are no current therapeutic treatments for CAVD, and that patients seeking treatment must get surgical valve replacement (page 1345, column 2, paragraph 3). Driscoll teaches that cost-effective and accessible alternatives to current treatments for aortic valve disease must be developed to meet the ever-increasing demands of growing population and demographic discrepancies (page 1345, column 2, paragraph 5). Driscoll teaches that CAVD is thought to start with early endothelial inflammation and dysfunction (page 1352, column 2, paragraph 4). Driscoll teaches that endothelial dysfunction allows for extravasation of inflammatory cells into the valve tissue and deposition of proinflammatory molecules and lipid deposition (page 1352, column 2, paragraph 4). Driscoll also teaches that diseased valves and in vitro models, vascular endothelium upregulates Lox1, which is involved in endocytosis of OxLDL (page 1356, column 2, paragraph 2).
It would have been obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention to modify the method of Toba with the methods of Driscoll to arrive at a method of treating calcific aortic valve disease via administering manidipine. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-Toba teaches the vasoprotective effects of manidipine,
-Toba teaches that rennin-angiotensin system plays a large role in the pathogenesis of numerous cardiovascular diseases, including hypertension, hypercholesterolemia, and diabetes,
-Toba teaches that angiotensin II (Ang II) is the principle effector of the renin-angiotensin system and is known to a potent vasoconstrictor by itself,
-Toba teaches that one of the important effects of Ang II is to promote oxidative stress by the enhancement of reactive oxygen species (ROS) such as superoxide through activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, a major source of the production of ROS in vascular cells,
-Toba teaches that calcium channel blockers ameliorate endothelial dysfunction, decrease proliferation of vascular smooth muscle cells, oxidative stress, and inflammation,
-Toba also teaches that calcium channel blockers have been shown to limit the progression of atherosclerosis and decrease the incidence of cardiovascular events and investigates the vasoprotective effects beyond the blood pressure-lowering effects of these agents with manidipine,
-Toba teaches that manidipine attenuated the increased production of superoxide and the overexpression of NADPH oxidase as well as prevented the Ang II-induced increase in lectin-like oxidized low-density lipoprotein receptor -1 content, thereby restoring control levels,
-Toba suggests that the antioxidative and anti-inflammatory effects of calcium channel blockers is due to the inhibition of LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1; a receptor for OxLDL),
-Driscoll teaches calcific aortic valve disease (CAVD) is a complex, multifaceted disease involving widespread inflammation,
-Driscoll teaches that CAVD is not merely a pathological occurrence of degradation but a mechanobiological manifestation controlled by key cellular regulators of osteogenesis and inflammatory factors,
-Driscoll teaches that CAVD has a high global prevalence, that there are no current therapeutic treatments for CAVD, and that patients seeking treatment must get surgical valve replacement,
-Driscoll teaches that cost-effective and accessible alternatives to current treatments for aortic valve disease must be developed to meet the ever-increasing demands of growing population and demographic discrepancies,
-Driscoll teaches that CAVD is thought to start with early endothelial inflammation and dysfunction,
-Driscoll teaches that endothelial dysfunction allows for extravasation of inflammatory cells into the valve tissue and deposition of proinflammatory molecules and lipid deposition, and
-Driscoll also teaches that diseased valves and in vitro models, vascular endothelium upregulates Lox1, which is involved in endocytosis of OxLDL.
Thus, an artisan having ordinary skill in the art would have been motivated to make such a selection to predictably arrive at a method of treating calcific aortic valve disease via manidipine.
Regarding claim 2, Toba teaches that manidipine is a calcium channel blocker, which is a drug, and has vasoprotective effects (abstract; page 106, column 2, paragraphs 2 and 4).
Regarding claim 3, Toba teaches administration of manidipine alone (10^-6 mol/L) for 60 minutes (page 106, column 2, paragraph 4).
4. Claim(s) 1-6 are rejected under 35 U.S.C. 103 as being unpatentable over Toba (Hyperten. Res.¸2006, 29(2)¸105-116) in view of Driscoll (Circ. Res.¸2021, 128, 1344-1370) as applied to claim 1-3 above, and further in view of Zheng (CN 103,120,651, published 5 Nov 2014).
Toba (Hyperten. Res.¸2006, 29(2)¸105-116) in view of Driscoll (Circ. Res.¸2021, 128, 1344-1370) are applies as discussed in the 35 U.S.C. 103 rejection above.
Regarding claim 4, while the combination of Toba and Driscoll teaches a method of treating calcific aortic valve disease via administering manidipine, the combination of Toba and Driscoll fails to teach that the drug further comprises a medically acceptable auxiliary material.
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the method of treating of Toba and Driscoll with the compositions/formulations taught by Zheng to arrive at the instantly claimed invention.
One of ordinary skill in the art would have been motivated to modify the composition of manidipine to include a medically acceptable auxiliary material, because Zheng teaches pharmaceutical compositions of a manidipine tablet with auxiliary materials for hypertension (abstract; page 2, paragraph 2; page 3, paragraphs 3-4). Zheng teaches that hypertension is a cardiovascular and cerebrovascular disease of serious threat to people’s health that easily causes damage to the heart, brain, and kidneys (page 2, paragraph 2). Zheng teaches that there are several generations of calcium channel blockers with each building upon the previous generation for slow, controlled release with good pharmacokinetic performance that does not cause blood pressure to decline suddenly in the heart (third generation; page 2, paragraph 3). Zheng teaches that manidipine was developed as a tablet but that previous manidipine formulations suffered from α-crystal formation in situ (page 2, paragraph 4; page 3, paragraph 3; page 4, paragraph 29). Zheng teaches that their manidipine formulation avoids crystal formation of the crude drug (α-crystal formation) and thus has guaranteed effectiveness and safety in clinical practice (page 4, paragraph 29). Thus, one of ordinary skill in the art would have selected the formulation of Zheng with the method of treating calcific aortic valve disease via manidipine, and the results would be predictable.
Regarding claim 5, Zheng teaches a tablet (abstract; page 3, paragraph 4). Additionally, Toba teaches administration of manidipine as a solution (page 106, column 2, paragraph 4).
Regarding claim 6, Zheng teaches a tablet (abstract; page 3, paragraph 4). Additionally, Toba teaches administration of manidipine as a solution (page 106, column 2, paragraph 4).
Conclusion
No claim is allowed.
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/MADELINE M. DEKARSKE/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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