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 .
Priority
This application is a national stage entry of PCT/KR2021/011353 filed on 08/25/2021. Acknowledgment is made of applicant's claim for foreign priority based on an application filed in REPUBLIC OF KOREA (10-2020-0107083) on 08/25/2020. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Response to Amendment
Applicant’s amendment filed on November 11, 2025 amending claims 1, 20-23 and cancelling claims 2-11 has been entered. Claims 1 and 12-25 are currently pending and presented for examination.
Response to Arguments
Due to Applicant’s amendments to the claims, the previous rejection of claims 20-23 under 35 U.S.C. 112(b) is hereby withdrawn.
Due to Applicant’s amendments to the claims, specifically requiring a single-layer tablet dosage form, the previous double patenting rejection is hereby withdrawn. Applicant’s arguments with respect to said rejection have been fully considered but are moot in view of the withdrawal of the rejection.
Applicant's arguments filed November 11, 2025 with regard to the remaining rejection under 35 USC 103 have been fully considered but they are not persuasive.
Applicant argues that Wang exemplifies a fixed-dosage, triple combination formulation containing amlodipine besylate, olmesartan medoxomil, and pitavastatin calcium dispersible tablets in Example 3. Applicant argues notwithstanding the Examiner's assertion that substituting rosuvastatin for pitavastatin would have been obvious to a person of ordinary skill in the art, Applicant submits that Wang's disclosure does not provide any data or experimental results with respect to individual drug dissolution rates or bioavailability. Applicant argues that Wang merely provides a list of nine possible fixed-dose, triple combination formulations without any indication as to whether these formulations exhibit uniform dissolution rates across all three ingredients and ensure bioequivalence. In fact, Wang is completely devoid of any bioequivalence testing or similar evaluation data to provide adequate insight into the pharmacokinetic behavior of the exemplified triple combination formulations, as only the preparation of these formulations is described with no analysis thereof.
Applicants further argues that Wang's Example 3 triple combination formulation of amlodipine besylate, olmesartan medoxomil, and pitavastatin calcium is further distinguishable from the formulation of the present claims because a microencapsulated, rather than a granule, form of the pitavastatin calcium statin component is used and thus, because Wang incorporates a statin (pitavastatin) microcapsule, the additive composition of Wang's Example 3 tablet formulation is entirely different from that of the present claims which instead incorporates a (rosuvastatin) granulate.
These arguments are found not persuasive because in addition to Example 3, Wang also teaches Example 1. Wang specifically teaches preparing single layer tablets utilizing granulations to prepare granules of the active agents (page 15 Example 1). Wang specifically teaches the preparation of statin granules using excipients and disintegrants to form the granules and combining these granules with granules of the other two active ingredients (page 15 Example 1). Wang further teaches milling the mixture to make a fine powder, adding magnesium stearate and sodium carboxymethyl starch to the milled powder mixture and mixing in a mixing device such as a V-type mixer, a trough-type mixer or a three-way motion mixer; and then using the tableting equipment to compress the last mixed granules into tablets to make 1000 tablets (page 16 Example 1).
In addition, Applicant’s arguments are found not persuasive because prior art is presumed to be operable/enabling when the reference relied on expressly anticipates or makes obvious all of the elements of the claimed invention. Once such a reference is found, the burden is on applicant to provide facts rebutting the presumption of operability. In re Sasse, 629 F.2d 675, 207 USPQ 107 (CCPA 1980). See also MPEP § 716.07. Furthermore, efficacy is not a requirement for prior art enablement. “Even if a reference discloses an inoperative device, it is prior art for all that it teaches.” Beckman Instruments v. LKB Produkter AB, 892 F.2d 1547, 1551, 13 USPQ2d 1301, 1304 (Fed. Cir. 1989). Therefore, “a non-enabling reference may qualify as prior art for the purpose of determining obviousness under 35 U.S.C. 103.” Symbol Techs. Inc. v. Opticon Inc., 935 F.2d 1569, 1578, 19 USPQ2d 1241, 1247 (Fed. Cir. 1991). See also MPEP § 2121.01.
Furthermore, these arguments are found not persuasive since “prior art printed publication cited by an examiner is presumptively enabling barring any showing to the contrary by a patent applicant.” In reMorsa, 713 F.3d 104, 109 (Fed. Cir. 2013). The prior art is enabling if “a person of ordinary skill in the art could make or use the claimed invention without undue experimentation based on the disclosure of that particular document.” Id. at 110. Here, Applicant provides no specific evidence or persuasive reasoning as to why undue experimentation would have been required for an ordinary artisan to follow the disclosure of Wang and prepare a composition comprising Olmesartan medoxomil, amlodipine, rosuvastatin, and suitable disintegrants and excipients. Simply stating that Wang’s specification does not exemplify this embodiment is not sufficient because working “examples are not required to satisfy section 112, first paragraph.” In re Strahilevitz, 668 F.2d 1229, 1232 (CCPA 1982). Furthermore, Wang specifically provides a working example preparing granulates (Example 1 pages 15-16). All Applicant presents is attorney argument, but “attorney argument [is] not the kind of factual evidence that is required to rebut a prima facie case of obviousness.” In re Geisler, 116 F.3d 1465, 1470 (Fed. Cir. 1997).
Applicant’s argument with respect to the Oh reference is found not persuasive, since the primary reference with all of the pertinent teachings is Wang et al. and the teachings of Oh were merely provided to support the selection of the combination of amlodipine, olmesartan and rosuvastatin which is suggested by the teachings of Wang but not specifically exemplified.
Based on the teachings of Oh et al. which specifically teaches that rosuvastatin is widely used to treat hyperlipidemia and compared to other hyperlipidemic agents, rosuvastatin, in particular, has a high affinity for HMG-CoA reductase and a high inhibitory effect, which effectively reduces LDL cholesterol and increases HDL cholesterol and specifically teaches the combination of amlodipine, olmesartan and rosuvastatin, it would have been obvious to a person of ordinary skill in the art to form the claimed combination from the teachings of Wang which teaches a combination of amlodipine; an Angiotension II receptor antagonist such as olmesartan medoxomil; and a statin such as rosuvastatin, or a pharmaceutically acceptable salt thereof. Thus an ordinary skilled artisan would have been highly motivated to combine rosuvastatin with amlodipine besylate, and olmesartan medoxomil, to arrive at the instant invention, with a reasonable expectation of predictable and successful results.
Applicants further argues that none of Kim, Zupancic, and Lee (merely relied on by the Examiner for teaching the particle size of respective olmesartan medoxomil, amlodipine, and rosuvastatin components) teaches a single-layer tablet dosage formulation for treating hypertension and hyperlipidemia which corresponds to the presently claimed pharmaceutical composition. Thus Applicant argues that the combination of Wang in view of Oh, Kim, Zupancic, and Lee would not establish a prima facie case of obviousness with respect to the dependent claims, as this combination fails to teach a monolayer tablet formulation including the precise combination of disintegrant and excipient additives of the presently claimed pharmaceutical composition.
Applicant further argues that the technical benefits of stability, uniform drug dissolution rate, retention of bioequivalence, reduced manufacturing costs, and improved production efficiency of the presently claimed single-layer table dosage formulation would not have been expected. Finally, the claimed specific amounts of disintegrants would not have been obvious to a person of ordinary skill in the art, nor a matter of mere routine optimization or experimentation, as the highly optimized interactions among each disintegrant and additive component contribute to the synergistic nature and efficacy of the presently claimed pharmaceutical composition.
These arguments are found not persuasive since Applicant has not provided any evidence of unexpected or surprising results. Applicant has not provided any data demonstrating criticality for any particular component or any particular amount. As detailed above, a prima facie case of obviousness has been established because Wang specifically teaches preparing a single layer dosage form comprising the formation of granulates of the active ingredients along with suitable excipients and disintegrants. With respect to the specific components as claimed, these are newly added limitations which will be addressed in the modified rejection detailed below. Applicant has not provided any comparison data with the closest related prior art which is determined to be Wang et al.
It is Applicant’s burden to demonstrate unexpected results over the prior art. See MPEP 716.02, also 716.02 (a) - (g). Furthermore, the unexpected results should be demonstrated with evidence that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance. Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992). Arguments presented by applicant cannot take the place of evidence in the record. See In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984); In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) ("An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness."). Examples of attorney statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the applicant.
Thus, Applicant’s arguments are found not persuasive and therefore, the previous rejection under 35 USC 103 is hereby maintained, however the rejection has been modified in view of Applicant’s amendments to the claims.
This action is FINAL.
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.
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.
Claims 1 and 12-25 are rejected under 35 U.S.C. 103 as being unpatentable over Wang CN-101637609 A (Machine English Translation provided) in view of Oh et al. (Drug Design, Development and Therapy, published online April 3, 2019, Vol. 13, pages 991-997 Provided on IDS); Kim WO 2017/003186 A1; Zupancic WO 2010026255 A1; and Lee et al. KR-100795313 B1 (Machine English translation provided).
The cited claims of the instant application claim a pharmaceutical composition in a single-layer tablet dosage form, comprising: a mixture of granulates comprising olmesartan medoxomil; and amlodipine or a salt thereof; and granulates comprising rosuvastatin or a salt thereof, wherein the granulates comprising olmesartan medoxomil and amlodipine or a salt thereof comprise silicified microcrystalline cellulose as an excipient and pre-gelatinized starch and sodium croscarmellose as disintegrants, wherein the granulates comprising rosuvastatin or a salt thereof comprise lactose hydrate and silicified microcrystalline cellulose as excipients, sodium croscarmellose and crospovidone as disintegrants, and dibasic calcium phosphate hydrate, and wherein the pharmaceutical composition comprises, with regard to 100 total parts by weight of the pharmaceutical composition, 4 to 40 parts by weight of pre-gelatinized starch, 2 to 30 parts by weight of sodium croscarmellose and crospovidone, and 3 to 20 parts by weight of dibasic calcium phosphate hydrate.
Wang teaches a novel pharmaceutical composition comprising (1) either of: (a) L-Amlodipine or a pharmaceutically acceptable salt thereof, or (b) Amlodipine or a pharmaceutically acceptable salt thereof; (2) an angiotensin II receptor antagonist or a pharmaceutically acceptable salt or ester thereof; (3) a statin or a pharmaceutically acceptable salt thereof; and (4) a pharmaceutically acceptable carrier (abstract and page 1). Wang teaches that the composition is a fixed-dose pharmaceutical composition (page 3). Wang teaches that the preparation with a fixed dose is very convenient for patients to use, 1 to 2 times a day, preferably only once a day, which can effectively prevent the drastic change of blood pressure, keep the blood pressure in a more balanced state, and improve at the same time, which improves the patient's compliance with medication and improves the patient's quality of life (page 4).
Wang teaches that the pharmaceutical composition is used to treat various primary hypertension and secondary hypertension with or without various types of familial or nonfamilial hyperlipidemia, angina pectoris, atherosclerosis, and prevent or treat diabetes, diabetes complications, stroke, myocardial infarction, cardiac insufficiency, renal impairment, ventricular hypertrophy, aneurysm, myocardial ischemia, and glaucoma (pages 6 and 8). Wang teaches that several active ingredients have a synergistic effect on blood pressure and lipid reduction and the obvious effects of lowering blood pressure and lipid, significantly reducing the morbidity and/or mortality of cardiovascular and cerebrovascular diseases related to hypertension, improving patient medication compliance, reducing adverse drug reactions caused by excessive use of a single drug, prolong patient's life and other advantages (pages 6 and 8). Wang further teaches for patients with hypertension, whether with or without increased blood lipids (total cholesterol), antihypertensive treatment with amlodipine or a pharmaceutically acceptable salt thereof in combination with an angiotensin II receptor antagonist or a pharmaceutically acceptable salt or ester thereof, at the same time, the use of statins is beneficial; all patients with hypertension diagnosed with cardiovascular disease or type 2 diabetes should consider statin treatment so that total cholesterol (TC) is less than 4.5 mmol / L and LDL-C is less than 2.5mmol / L, lower if possible (page 10).
Wang teaches that the amlodipine is selected from the group consisting of amlodipine besylate, amlodipine L-aspartate, amlodipine mesylate, amlodipine maleate, amlodipine d-camphorsulfonate, and nicotinic acid (page 7). Wang teaches the angiotensin II receptor antagonist is selected from the group consisting of: telmisartan, losartan, valsartan, olmesartan, irbesartan, candesartan, ipsartan, tasosartan , Irbesartan, elisartan, abisartan, elisartan, embusartan, flassartan, mifasartan, permisartan, prasartan, lipsartan, sapri Lisartan, zorasartan, or a pharmaceutically acceptable salt or ester thereof (page 7). Wang further teaches that the statin is selected from the group consisting of atorvastatin, simvastatin, pitavastatin, pravastatin, rosuvastatin, fluvastatin, lovastatin, rosuvastatin, levavastatin, clovastatin, davastatin, glenvastatin, mevastatin, telvastatin, nivastatin, or a pharmaceutically acceptable salt thereof (page 7).
Wang teaches that one most preferred amlodipine is amlodipine besylate, and the angiotensin II receptor antagonists are most preferably telmisartan, losartan, valsartan, olmesartan, or a pharmaceutically acceptable salt or ester thereof (page 7). Wang teaches that the effective amount of amlodipine besylate is 2.5 mg to 20 mg, more preferably 2.5 mg to 10 mg (pages 8 and 12). Wang teaches that the effective amount of olmesartan medoxomil is 2.5 mg to 160 mg, and more preferably 5 mg to 40 mg (pages 8 and 12).
Wang teaches a preferred example, the dosage form of the pharmaceutical composition is a tablet, a capsule, a dispersible tablet, an orally disintegrating tablet, a chewable tablet, a pill, or an injection (pages 9 and 13).
Wang teaches that there are no particular restrictions on the statins that can be used in the present invention and representative examples of statins are selected from (but not limited to): atorvastatin, simvastatin, pitavastatin, pravastatin, rosuvastatin, fluvastatin, lovastatin, rosuvastatin , Atorvastatin, clavastatin, dalvastatin, glivastatin, mevastatin, telvastatin, nivastatin, or a pharmaceutically acceptable salt thereof (page 11).
Wang specifically teaches preparing single layer tablets utilizing granulations to prepare granules of the active agents (page 15 Example 1). Wang further teaches the use of disintegrants, specifically hydroxypropyl cellulose, calcium carbonate, microcrystalline cellulose, pre-crosslinked starch, crospovidone and croscarmellose sodium, and fine powder silica gel (page 15 Example 1). Wang further teaches milling the mixture to make a fine powder, adding magnesium stearate and sodium carboxymethyl starch to the milled powder mixture and mixing in a mixing device such as a V-type mixer, a trough-type mixer or a three-way motion mixer; and then using the tableting equipment to compress the last mixed granules into tablets to make 1000 tablets (page 16 Example 1).
Wang further teaches the preparation of capsules utilizing granulation of statin granules comprising hydroxypropyl cellulose, calcium carbonate, microcrystalline cellulose, pre-cross-linked starch, sodium lauryl sulfate, and croscarmellose sodium in a granulator, followed by combining the amlodipine besylate, and other active agent with microcrystalline cellulose, croscarmellose sodium, and micropowder silica gel and milling into a fine powder, adding magnesium stearate and sodium carboxymethyl starch to the milled powder mixture and mixing in a mixing device such as a V-type mixer, a trough-type mixer or a three-way motion mixer; and dividing the mixture into 1000 capsules (Example 2 pages 16-17).
Wang further teaches preparing Amlodipine besylate, olmesartan medoxomil and pitavastatin calcium dispersible tablets; and L-Amlodipine maleate, olmesartan medoxomil and atorvastatin calcium chewable tablets (pages 16-18 Examples 3 and 4).
Wang does not specifically exemplify the combination of olmesartan medoxomil; amlodipine or a salt thereof; and rosuvastatin or a salt thereof. Although Wang teaches the use of starch as a disintegrant, Wang does not specifically teach pre-gelatinized starch. Wang does not teach the use of lactose hydrate and dibasic calcium phosphate hydrate. Although Wang teaches the use of microcrystalline cellulose, Wang does not teach the use of silicified microcrystalline cellulose. Wang does not specifically teach the amount of pre-gelatinized starch, sodium croscarmellose, crospovidone and dibasic calcium phosphate hydrate as claimed. Wang does not specifically teach the particle sizes of the components as claimed in claims 16-18. Wang does not specifically teach the properties of the formulation as claimed in claims 20-23
Although Wang does not specifically exemplify the combination of olmesartan medoxomil; amlodipine or a salt thereof; and rosuvastatin or a salt thereof, Wang does specifically teach a combination of amlodipine besylate, olmesartan medoxomil and pitavastatin calcium. Furthermore, Wang further teaches that there are no particular restrictions on the statins that can be used in the present invention and representative examples of statins are selected from (but not limited to): atorvastatin, simvastatin, pitavastatin, pravastatin, rosuvastatin, fluvastatin, lovastatin, rosuvastatin, clavastatin, dalvastatin, glivastatin, mevastatin, telvastatin, nivastatin, or a pharmaceutically acceptable salt thereof (page 11). Thus Wang specifically teaches that rosuvastatin is a suitable statin for use in the combination. Accordingly, prior to the effective filing date, it would have been obvious to a person of ordinary skill in the art to combine rosuvastatin with amlodipine besylate, and olmesartan medoxomil, to arrive at the instant invention, with a reasonable expectation of similar and predictable results.
In addition, Oh et al. teaches that amlodipine and olmesartan are antihypertensive agents with different mechanisms, wherein amlodipine is a dihydropyridine calcium channel blocker that blocks Ca2+ from entering the cell membrane of the heart and vascular smooth muscle, which directly relaxes the smooth muscle to lower blood pressure, and olmesartan, is an angiotensin II receptor blocker that blocks the binding of angiotensin II to the receptor that contracts the blood vessels (page 992). Oh et al. teaches that together, they are often used as a combination therapy for the treatment of hypertensive patients who are unresponsive to single therapy (page 992). Oh et al. teaches that hyperlipidemia is a cardiovascular disease (CVD) that is characterized by an increase in serum concentrations of cholesterol, triglycerides, or both, resulting from a metabolic lipoprotein abnormality and is a major risk factor for arteriosclerosis and increases the risk of coronary artery disease (page 992). Oh et al. teaches that rosuvastatin is widely used to treat hyperlipidemia and compared to other hyperlipidemic agents, rosuvastatin, in particular, has a high affinity for HMG-CoA reductase and a high inhibitory effect, which effectively reduces LDL cholesterol and increases HDL cholesterol (page 992). Oh et al. specifically teaches a single FDC tablet containing 10 mg amlodipine, 40 mg olmesartan and 20 mg rosuvastatin (page 992).
Accordingly, prior to the effective filing date of the claimed invention, it would have been obvious to a person of ordinary skill in the art to combine the teachings of Wang which teaches a combination of amlodipine besylate, an angiotensin II receptor antagonist such as olmesartan medoxomil and a statin wherein there are no particular restrictions on the statins that can be used in the composition and representative examples of statins include rosuvastatin, or a pharmaceutically acceptable salt thereof; with the teachings of Oh et al. which specifically teaches that rosuvastatin is widely used to treat hyperlipidemia and compared to other hyperlipidemic agents, rosuvastatin, in particular, has a high affinity for HMG-CoA reductase and a high inhibitory effect, which effectively reduces LDL cholesterol and increases HDL cholesterol and specifically teaches the combination of amlodipine, olmesartan and rosuvastatin. Thus an ordinary skilled artisan would have been highly motivated to combine rosuvastatin with amlodipine besylate, and olmesartan medoxomil, based on the teachings Wang to arrive at the instant invention, with a reasonable expectation of improved and predictable results since Oh et al. specifically teaches that rosuvastatin has improved results compared to other statin drugs. Thus the use of 20 mg of rosuvastatin in the formulation of Wang to arrive at a formulation comprising amlodipine besylate, olmesartan medoxomil and rosuvastatin is rendered obvious.
Although Wang does not specifically teach the particle sizes of the components as claimed in claims 16-18, Wang specifically teaches milling the mixture containing the active agents to make a fine powder.
In addition, Kim et al. teaches preparing a similar composition comprising similar ingredients including amlodipine, rosuvastatin and losartan (which is similar to olmesartan in that it is a type of angiotensin II receptor antagonist as taught in Wang) (abstract). Kim et al. teaches that rosuvastatin having a specific particle size exhibits excellent solubility profile and bioavailability (page 2 [12]). Kim et al. teaches that the pharmaceutical composition exhibits improved dissolution rate, bioavailability, and so on, due to the rosuvastatin or a pharmaceutical acceptable salt thereof having a specific particle size range, specifically, the particle size (D90) of rosuvastatin or a pharmaceutical acceptable salt thereof is about 50 μm or less (page 4 [32]). Kim et al. teaches the particle size (D90) of rosuvastatin or a pharmaceutical acceptable salt thereof is about 25 μm or less, more preferably, about 10 μm or less (page 4 [32]). Kim et al. further teaches a suitable salt of rosuvastatin is rosuvastatin calcium (page 10 [67]).
Kim et al. further teaches the use of the same disintegrants as Wang in preparing tablets and further teaches other suitable disintegrants include sodium starch glycolate, starch, or pregelatinized starch or combinations thereof (page 8 [49]). Kim teaches the use of crospovidone, croscarmellose sodium, sodium starch glycolate, starch, pregelatinized starch or combinations thereof as disintegrating agents [49]. Kim teaches the disintegrating agent may be comprised in an amount of from 3 to 10 wt.% based on the total weight and if the disintegrating agent is employed in the above range, the dissolution rate is improved, production of related substances decreases, and sufficient stability may be secured under heat-stressed condition with elapsed time [49].
Kim et al. further teaches that examples of the pharmaceutically acceptable carrier or excipient include lactose (lactose hydrate), microcrystalline cellulose, calcium phosphate, and starch, a disintegrating agent (e.g., crospovidone, copovidone, croscarmellose sodium, sodium starch glycolate, starch, pregelatinized starch and composite silicates) and a binder (e.g., polyvinylpyrrolidone, hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), sucrose, gelatin and acacia gum) [46]. Kim specifically teaches the combination of lactose hydrate and microcrystalline cellulose as additives [47[. Kim teaches that when the lactose hydrate is employed as a water-soluble additive, the lactose hydrate may form hydrophilic channels which promote dissolution of active ingredients, thereby allowing a fast dissolution [48]. Thus Kim teaches that the dissolution rates of amlodipine and rosuvastatin may be improved significantly by employing the lactose hydrate and microcrystalline cellulose [48].
Thus Kim et al. provides motivation to use microcrystalline cellulose, calcium phosphate, lactose hydrate, pregelatinized starch, sodium croscarmellose and crospovidone as routine excipients and disintegrants known in the art for preparing tablets from granulates comprising amlodipine, rosuvastatin and angiotensin II receptor antagonists.
Accordingly, prior to the effective filing date of the claimed invention, it would have been obvious to a person of ordinary skill in the art to prepare the formulation of Wang comprising rosuvastatin calcium as the statin wherein the rosuvastatin calcium has a particle size (D90) of 50 mm or less since Kim et al. teaches that a pharmaceutical composition exhibits improved dissolution rate and bioavailability, due to the rosuvastatin or a pharmaceutical acceptable salt thereof having a specific particle size range, specifically, the particle size (D90) of rosuvastatin or a pharmaceutical acceptable salt thereof is about 50 μm or less. Thus a person of ordinary skill in the art would have been motivated to use the rosuvastatin calcium having a particle size (D90) of 50 mm or less in the formulation of Wang with a reasonable expectation of improving the properties of the formulation. Thus claim 18 of the instant application is rendered obvious.
Furthermore, it would have been within the skill of an artisan to use routine disintegrants and excipients known in the art including those taught in Wang and those taught in Kim et al. including microcrystalline cellulose, calcium phosphate, lactose hydrate, pregelatinized starch, sodium croscarmellose and crospovidone in formulating the tablets of Wang with a reasonable expectation of predictable results.
With respect to the particle size of Olmesartan as claimed, Zupancic teaches Olmesartan medoxomil formulations (abstract). Zupancic teaches Olmesartan medoxomil particles prepared may be characterized by particle size or by specific surface area (page 11). Zupancic teaches that the mean particle size of Olmesartan medoxomil particles is between 1 and 150 microns, preferably between 5 and 120 microns, more preferably between 10-100 microns (page 11). Zupancic further teaches that the optionally, the tablet cores may for example be coated with conventional materials used for film coating such as polymers used in film coating which are either cellulose derivatives, such as the cellulose ethers, or acrylic polymers and co-polymers, as well as high molecular weight polyethylene glycols, polyvinyl pyrrolidone, polyvinyl alcohol and waxy materials (page 16). Zupancic specifically teaches coating the tablet with the polyvinyl alcohol Opadry (pages 21-23).
Zupancic further teaches the use of the same excipients as Wang and Kim including microcrystalline cellulose, lactose monohydrate, in addition to siliconized microcrystalline cellulose, and calcium hydrogen phosphate (pages 14-15). Zupancic further teaches the use of the same disintegrants as Wang and Kim including starch, croscarmellose and crospovidone (page 15).
Accordingly, prior to the effective filing date of the claimed invention, it would have been obvious to a person of ordinary skill in the art following the teachings of Wang to prepare the formulation containing Olmesartan medoxomil wherein the Olmesartan medoxomil has a suitable particle size for preparing tablets known in the art. Thus since Zupancic specifically teaches preparing a tablet dosage form wherein the suitable mean particle size of Olmesartan medoxomil particles is between 1 and 150 microns, preferably between 5 and 120 microns, more preferably between 10-100 microns, an ordinary skilled artisan would have been motivated to prepare the formulation of Wang which contains Olmesartan medoxomil such that the particle size is a suitable size known in the art. Thus ensuring that the particle size of Olmesartan medoxomil is between 1 and 150 microns, preferably between 5 and 120 microns, more preferably between 10-100 microns, to arrive at the instant application is rendered obvious. Thus claim 16 is rendered obvious.
In addition since coating a tablet with a polyvinyl alcohol is well-known in the art as taught by Zupancic, it would have been obvious and within the skill of an artisan practicing the invention of Wang to apply procedures well-known in the art to yield predictable results. Thus claims 12 and 13 of the instant application are rendered obvious in view of the cited prior art teachings.
In addition, as detailed above Zupancic further teaches that siliconized microcrystalline cellulose is an alternative for microcrystalline cellulose as an excipient. Zupancic also teaches the specific calcium hydrate phosphate form as a suitable excipient. Thus, it would have been within the skill of an artisan to use routine disintegrants and excipients known in the art including those taught in Wang and Kim and those taught in Zupancic et al. including microcrystalline cellulose or siliconized microcrystalline cellulose as an alternative, calcium phosphate or calcium hydrate phosphate as an alternative, lactose hydrate, pregelatinized starch, sodium croscarmellose and crospovidone in formulating the tablets of Wang with a reasonable expectation of predictable results.
With respect to the particle size of amlodipine or a salt thereof as claimed, Lee et al. teaches a pharmaceutical composition comprising amlodipine besylate is provided to improve stability by inhibiting decomposition of amlodipine besylate during long-term storage, so that it is useful for prevention and treatment of angina pectoris, hypertension and cardiac failure (abstract). Lee et al. teaches that in manufacturing processes such as tablets or capsules, the amlodipine besylate to be mixed is usually in the form of particles, and in consideration of the stability of the pharmaceutical composition and the convenience of the manufacturing process, it is suitable that amlodipine besylate has a particle size of 90% or more, preferably 99% or more and 150 μm or less, in particular, the average, it is preferable to make the particle size of about 16 micrometers or more and 90% or more have 84 micrometers or less (page 5).
Lee et al. also teaches the use of the same excipients and disintegrants as Wang, Kim and Zupancic including lactose, microcrystalline cellulose, crospovidone, croscarmellose sodium, calcium hydrogen phosphate dihydrate (page 4). Lee et al. specifically teaches that calcium hydrogen phosphate dihydrate is used to improve stability of the pharmaceutical composition (page 4).
Accordingly, prior to the effective filing date of the claimed invention, it would have been obvious to a person of ordinary skill in the art following the teachings of Wang to prepare the formulation containing amlodipine besylate, wherein the amlodipine besylate has a suitable particle size for preparing tablets known in the art. Thus since Lee et al. specifically teaches that in manufacturing processes such as tablets or capsules, the amlodipine besylate to be mixed is usually in the form of particles, and in consideration of the stability of the pharmaceutical composition and the convenience of the manufacturing process, it is suitable that amlodipine besylate has a particle size of 90% or more, preferably 99% or more and 150 μm or less, in particular, the average, it is preferable to make the particle size of about 16 micrometers or more and 90% or more have 84 micrometers or less, an ordinary skilled artisan would have been motivated to prepare the formulation of Wang which contains amlodipine besylate such that the particle size is a suitable size known in the art for manufacturing. Thus ensuring that the particle size D(90) of amlodipine besylate is 150 μm or less as taught by Lee et al., to arrive at the instant application is rendered obvious. Thus claim 17 of the instant application is rendered obvious.
In addition, it would have been within the skill of an artisan to use routine disintegrants and excipients known in the art including those taught in Wang, Kim, Zupancic and Lee et al. including microcrystalline cellulose or siliconized microcrystalline cellulose, calcium phosphate including calcium hydrogen phosphate dihydrate, lactose hydrate, pregelatinized starch, sodium croscarmellose and crospovidone in formulating the tablets of Wang with a reasonable expectation of predictable results.
With regard to the amount of pre-gelatinized starch, sodium croscarmellose, crospovidone and dibasic calcium phosphate hydrate as claimed, aalthough Wang does not specifically teach the specific amounts as claimed, it is obvious and within the skill of an ordinary artisan to vary and/or optimize the amount of components within a composition such that optimal amounts are achieved. An ordinary skilled artisan would have been able to optimize the amounts such that optimal results are achieved since the prior art provides general amounts for the components that overlap with the claimed amounts. For example, Kim teaches the disintegrating agent may be comprised in an amount of from 3 to 10 wt.% (sodium croscarmellose and crospovidone) based on the total weight, Lee et al. teaches examples of amounts in Table 1, and Zupancic teaches the use of preferably 2-40% of disintegrant or superdisintegrant (sodium croscarmellose and crospovidone) and 1-50% of the binder (pre-gelatinized starch) (page 14). Furthermore, it has been held that it is within the skill in the art to select optimal parameters, such as amounts of ingredients, in a composition in order to achieve a beneficial effect. See In re Boesch, 205 USPQ 215 (CCPA 1980).
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree "will not sustain a patent"); In re Williams, 36 F.2d 436, 438 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (identifying "the need for caution in granting a patent based on the combination of elements found in the prior art.").
Thus the amounts as claimed which are achieved through routine optimization are rendered obvious in view of the cited prior art teachings.
Therefore, since as detailed above, the cited references render obvious the same formulation as claimed comprising the same components as claimed in the same amounts, the properties of the composition as claimed in claims 20-23 are also rendered obvious. "Products of identical chemical composition cannot have mutually exclusive properties." A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. In re Spada, 911 F.2d 705,709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). Thus the composition rendered obvious over the prior art teachings will necessarily have the same properties as claimed in claims 20-23. In addition, it is not necessary that the prior art suggests the same advantage or result discovered by applicant when the steps of the claim are the same as those described or suggested by the prior art. See, e.g., In re Kahn, 441 F.3d 977, 987 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323 (Fed. Cir. 2005) (“One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings.”); In re Lintner, 458 F.2d 1013 (CCPA 1972); In re Dillon, 919 F.2d 688 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991).
Thus the cited claims of the instant application are rendered obvious in view of the cited prior art teachings.
Prior art deemed pertinent to the instant invention:
WO 2010/140992 A1
Conclusion
Claims 1-25 are rejected. No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KARA R. MCMILLIAN whose telephone number is (571)270-5236. The examiner can normally be reached Tuesday-Friday 12:00 PM-6:00 PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam C. Milligan can be reached at (571)270-7674. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/KARA R. MCMILLIAN/Primary Examiner, Art Unit 1623
KRM