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 .
Response to Amendments
Applicant filed Terminal Disclaimer that was approved by the Office on February 12, 2026. As such, the DP rejections are withdrawn. No amendments were made to the claims.
Response to Arguments
Unexpected results have not been alleged or shown as compared to the closest prior art. As such, the examiner is determining if a prima facie showing is set forth for the record.
Applicant argues that the examiner is required to use the specific formulation recited in Example 3 of the Specification because they recite “means for” and/or equivalent language in the claims. As such, Applicant argues that the specifics are not taught by Davis nor Nidorf of release less than 30% of a drug in 2 hours.
The examiner notes that the Specification explicitly describes the invention to be a pharmaceutical formulation that provides for sustained release through any form conceivable to the skilled artisan as long as a sustained release is ensured. See Specification at par. 47. The Specification also includes embodiments that include a coating, e.g. See par. 49. In context, a POSA would not read the claims in light of the instant Specification and properly interpret the claims to be limited to Example 3. Applicant’s own words in their own Specification traverse this argument.
Applicant also argues that Davis teaches sustained release on a single occasion.
The examiner also notes that Davis teaches immediate release and sustained release compositions. The immediate release composition is defined as release equal to about 75% of the active agent within two hours of administration. See par. 141. Immediate release rate would be at least as fast as a sustained release composition as claimed. As such, the release rate claimed overlaps the immediate release rate taught by Davis. Not only does Davis teach a sustained release form, but Davis also explains that binders can be used with cohesive qualities at varying percentages to ensure the form remains intact after compaction. A POSA would understand that percentage of binder used can alter release PK with optimizable parameters. See par.’s 107 and 108. As such, to the extent there is any difference between the teachings of Davis and “about” 70% release in two hours, Davis also teaches components to sustain release. The examiner, therefore, believes that the amendments to the claims do not obviate the teachings of the cited prior art. The examiner also notes that even if any difference were to exist, non-obvious may require more than any mere distinction.
The examiner further notes that Davis teaches a sustained release coating. The instant claims do not preclude a coating. See par. 49.
The examiner notes that, as explained above, Davis teaches an immediate release form with an almost identical and overlapping release profile based on Applicant’s own definitions. Further, Davis also teaches using binders, which have a release retarding effect, and are taught to maintain cohesion of a product. Further, in one embodiment a uniform distribution of granulating liquid is achieved. See par. 135. However, uniformity is also not required by the claims such that it excludes using a coating. Other teachings produce homogenous mixtures and blends, and substantial homogeneity is taught to be advantageous. See par.’s 135, 136, and 162. Overall, a sustained release coating can be used; binders can also be used at varying percentages and would be expected to slow release; uniform and homogeneous processes would yield a substantially uniform product, which is advantageous; and a non-obvious distinction, among others, has not been established between the release rates taught and claimed. Moreover, a POSA would understand how to slow release rate of a pharmaceutical composition by increasing compression force, percentage of binding agent, etc.
Overall, the claims remain broad, the Specification supports any conceivable component to achieve sustained release, the claims are not limited to a uniform structure, and unexpected results have not been shown.
As such, the rejections of record are maintained.
Status of the Claims
Claims 1-4 are pending and examined.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-4 are rejected under 35 U.S.C. 103 as being unpatentable over Nidorf et al., “Low-dose colchicine for secondary prevention of cardiovascular disease," Journal of American College of Cardiology, 2013 Jan 29;61(4):404-10, (Epub 2012 Dec 19), in view of Davis et al., (US2009/0170952).
Nidorf teaches colchicine administered at 0.5 mg/day in addition to statins and other standard secondary care prevention therapies appeared effective for the prevention of cardiovascular events in patients with stable coronary disease (abstract). The mechanism of action is to inhibit the functionality of neutrophils, which are known to enter the interstitial space and become active when exposed to plaque contents- which, in turn, results in an aggressive inflammatory response. The response can lead to plaque enlargement and rupture, which increases the risk of cardiovascular events (p404, par. 1). Thus, colchicine's anti-inflammatory properties can counteract these events. Patients were selected based on proven coronary disease and were clinically stable for 6 months, inter alia, were considered for the study (p405, par. 4). The study demonstrated that 0.5 mg/day colchicine in addition to standard therapy in patients with stable coronary disease significantly reduced the risk of a cardiovascular event, including ACS, out-of-hospital cardiac arrest, and noncardioembolic ischemic stroke (p408, par. 5). In summary, colchicine (0.5mg/day) in addition to high-dose statins and other standard prevention therapies appeared effective for the prevention of cardiovascular events in patients with stable coronary heart disease (p401, par. 3).
Nidorf does not teach sustained release and the claimed excipient combination.
Davis teaches a composition comprising colchicine, waxes, natural and synthetic gums as binders, including hydroxypropylmethyl cellulose (i.e., “hypromellose”) (par. 107), and lactose monohydrate (par. 115). Further, the colchicine is present in an amount that comprises 0.6 mgA colchicine, wherein mgA means mg of active colchicine (par. 52). Dosage forms can also include 1/2 of the form for administration more times daily, wherein each dosage contains anywhere from 0.3 to 2.4 mgA daily (par. 160). Further, sustained release tablets are created by a coating process if desired (par. 138). One example of a tablet includes colchicine comprising about 0.6 mgA, lactose monohydrate, microcrystalline cellulose, magnesium stearate, and other excipients (par. 16). The blends are compressed to obtain a tablet (par. 23). Advantages to the composition taught by Davis include a low level of impurities, as well as minimizing the need for toxicity testing. Pregelatinized starch and sodium starch glycolate can be used (par. 16). Lubricants including PEG, magnesium stearate, polyethylene oxide, talc and others are taught (par. 111). They can be included in a concentration of 0.01 to 10 wt% (par. 112).
Davis teaches colchicine wherein a single dose provides a Cmax of 1.3 ng/mL and 4 ng/mL (par. 20). Further, peak concentrations generally occur in 0.5 to 2 hours (par. 11). Davis also teaches an immediate release formulation that releases an amount of at least 75% of the active ingredient within two hours of administration (par. 41). Further, AUC0-T occurs between 4.4 ng-hr/mL and 30.8 ng-hr/mL (par. 20). As such, a person having ordinary skill in the art could easily optimize a concentration of colchicine and a statin, which would result in the claimed Cmax, AUC0-T, and blood plasma concentrations that are claimed. According to M.P.E.P. § 2144.05, “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Even if the ranges do not overlap- “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). Further, Davis teaches forming a tablet through compression and that a binder may be used to impart cohesive qualities, including to ensure that the tablet remains intact after compaction. See par. 107. This would impart a sustained release property, at least to a degree, to the composition.
Davis teaches treating acute pericarditis, recurrent pericarditis, and postpericardiotomy syndrome (par. 157).
The prior art does not teach a specific statin for use with colchicine. However, a person having ordinary skill in the art would understand that any statin could be used interchangeably based on the general teaching of any statin in combination with colchicine. Arriving at a specifically claimed statin can be achieved by substituting one statin for another. "Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious.” M.P.E.P. § 2143.
It would have been prima facie obvious to a person having ordinary skill in the art prior to the effective date of the instant application to combine the teachings of Nidorf and Davis to arrive at the instantly claimed methods. One would have been motivated to do so because Nidorf teaches administering colchicine at a low dose (i.e., 0.5 mg/day) with a statin to prevent cardiovascular events in subjects with stable coronary disease. Davis teaches formulations of colchicine that include immediate and sustained release formulations that can be combined with additional active ingredients and comprise hypromellose, lactose monohydrate, in addition to many other claimed and well-known pharmaceutically acceptable excipients. Further, Davis teaches its formulation to have advantages over previous colchicine formulations because it is free from impurities (par. 12). Even further, Davis teaches its formulations of colchicine as capable of treating acute pericarditis, recurrent pericarditis, and postpericardiotomy syndrome, which are claimed cardiovascular disorders. A person having ordinary skill in the art would understand that administering the formulations of colchicine taught by Davis with a statin (as taught by Nidorf), would be effective in treating and preventing cardiovascular disease in a patient with stable coronary disease with a reasonable and predictable expectation of success.
Claims 1-4 are rejected under 35 U.S.C. 103 as being unpatentable over Nidorf et al. (“Nidorf2”), “Low-dose colchicine for secondary prevention of cardiovascular disease, (The LoDoCo Trial) ACTR Number: ACTR12610000293066, ethics approval at QII July 2008," in view of Davis et al., (US2009/0170952), and in view of Antonopoulos et al., “Statins as Anti-Inflammatory Agents in Atherogenesis: Molecular Mechanisms and Lessons from the Recent Clinical Trials,” Current Pharmaceutical Design, 2012, 18, 1519-1530.
The Nidorf2 clinical trial was used to determine if colchicine would be able to reduce the risk of cardiovascular events in patients with stable coronary disease by preventing neutrophil mediated inflammation (slide 3). Patients were administered colchicine at a dosage of 0.5 mg/day for a minimum of 2 years (slide 4). More specifically, between August 2008 and May 2010 patients were selected and 282 patients were administered 0.5 mg/day colchicine for an average of 3 years (slide 9). Colchicine was shown to reduce the risk of each component measured, including: acute cardiac syndrome, out-of-hospital cardiac arrest, and non-cardio embolic ischemic stroke (slide 13). The mechanism of action is by inhibiting the aggressive response of neutrophils, the inflammatory response is mitigated.
Nidorf2 does not teach once a day administration, the claimed excipient combination, and sustained release formulations.
Davis teaches a composition comprising colchicine, waxes, natural and synthetic gums as binders, including hydroxypropylmethyl cellulose (i.e., “hypromellose”) (par. 107), and lactose monohydrate (par. 115). Further, the colchicine is present in an amount that comprises 0.6 mgA colchicine, wherein mgA means mg of active colchicine (par. 52). Dosage forms can also include 1/2 of the form for administration more times daily, wherein each dosage contains anywhere from 0.3 to 2.4 mgA daily (par. 160). Further, sustained release tablets are created by a coating process if desired (par. 138). One example of a tablet includes colchicine comprising about 0.6 mgA, lactose monohydrate, microcrystalline cellulose, magnesium stearate, and other excipients (par. 16). The blends are compressed to obtain a tablet (par. 23). Advantages to the composition taught by Davis include a low level of impurities, as well as minimizing the need for toxicity testing. Pregelatinized starch and sodium starch glycolate can be used (par. 16). Lubricants including PEG, magnesium stearate, polyethylene oxide, talc and others are taught (par. 111). They can be included in a concentration of 0.01 to 10 wt% (par. 112).
Davis teaches colchicine wherein a single dose provides a Cmax of 1.3 ng/mL and 4 ng/mL (par. 20). Further, peak concentrations generally occur in 0.5 to 2 hours (par. 11). Davis also teaches an immediate release formulation that releases an amount of at least 75% of the active ingredient within two hours of administration (par. 41). Further, AUC0-T occurs between 4.4 ng-hr/mL and 30.8 ng-hr/mL (par. 20). As such, a person having ordinary skill in the art could easily optimize a concentration of colchicine and a statin, which would result in the claimed Cmax, AUC0-T, and blood plasma concentrations that are claimed. According to M.P.E.P. § 2144.05, “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Even if the ranges do not overlap- “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). Further, Davis teaches forming a tablet through compression and that a binder may be used to impart cohesive qualities, including to ensure that the tablet remains intact after compaction. See par. 107. This would impart a sustained release property, at least to a degree, to the composition.
Davis teaches treating acute pericarditis, recurrent pericarditis, and postpericardiotomy syndrome (par. 157).
It would have been prima facie obvious to a person having ordinary skill in the art prior to the effective date of the instant application to combine the teachings of Nidorf2 and Davis to arrive at the instantly claimed methods. One would have been motivated to do so because Nidorf2 teaches administering colchicine at a low dose (i.e., 0.5 mg/day) to prevent cardiovascular events in subjects with stable coronary disease. Davis teaches formulations of colchicine that include immediate and sustained release formulations that can be combined with additional active ingredients and comprise hypromellose, lactose monohydrate, in addition to many other claimed and well-known pharmaceutically acceptable excipients. Further, Davis teaches its formulation to have advantages over previous colchicine formulations because it is free from impurities (par. 12). Even further, Davis teaches its formulations of colchicine as capable of treating acute pericarditis, recurrent pericarditis, and postpericardiotomy syndrome, which are claimed cardiovascular disorders. A person having ordinary skill in the art would understand that administering the formulations of colchicine taught by Davis with a statin (as taught by Nidorf2), would be effective in treating and preventing cardiovascular disease in a patient with stable coronary disease with a reasonable and predictable expectation of success.
Nidorf2 and Davis do not teach statin combination therapy.
Antonopoulos teaches “randomized clinical trials have demonstrated that further to their lipid lowering effects, statins are useful in the primary and secondary prevention of coronary heart disease (CHD) due to their anti-inflammatory potential.” (Abstract). Additionally, statin administration to subjects with stable coronary disease has consistently shown the ability to improve endothelial function (p1521, par. 1). Further, Table 1 refers to studies including those using: pravastatin, atorvastatin, rosuvastatin, and simvastatin. Thus, each of these would be immediately envisaged as a statin for use.
It would have been prima facie obvious to a person having ordinary skill in the art prior to the effective date of the instant application to combine the teachings of Antonopoulos with those of Nidorf and Davis to arrive at the instantly claimed methods. One would have been motivated to do so because Nidorf and Davis teach therapy, including combination therapy that is beneficial to administer to subjects with stable coronary disease. Similarly, Antonopoulos teaches statins to provide benefits when administered to subjects with stable coronary disease. According to M.P.E.P. § 2144.06, “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Antonopoulos does not teach a specific statin for use with colchicine. However, a person having ordinary skill in the art would understand that any statin could be used interchangeably based on the general teaching of any statin in combination with colchicine. Arriving at a specifically claimed statin can be achieved by substituting one statin for another. "Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious.” M.P.E.P. § 2143.
As such, no claim is allowed.
Conclusion
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 extension fee 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 JARED D. BARSKY whose telephone number is (571)-272-2795. The examiner can normally be reached on Monday through Friday from 8:30 to 5:30. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Amy L. Clark can be reached on 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JARED BARSKY/Primary Examiner, Art Unit 1628