DETAILED ACTION
Claims 1-9, 11-12, 14-19, 21-24, and 86-91 are pending and under consideration on the merits.
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 .
Status of the Rejections
The 103 rejections are maintained, and a new rejection is applied to newly added claims 90-91.
The 35 USC 112(b) rejection is withdrawn in view of the amendment.
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, 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.
Claims 1-9, 11-12, 14-15, 21-23, and 86-88 are rejected under 35 U.S.C. 103 as unpatentable over Berkland et al. (US Pat. Pub. 2016/0354317; of record in IDS) in view of Nelson et al. (US Pat. Pub. 2018/0200221; of record in IDS), Dargelas et al. (US Pat. Pub. 2009/0220611), and Grenier et al. (US Pat. Pub. 2008/0057123).
As to claims 1-9, 11-12, 14-15, 21-23, and 86-88, Berkland discloses a microcapsule composition comprising a core portion comprising a drug and a shell portion (“outer layer”) comprising a hydrophobic matrix (“hydrophobic compound”) and a pH-responsive material, wherein the hydrophobic matrix may comprise glycerol fatty acid esters (“vegetable oils”) or wax, and the pH-responsive material may comprise an aminoalkyl methacrylate copolymer (“gastro-soluble polymer”)(paragraphs 3-4, 8, and claims 7-8 of Berkland). Claim 1 of Berkland recites that the pH-responsive material/gastro-soluble polymer is present in the amount of about 1-25 wt% with the balance being the hydrophobic matrix components, i.e., 74-99 wt%. These ranges read on the ranges recited by claims 3-7, and as well as the weight ratios of at least 2.3 or about 4 recited by claims 1-2. For example, the use of 80 wt% of the hydrophobic matrix and 20 wt% of the pH responsive material would be within the amounts suggested by Berkland and results in a ratio of 4, which is within the claimed ratios. Berkland does not require the presence of any additional ingredients in the shell, therefore reading on the “consists of” language of claims 6-7. Berkland teaches that the invention is based on the discovery that release profiles, bioavailability, and palatability can be precisely controlled by encapsulating the drug core with a pH-responsive shell that prevents release of the active until an appropriate pH is encountered (paragraph 3).
As to claims 1-9, 11-12, 14-15, 21-23, and 86-88, Berkland does not further expressly disclose that the aminoalkyl methacrylate copolymer is the elected species, i.e., a copolymer of methyl methacrylate and diethylaminoethyl methacrylate having the Tg and Mw of claim 1, nor that the vegetable oil is the elected species of hydrophobic compound, i.e., hydrogenated vegetable oil having a melting temperature within the range recited by claim 1 and a Tm within the range of claim 11 such as a lubricant made from hydrogenated cottonseed oil (claim 12), nor the presence of a sustained release layer comprising a water soluble polymer, a cellulosic derivative insoluble in the GI tract, and a plasticizer (claim 1) such as a sustained release layer comprising PVP polymer, ethylcellulose cellulosic derivative, and castor oil as the plasticizer (claims 86-88) and in the amounts recited by these claims, nor the coating ratio of the outer layer as recited by claims 14-15. Nor does Berkland expressly teach that the particle possesses the stable in vitro dissolution profiles recited by claims 1 and 22-23 or the amount of drug in the continuous phase recited by claims 21-23.
Nelson discloses a functional coating for a pharmaceutical composition comprising a pH-sensitive polymer which solubilizes in low acid environment that may be Kollicoat® Smartseal 30D (a species of the elected genus of methyl methacrylate and diethylaminoethyl methacrylate copolymer pH-sensitive material of claims 1 and 8-9 which has a minimum of 50% molar ratio of methyl methacrylate and a maximum of 50% molar ratio of an amino alkyl methacrylate and a Tg and Mw within the range of claim 1)(paragraph 76).
Dargelas discloses microparticles comprising a core comprising a pharmaceutical active and which is coated with two coated films A and B, wherein A comprises a film forming polymer insoluble in the GI tract and an ethylcellulose copolymer that is soluble in the GI tract, and B comprises a hydrophilic polymer combined with a hydrophobic compound that is LUBRITRAB® (i.e., hydrogenated cottonseed oil, which is a species of the hydrogenated vegetable oil that is the elected genus of hydrophobic compound of claims 1 and 11-12 and which has a melting temperature and Tm within the ranges recited by claims 1 and 11)(Abstract; paragraphs 139 and 141). The hydrophilic polymer may be a pH-dependent providing for release in the colon such as EUDRAGIT S100 (paragraph 138). The coatings may provide for delayed and sustained release properties as recited by claim 13 (paragraph 151). Either of films A and B may be the outer layer or the intermediate layer between the outer layer and the drug-containing core (paragraph 163).
Grenier discloses controlled release formulations having a sustained release coating (claim 16 of Grenier), the formulation comprising a core comprising an active ingredient and a barrier layer over the core for preventing release of the active agent for a predetermined amount of time (paragraphs 9 and 43). The barrier layer may comprise ethylcellulose (paragraph 46) in the amount of about 5-90 wt% (paragraph 47) which encompasses the amounts recited by claims 87-88, and the barrier layer further may comprise one or more adjuvants allowing for further modulation of the release of the active including castor oil and polyvinylpyrrolidone, wherein the adjuvants may be used in the amount of about 1-25 wt% (paragraph 49), which encompasses the amounts recited by claims 87-88. No other ingredients are required to be present in the layer, thus meeting the “consisting of” language of claims 87-88.
As to claims 1-9, 11-12, 14-15, 21-23, and 86-88, it would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the present invention to modify the Berkland particles by selecting a methyl methacrylate and diethylaminoethyl methacrylate copolymer such as Kollicoat® Smartseal 30D as the pH-sensitive material, because Berkland expressly teaches that the pH-responsive material may be an aminoalkyl methacrylate copolymer, and Nelson expressly teaches Kollicoat® Smartseal 30D as a known pH-responsive aminoalkyl methacrylate copolymer that is suitable for use in a pharmaceutical composition, such that the skilled artisan reasonably would have expected that it could serve as the pH-responsive material in the Berkland particles. Such a modification is merely the substitution of one known element for another according to known methods to achieve predictable results, which is prima facie obvious. MPEP 2143. It further would have been prima facie obvious to select a hydrogenated vegetable oil such as hydrogenated cottonseed oil as the hydrophobic compound, because Berkland does not limit the identity of the vegetable oil, and Dargelas expressly teaches that hydrogenated cottonseed oil is a type of vegetable oil that is suitable for use as a hydrophobic compound in a coating on microparticles comprising a drug-containing core, such that the skilled artisan reasonably would have expected that it could serve as the hydrophobic compound in the coating of the Berkland drug-core containing microparticles. Such a modification is merely the substitution of one known element for another according to known methods to achieve predictable results, which is prima facie obvious. MPEP 2143. It further would have been prima facie obvious to incorporate an additional sustained release coating layer between the drug-containing core and the outer layer when it would be desirable to impart sustained release properties to the particles, because Dargelas teaches that sustained release properties can be imparted to coated particles comprising a drug-containing core by providing an additional coating comprising a sustained release polymer, and that said additional coating can be located between the drug-containing core and the outer layer. Such a modification is merely the combining of prior art elements according to known methods to achieve predictable results, which is prima facie obvious. MPEP 2143. It further would have been prima facie obvious to select PVP, ethylcellulose, and castor oil as components of the sustained release layer and in the amounts recited by claims 87-88, because Grenier teaches that sustained release properties may be imparted to a pharmaceutical formulation by application of a sustained release layer comprising these ingredients in such amounts, such that the skilled artisan reasonably would have expected that they could be used to impart sustained release properties to the Berkland pharmaceutical particles.
As to claims 14-15, it further would have been prima facie obvious to select the coating ratio of the outer layer as recited by claims 14-15, because the amount of the coating layer comprising the pH-responsive material is a result effective variable that will affect the drug release profile of the particles including where in the GI tract the drug is released and therefore affect the ability to tailor the drug release profile as taught by Berkland. Discovering optimum or working ranges involves only routine skill in the art in cases where the general conditions of a claim are disclosed in the prior art. In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
The resulting composition will possess the functional properties regarding stable dissolution profiles and amount of drug in the continuous phase recited by claims 1 and 21-23 because it comprises the same ingredients in the same amounts recited by the claims, and a product cannot be separated from its properties. The U.S. Patent Office is not equipped with analytical instruments to test prior art compositions for the countless ways that an Applicant may present previously unmeasured characteristics. When the prior art appears to contain the same ingredients that are disclosed by Applicants' own specification as suitable for use in the invention, a prima facie case of obviousness has been established, and the burden is properly shifted to Applicants to demonstrate otherwise. See MPEP 2112.01.
Claims 16-19 and 24 are rejected under 35 U.S.C. 103 as unpatentable over Berkland et al. (US Pat. Pub. 2016/0354317) in view of Nelson et al. (US Pat. Pub. 2018/0200221) and Grenier et al. (US Pat. Pub. 2008/0057123) as applied to claims 1-9, 11-12, 14-15, 21-23, and 86-88 above, and further in view of Kuman et al. (US Pat. Pub. 2016/0228379).
The teachings of Berkland, Nelson, and Grenier are relied upon as discussed above, but they do not further expressly disclose a suspension comprising the particles comprising a continuous phase comprising an osmotic agent and which is not saturated by the drug and has a pH above the gastro-soluble polymer’s pKa and wherein the osmolality is higher than saturated solution of the drug in water and higher than 1300 mOsm/kg as recited by claim 24. Nor do they expressly disclose the drug is one of those recited by claim 16 such as metformin hydrochloride and which is crystalline form (claim 19), or that the drug-containing core comprises a drug-coated pellet or bead (claims 17-18).
Kumar discloses extended release liquid suspension pharmaceutical compositions comprising multiple cores comprising an active ingredients that are coated with one or more release controlling polymers such as a dimethylaminoethyl methacrylate polymers along with a suspension base comprising an osmotic agent to generate a hypertonic condition such that there is no substantial change in the in vitro dissolution release profile of the composition upon storage for at least seven days (paragraphs 19-29, 84,and 86). Kumar teaches that the suspension base has an osmolality of not less than 2 osmol/kg, which is within the range recited by claim 24 (paragraph 29). Kumar further teaches that the core may be in the form of a bead or pellet (paragraph 32), and that the active may be metformin hydrochloride (a crystalline drug)(paragraph 112). Kumar teaches that liquid suspension compositions have advantages over solid compositions due to easier swallowing more accurate dosing, and enhanced patient compliance (paragraph 2).
Regarding claims 16-18, it further would have been prima facie obvious to select metformin hydrochloride as the active and to coat the drug onto a pellet or bead, because Berkland does not limit the identity of the active that may be used and Kumar expressly teaches that this active is suitably delivered via particles comprising a drug-coated pellet or bead core and a coating comprising a pH-dependent polymer, such that the skilled artisan reasonably would have expected that this drug also could be delivered using the coated core particles of Berkland. Such a modification is merely the simple substitution of one known element for another according to known methods to yield predictable results, which is prima facie obvious. MPEP 2143.
Regarding claim 24, it further would have been prima facie obvious to mix the particles with a suspension base comprising an osmotic agent to form a plurality of the particles dispersed in a continuous phase having an osmolality within the range of claim 24, because Kumar teaches that liquid suspension compositions have advantages over solid compositions due to easier swallowing, more accurate dosing, and enhanced patient compliance, and that inclusion of an osmotic agent to generate an osmolality within the claimed range advantageously will generate a hypertonic condition such that there is no substantial change in the in vitro dissolution release profile of the composition upon storage for at least seven days. The skilled artisan further would have been motivated to use a continuous phase having a pH above the gastro-soluble polymer’s pKa, because the skilled artisan readily would have recognized that this will be necessary to prevent premature release of the active prior to administration to a subject. The resulting composition is viewed as having a continuous phase that is not saturated by the drug and the osmolality higher than saturated solution of the drug in water as recited by claim 24 due to the inclusion of the osmotic agent resulting in no substantial change in the in vitro dissolution release profile of the composition upon storage for at least seven days as taught by Kumar. The U.S. Patent Office is not equipped with analytical instruments to test prior art compositions for the countless ways that an Applicant may present previously unmeasured characteristics. When the prior art appears to contain the same ingredients that are disclosed by Applicants' own specification as suitable for use in the invention, a prima facie case of obviousness has been established, and the burden is properly shifted to Applicants to demonstrate otherwise. See MPEP 2112.01. Additionally, discovering optimum or working ranges involves only routine skill in the art in cases where the general conditions of a claim are disclosed in the prior art. In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Claim 89 is rejected under 35 U.S.C. 103 as unpatentable over Berkland et al. (US Pat. Pub. 2016/0354317) in view of Nelson et al. (US Pat. Pub. 2018/0200221) and Grenier et al. (US Pat. Pub. 2008/0057123) as applied to claims 1-9, 11-12, 14-15, 21-23, and 86-88 above, and further in view of Tiwari et al. (WO 2018/065826).
The teachings of Berkland, Kuman, and Grenier are relied upon as discussed above, but they do not further expressly disclose that the castor oil is in the form of polyoxyl 40 hydrogenated castor oil such as Kolliphor® RH40.
Tiwari discloses beads for pharmaceutical use comprising a core particle and multiple layers coated onto the core particle, wherein the layers may comprise a plasticizer for coating ease such as castor oil (paragraph 26). Tiwari discloses a specific embodiment wherein the castor oil plasticizer is polyoxyl 40 hydrogenated castor oil Kolliphor® RH40.
As to claim 89 it would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the present invention to modify the Berkland particles by selecting polyoxyl 40 hydrogenated castor oil as the plasticizer, because Tiwari expressly teaches that this is a suitable type of castor oil for use as a plasticizer in a layer over a particle in a pharmaceutical composition, such that the skilled artisan reasonably would have expected that it also could be used as the type of castor oil plasticizer in the Berkland particle composition. Such a modification is merely the simple substitution of one known element for another according to known methods to yield predictable results, which is prima facie obvious. MPEP 2143.
Response to Applicant’s Arguments
Applicant asserts that the cited references describe many thousands of possible combinations. Applicant argues that Example 4 illustrates superior results of the claimed invention by showing that the amount of drug leaching out of the particles into a continuous phase was reduced by a factor of 10 compared to saturation of the continuous phase by the drug, while maintaining a sustained release profile over time once dissolution was performed, which is allegedly unpredictable from the disclosures of the cited art, which is said to describe many thousands of possible combinations, such that arriving at the claimed combination could only happen through hindsight.
In response, evidence of unexpected results must compare the claimed invention with the closest prior art. MPEP 716.02(e). Additionally, in situations where the Applicants are relying upon unexpected results to rebut a prima facie case of obviousness, Applicants bear the burden to establish that the results are unexpected and significant. The evidence relied upon should establish "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). See MPEP 716.02(b).
Example 4, however, does not compare the claimed invention with any prior art composition. Rather, Example 4 compares the amount of drug that leaches from particles of the invention after at least 1 month of storage with the amount of drug that is present in a continuous phase that is saturated with the drug (see paragraphs 156 as published). The tested inventive particles comprise a drug-containing core with a sustained release layer comprising ethylcellulose, PVP, and castor oil, and an outer layer comprising a KOLLICOAT coating, which comprises methyl methacrylate and diethylaminoethylmethacrylate (see paragraphs 152-153 as published). The skilled artisan would recognize that the sustained release layer, by design, reduces the rate of drug that otherwise would be released from the drug-containing cores, such that it is not surprising that the amount of drug that leaches into a continuous phase would be lower than the amount of drug in a continuous phase that is saturated with the drug. Therefore, the results of Example 4 are not of an unexpected nature based upon the evidence that is currently of record.
New Rejection
Claims 90-91 are rejected under 35 U.S.C. 103 as unpatentable over Berkland et al. (US Pat. Pub. 2016/0354317) in view of Nelson et al. (US Pat. Pub. 2018/0200221), Grenier et al. (US Pat. Pub. 2008/0057123), and Kumar et al. (US Pat. Pub. 2016/0228379) as applied to claims 16-19 and 24 above, and further in view of Quagliano (US Pat. No. 9,585,973 (issued 3/7/2017).
The teachings of Berkland, Nelson, Grenier, and Kumar are relied upon as discussed above. Berkland does not further disclose that the osmotic agent is 60 wt% maltitol (claim 90) or the presence of monopotassium phosphate as a buffering agent to achieve a buffered pH of 7.5 and 0.2% xanthan gum in the continuous phase (claim 91), although Kumar further teaches that the suspensions taught therein may comprise a buffering agent such as sodium phosphate or potassium citrate or mixtures thereof (paragraph 94) to attain a pH of from about 2-10, which overlaps the range of claim 92and that the osmotic agent may be xanthan gum (paragraphs 82 and 86).
Quagliano discloses liquid vehicles for pharmaceutical contrast agents that may be in the form of a suspension (column 1, 1st paragraph and column 2, 1st full paragraph), the vehicle comprising an osmotically active material such as maltitol, wherein the amount may be 20 wt% or less, the amount depending on the osmotic agent selected and the intended characteristics of the selected liquid vehicle (column 7, 4th paragraph).
As to claims 90-91, it would have been prima facie obvious to 1) incorporate potassium phosphate as a buffering agent to obtain a composition buffered to a pH of 7.5, because Kumar expressly suggests that liquid suspension pharmaceuticals comprising particles comprising an active and which are coated with release controlling polymers may advantageously comprise a buffering agent to control the pH and to achieve a pH within the recited range, and that suitable buffering agents may comprise mixtures of buffering agents such as sodium phosphate and potassium citrate, which the skilled artisan would recognize as resulting in a continuous phase comprising potassium and phosphate ions, and 2) by selecting maltitol and xanthan gum as the osmotic agents, because Kumar expressly teaches that xanthan gum can serve as the osmotic agent and Quagliano expressly teaches that maltitol is useful as an osmotic agent in pharmaceutical suspension, such that the skilled artisan reasonably would have expected that it could be used as an osmotic agent in the pharmaceutical suspension of Berkland, Nelson, Grenier, and Kumar as combined supra. It further would have been prima facie obvious to select amounts of the osmotic agents that read on the amounts recited by claims 90-91, because Quagliano expressly teaches that the amount of the osmotic agent depends on the identity of the osmotic agent and the intended characteristics of the selected liquid vehicle, which would have motivated the skilled artisan to perform an optimization process to determine the appropriate amounts to use in the suspension of Berkland, Nelson, Grenier, and Kumar as combined supra. There is no evidence of record of any unexpected criticality of the recited amounts of maltitol and xanthan gum, and discovering optimum or working ranges involves only routine skill in the art in cases where the general conditions of a claim are disclosed in the prior art. In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
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 nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/GAREN GOTFREDSON/Examiner, Art Unit 1619
/ANNA R FALKOWITZ/ Primary Examiner, Art Unit 1600