DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim interpretation
The claims recite wherein the solid composition has been prepared by dry granulation. This is a product-by-process limitation because the claims are drawn to the solid composition itself not the process of making the solid composition. Thus, “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 3, 5, 7-8, 10-13, 16-18, 20, and 29-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17, and 19 of U.S. Patent No. 8710058 (‘058) in view of Venkatesh et al. (US20050232988) and further in view of Khadka et al. (Asian J. of Pharm. Sci., 2014, 304-316, from IDS), WO02/20464 (‘464), US8580781 (‘0781).
‘058 teaches the claimed 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile in the form a hydrochloride solvate which reads on claims 1, 3, 5, 7-8, 10-13, 16-18, and 20 and compositions comprising this compound and excipients and/or carriers.
‘058 does not teach wherein the composition comprises the claimed filler and binder or wherein the filler is a sugar alcohol or wherein the claimed 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile (drug) is present in the claimed amounts and is micronized or wherein the drug has the claimed mean particle size or the sugar alcohol is mannitol or wherein the binder are the specifically claimed binders or wherein the solid composition has the claimed particle size or wherein the composition is suitable for pharmaceutical administration, and is suitable for oral administration or is immediate release, or is a tablet or wherein the composition contains the claimed amounts of each component. However, these deficiencies in ‘058 are addressed by Venkatesh et al. (US20050232988) and further in view of Khadka et al. (Asian J. of Pharm. Sci., 2014, 304-316, from IDS), WO02/20464 (‘464), US8580781 (‘0781).
Venkatesh teaches tablets for oral administration/pharmaceutical administration, specifically immediate release as Venkatesh teaches their formulations are bioequivalent to immediate release, comprising mannitol/sugar alcohol which reads on the claimed filler, and which comprises micronized drug, wherein the drug particles have an average particle diameter of less than 50 microns, preferably less than 25 microns, which reads on the claimed 5 microns to 80 microns as a d50 value and wherein the solid composition granules have an average particle size of 200 microns which read on the claimed 50 microns to 1mm d50 value, and wherein the micronized drug particles are blended with the binder, e.g. hydroxypropylmethylcellulose (see [0014-0015]; [0002]; [0038]; [0020-0026]; [0028-0029]; claims).
Venkatesh teaches that their solid compositions which contain micronized drug which is not limited and includes any drug which can be administered orally and as such would broadly include the claimed tepotinib ([0025]).
Venkatesh teaches that their solid compositions which contain micronized drug which is not limited and includes any drug which can be administered orally, and as such would broadly include the claimed tepotinib, and they teach wherein the drug is present in the tablets in amounts of about 0.01 to about 30% by weight based on the total weight of the tablet ([0025]), the claimed binder(s) which may or may not be present (claims; [0014-0015]; [0002]; [0038]; [0020-0026]; [0028-0029]), the claimed fillers typically in amounts of about 30 to 70% by weight based on the total weight of the tablet ([0028]), can further comprise disintegrants, specifically the instantly claimed crospovidone, which is typically present in amounts of about 1 to 10% by weight based on the total tablet weight ([0029]), which read on the instant claims. Venkatesh also teaches wherein a lubricating agent such as the claimed magnesium stearate is not typically added to the mix but, can be added as is conventional, but they prefer applying the lubricant to the tableting punches and dies are lubricated with the lubricants in a fine mist prior to tableting, thus placing trace amounts of lubricant on the tablet surface, which reads on the amounts of lubricant contained. Though Venkatesh clearly states that the act of blending the lubricant with the lubricant with the compression mix and tableting using a conventional tablet press is also an embodiment of their invention ([0030]).
Khadka teaches that particle size reduction, specifically micronization is a conventional technique for particle size reduction that is commonly used to increase solubility of BCS class II drugs because it is a simple and safe method that leads to increasing the dissolution rate of drugs by increasing the surface area to drug ratio by which the active ingredient can dissolve or diffuse from the drug particles (see section 2.1; see section 2 conventional particle size reduction techniques: 1st paragraph). Khadka further teaches wherein BCS class IV drugs (includes tepotinib) have their solubilities improved by micronizing as is done for BCS class II drugs with the addition of absorption enhancers (see section 1.2 last complete paragraph).
‘0781 teaches that tepotinib, compound A257, specifically the claimed salts were known in the art, and were known to be formulated for oral delivery and could be formulated with binders, fillers, lubricants, disintegrants, etc. and that it was known to make the compound into a fine size (e.g. micronized) and mix with excipients such as mannitol, etc. (abstract; Col. 14, ln. 51-53; compound A257; Pharmacological Data section; claims; Col 15, ln. 59-Col. 16, ln. 17; Col. 16, ln. 18-Col. 17, ln. 3).
‘464 teaches that 0.5% of magnesium stearate is a known amount of lubricant to add to oral solid dosage formulations (See Example 4).
It would have been obvious to one of ordinary skill in the art to formulate the claimed compositions when looking to the inventions of ‘058 and the combined references because it was known in the art to formulate micronized poorly water soluble orally administered drugs via the claimed types of immediate release tablets having the same mannitol filler and which can comprise binder on the surface or conventionally in the tablet formulation as is discussed above/taught by Venkatesh.
It also would have been obvious to use the claimed binders, with the mannitol in the claimed amounts with the claimed amounts of drug because as discussed above Venkatesh teaches using the poorly soluble drugs in amounts which overlap those instantly claimed and the claimed filler/mannitol in amounts which overlap those instantly claimed and it was known in the art to use the claimed binders in oral drug formulations in overlapping amounts to those instantly claimed, and it is known “[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 reAller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Thus, it would have been obvious to one of ordinary skill in the art at the time of the instant invention to have formed the claimed composition when looking to ‘058 and the combined references because it was known to formulate poorly water soluble drugs in micronized formulations comprising overlapping amounts of micronized drug, overlapping amounts of mannitol, and a binder as is instantly claimed because micronizing drugs is known to increase their solubility as discussed above and as such one of ordinary skill in the art would be motivated to formulate the claimed 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile as micronized particles having the claimed size and wherein the solid drug composition with binder, etc. has the claimed particle size because Venkatesh teaches forming the claimed immediate release oral tablets having the claimed particle sizes of drug, etc. and it would be obvious to micronize the 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile in order to increase the solubility of this poorly soluble drug as this is a conventional means of increasing solubility of poorly soluble drugs. Thus, one of ordinary skill in the art would find the instantly claimed compositions obvious when taken in view of ‘058 and the combined references for the reasons discussed above.
Claims 1, 3, 5, 7-8, 10-13, 16-18, 20, and 29-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 9289427 (‘427) in view of Venkatesh et al. (US20050232988) and further in view of Khadka et al. (Asian J. of Pharm. Sci., 2014, 304-316, from IDS), WO02/20464 (‘464), US8580781 (‘0781). ‘427 teaches methods for treating various cancers comprising administering effective amounts of claimed 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile to patients. “427 does not teach aspect of the claimed composition beyond the active agent. However, these deficiencies in ‘427 are addressed by Venkatesh et al. (US20050232988) and further in view of Khadka et al. (Asian J. of Pharm. Sci., 2014, 304-316, from IDS), WO02/20464 (‘464), US8580781 (‘0781).
Venkatesh teaches tablets for oral administration/pharmaceutical administration, specifically immediate release as Venkatesh teaches their formulations are bioequivalent to immediate release, comprising mannitol/sugar alcohol which reads on the claimed filler, and which comprises micronized drug, wherein the drug particles have an average particle diameter of less than 50 microns, preferably less than 25 microns, which reads on the claimed 5 microns to 80 microns as a d50 value and wherein the solid composition granules have an average particle size of 200 microns which read on the claimed 50 microns to 1mm d50 value, and wherein the micronized drug particles are blended with the binder, e.g. hydroxypropylmethylcellulose (see [0014-0015]; [0002]; [0038]; [0020-0026]; [0028-0029]; claims).
Venkatesh teaches that their solid compositions which contain micronized drug which is not limited and includes any drug which can be administered orally and as such would broadly include the claimed tepotinib ([0025]).
Venkatesh teaches that their solid compositions which contain micronized drug which is not limited and includes any drug which can be administered orally, and as such would broadly include the claimed tepotinib, and they teach wherein the drug is present in the tablets in amounts of about 0.01 to about 30% by weight based on the total weight of the tablet ([0025]), the claimed binder(s) which may or may not be present (claims; [0014-0015]; [0002]; [0038]; [0020-0026]; [0028-0029]), the claimed fillers typically in amounts of about 30 to 70% by weight based on the total weight of the tablet ([0028]), can further comprise disintegrants, specifically the instantly claimed crospovidone, which is typically present in amounts of about 1 to 10% by weight based on the total tablet weight ([0029]), which read on instant claims 17-18, and 20. Venkatesh also teaches wherein a lubricating agent such as the claimed magnesium stearate is not typically added to the mix but, can be added as is conventional, but they prefer applying the lubricant to the tableting punches and dies are lubricated with the lubricants in a fine mist prior to tableting, thus placing trace amounts of lubricant on the tablet surface, which reads on the amounts of lubricant contained in claims 17-18. Though Venkatesh clearly states that the act of blending the lubricant with the lubricant with the compression mix and tableting using a conventional tablet press is also an embodiment of their invention ([0030]).
Khadka teaches that particle size reduction, specifically micronization is a conventional technique for particle size reduction that is commonly used to increase solubility of BCS class II drugs because it is a simple and safe method that leads to increasing the dissolution rate of drugs by increasing the surface area to drug ratio by which the active ingredient can dissolve or diffuse from the drug particles (see section 2.1; see section 2 conventional particle size reduction techniques: 1st paragraph). Khadka further teaches wherein BCS class IV drugs (includes tepotinib) have their solubilities improved by micronizing as is done for BCS class II drugs with the addition of absorption enhancers (see section 1.2 last complete paragraph).
‘0781 teaches that tepotinib, compound A257, specifically the claimed salts were known in the art, and were known to be formulated for oral delivery and could be formulated with binders, fillers, lubricants, disintegrants, etc. and that it was known to make the compound into a fine size (e.g. micronized) and mix with excipients such as mannitol, etc. (abstract; Col. 14, ln. 51-53; compound A257; Pharmacological Data section; claims; Col 15, ln. 59-Col. 16, ln. 17; Col. 16, ln. 18-Col. 17, ln. 3).
‘464 teaches that 0.5% of magnesium stearate is a known amount of lubricant to add to oral solid dosage formulations (See Example 4).
It would have been obvious to form the claimed composition when looking to ‘427 because ‘427 teaches that the claimed compound is active for treating various types of cancer and one of ordinary skill in the art would be motivated to form the claimed micronized oral formulation in order to provide compositions for treating cancer which have improved solubility as micronization of poorly soluble actives is known in the art to increase their solubility and Venkatesh teaches formulations which comprise the claimed binder and filler which are useful for oral administration, immediate release, as tablets, etc. as claimed and discussed above and wherein the poorly soluble drug is micronized and wherein the solid formulations comprise overlapping amounts of the claimed components as is taught by the combined references above, and because it is known “[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 reAller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Further, Venkatesh teaches that their solid compositions lead to improved solubility of poorly water soluble active agents which can be orally administered. One of ordinary skill in the art would have been motivated to formulate the claimed composition for use in the method of ‘427 because micronizing of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile when in the formulation of Venkatesh as the active agent would be expected to increase the solubility of the 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile thereby leading to a more effective treatment of the claimed cancers of ‘427. Thus, the instantly claimed composition would have been obvious to one of ordinary skill in the art when taken in view of ‘427 and the combined references as discussed above.
Claims 1, 3, 5, 7-8, 10-13, 16-18, 20, and 29-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-34 of U.S. Patent No. 9308205 (‘205) in view of Venkatesh et al. (US20050232988) and further in view of Khadka et al. (Asian J. of Pharm. Sci., 2014, 304-316, from IDS), WO02/20464 (‘464), US8580781 (‘0781).
‘205 claims/teaches composition comprising effective amounts of the claimed 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile in composition with carriers and/or diluents, etc. ‘205 does not teach the specifically claimed composition having the claimed particle sizes, etc. and/or amounts of the claimed compounds as instantly claimed. However, these deficiencies in ‘205 are addressed by Venkatesh et al. (US20050232988) and further in view of Khadka et al. (Asian J. of Pharm. Sci., 2014, 304-316, from IDS), WO02/20464 (‘464), US8580781 (‘0781).
Venkatesh teaches tablets for oral administration/pharmaceutical administration, specifically immediate release as Venkatesh teaches their formulations are bioequivalent to immediate release, comprising mannitol/sugar alcohol which reads on the claimed filler, and which comprises micronized drug, wherein the drug particles have an average particle diameter of less than 50 microns, preferably less than 25 microns, which reads on the claimed 5 microns to 80 microns as a d50 value and wherein the solid composition granules have an average particle size of 200 microns which read on the claimed 50 microns to 1mm d50 value, and wherein the micronized drug particles are blended with the binder, e.g. hydroxypropylmethylcellulose (see [0014-0015]; [0002]; [0038]; [0020-0026]; [0028-0029]; claims).
Venkatesh teaches that their solid compositions which contain micronized drug which is not limited and includes any drug which can be administered orally and as such would broadly include the claimed tepotinib ([0025]).
Venkatesh teaches that their solid compositions which contain micronized drug which is not limited and includes any drug which can be administered orally, and as such would broadly include the claimed tepotinib, and they teach wherein the drug is present in the tablets in amounts of about 0.01 to about 30% by weight based on the total weight of the tablet ([0025]), the claimed binder(s) which may or may not be present (claims; [0014-0015]; [0002]; [0038]; [0020-0026]; [0028-0029]), the claimed fillers typically in amounts of about 30 to 70% by weight based on the total weight of the tablet ([0028]), can further comprise disintegrants, specifically the instantly claimed crospovidone, which is typically present in amounts of about 1 to 10% by weight based on the total tablet weight ([0029]), which read on instant claims 17-18, and 20. Venkatesh also teaches wherein a lubricating agent such as the claimed magnesium stearate is not typically added to the mix but, can be added as is conventional, but they prefer applying the lubricant to the tableting punches and dies are lubricated with the lubricants in a fine mist prior to tableting, thus placing trace amounts of lubricant on the tablet surface, which reads on the amounts of lubricant contained in claims 17-18. Though Venkatesh clearly states that the act of blending the lubricant with the lubricant with the compression mix and tableting using a conventional tablet press is also an embodiment of their invention ([0030]).
Khadka teaches that particle size reduction, specifically micronization is a conventional technique for particle size reduction that is commonly used to increase solubility of BCS class II drugs because it is a simple and safe method that leads to increasing the dissolution rate of drugs by increasing the surface area to drug ratio by which the active ingredient can dissolve or diffuse from the drug particles (see section 2.1; see section 2 conventional particle size reduction techniques: 1st paragraph). Khadka further teaches wherein BCS class IV drugs (includes tepotinib) have their solubilities improved by micronizing as is done for BCS class II drugs with the addition of absorption enhancers (see section 1.2 last complete paragraph).
‘0781 teaches that tepotinib, compound A257, specifically the claimed salts were known in the art, and were known to be formulated for oral delivery and could be formulated with binders, fillers, lubricants, disintegrants, etc. and that it was known to make the compound into a fine size (e.g. micronized) and mix with excipients such as mannitol, etc. (abstract; Col. 14, ln. 51-53; compound A257; Pharmacological Data section; claims; Col 15, ln. 59-Col. 16, ln. 17; Col. 16, ln. 18-Col. 17, ln. 3).
‘464 teaches that 0.5% of magnesium stearate is a known amount of lubricant to add to oral solid dosage formulations (See Example 4).
It would have been obvious to one of ordinary skill in the art at the time of the instant filing to have formed the claimed composition when looking to ‘205 and the combined references because it would have been obvious to form the claimed micronized 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile in the composition of ‘205 with the filler and binder as instantly claimed and taught by Venkatesh and ‘464 and the combined references because Venkatesh teaches that by combining poorly water soluble drugs in amounts that overlap those instantly claimed with the claimed filler, mannitol, in overlapping amounts and with lubricant which can be on the surface of the tablets or in the formulation (and which were known in the art to be used in oral tablets in amounts which overlap those instantly claimed as taught by ‘464) led to oral tablet formulations for immediate release and it is known “[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 reAller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Further, Venkatesh teaches wherein their compositions have improved drug solubility which is not unexpected because micronizing drugs is a known conventional way to safely improve solubility of drugs by increasing the surface area to drug ratio. Thus, it would have been obvious to form the claimed oral drug compositions/formulations instantly claimed when looking to the combined prior art in effort which together teach forming oral tablet formulations of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile which offer increased solubility over the formulations compositions of ‘205. Thus, one of ordinary skill in the art would conclude that the instantly claimed compositions are obvious when taken in view of ‘205 and the combined prior art for the reasons discussed above.
Claims 1-3, 5, 7-8, 10-13, 16-18, 20, and 29-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 10231972 (‘972) in view of Venkatesh et al. (US20050232988) and further in view of Khadka et al. (Asian J. of Pharm. Sci., 2014, 304-316, from IDS), WO02/20464 (‘464), US8580781 (‘0781).
‘972 claims/teaches a composition(s) comprising effective amounts of the claimed 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile in composition with acceptable excipients for oral administration. ‘972 does not teach the specifically claimed composition having the claimed particle sizes, etc. and/or amounts of the claimed compounds as instantly claimed. However, these deficiencies in ‘205 are addressed by Venkatesh et al. (US20050232988) and further in view of Khadka et al. (Asian J. of Pharm. Sci., 2014, 304-316, from IDS), WO02/20464 (‘464), US8580781 (‘0781).
Venkatesh teaches tablets for oral administration/pharmaceutical administration, specifically immediate release as Venkatesh teaches their formulations are bioequivalent to immediate release, comprising mannitol/sugar alcohol which reads on the claimed filler, and which comprises micronized drug, wherein the drug particles have an average particle diameter of less than 50 microns, preferably less than 25 microns, which reads on the claimed 5 microns to 80 microns as a d50 value and wherein the solid composition granules have an average particle size of 200 microns which read on the claimed 50 microns to 1mm d50 value, and wherein the micronized drug particles are blended with the binder, e.g. hydroxypropylmethylcellulose (see [0014-0015]; [0002]; [0038]; [0020-0026]; [0028-0029]; claims).
Venkatesh teaches that their solid compositions which contain micronized drug which is not limited and includes any drug which can be administered orally and as such would broadly include the claimed tepotinib ([0025]).
Venkatesh teaches that their solid compositions which contain micronized drug which is not limited and includes any drug which can be administered orally, and as such would broadly include the claimed tepotinib, and they teach wherein the drug is present in the tablets in amounts of about 0.01 to about 30% by weight based on the total weight of the tablet ([0025]), the claimed binder(s) which may or may not be present (claims; [0014-0015]; [0002]; [0038]; [0020-0026]; [0028-0029]), the claimed fillers typically in amounts of about 30 to 70% by weight based on the total weight of the tablet ([0028]), can further comprise disintegrants, specifically the instantly claimed crospovidone, which is typically present in amounts of about 1 to 10% by weight based on the total tablet weight ([0029]), which read on instant claims 17-18, and 20. Venkatesh also teaches wherein a lubricating agent such as the claimed magnesium stearate is not typically added to the mix but, can be added as is conventional, but they prefer applying the lubricant to the tableting punches and dies are lubricated with the lubricants in a fine mist prior to tableting, thus placing trace amounts of lubricant on the tablet surface, which reads on the amounts of lubricant contained in claims 17-18. Though Venkatesh clearly states that the act of blending the lubricant with the lubricant with the compression mix and tableting using a conventional tablet press is also an embodiment of their invention ([0030]).
Khadka teaches that particle size reduction, specifically micronization is a conventional technique for particle size reduction that is commonly used to increase solubility of BCS class II drugs because it is a simple and safe method that leads to increasing the dissolution rate of drugs by increasing the surface area to drug ratio by which the active ingredient can dissolve or diffuse from the drug particles (see section 2.1; see section 2 conventional particle size reduction techniques: 1st paragraph). Khadka further teaches wherein BCS class IV drugs (includes tepotinib) have their solubilities improved by micronizing as is done for BCS class II drugs with the addition of absorption enhancers (see section 1.2 last complete paragraph).
‘0781 teaches that tepotinib, compound A257, specifically the claimed salts were known in the art, and were known to be formulated for oral delivery and could be formulated with binders, fillers, lubricants, disintegrants, etc. and that it was known to make the compound into a fine size (e.g. micronized) and mix with excipients such as mannitol, etc. (abstract; Col. 14, ln. 51-53; compound A257; Pharmacological Data section; claims; Col 15, ln. 59-Col. 16, ln. 17; Col. 16, ln. 18-Col. 17, ln. 3).
‘464 teaches that 0.5% of magnesium stearate is a known amount of lubricant to add to oral solid dosage formulations (See Example 4).
It would have been obvious to one of ordinary skill in the art at the time of the instant filing to have formed the claimed composition when looking to ‘972 and the combined references because it would have been obvious to form the claimed micronized 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile in the claimed salt forms, in the composition of ‘972 with the filler and binder as instantly claimed and taught by Venkatesh and ‘464 and the combined references because Venkatesh teaches that by combining poorly water soluble drugs in amounts that overlap those instantly claimed with the claimed filler, mannitol in overlapping amounts and with lubricant which can be on the surface of the tablets or in the formulation (and which were known in the art to be used in oral tablets in amounts which overlap those instantly claimed as taught by ‘464) led to oral tablet formulations for immediate release and it is known, “[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 reAller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Further, Venkatesh teaches wherein their formulations had improved drug solubility which is not unexpected because micronizing drugs is a known conventional way to safely improve solubility of drugs by increasing the surface area to drug ratio. Thus, it would have been obvious to form the claimed oral drug compositions/formulations instantly claimed when looking to the combined prior art in effort which together teach forming oral tablet formulations of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile in the claimed salt forms which offer increased solubility over the formulations compositions of ‘972. Thus, one of ordinary skill in the art would conclude that the instantly claimed compositions are obvious when taken in view of ‘972 and the combined prior art for the reasons discussed above.
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.
Claim(s) 1-3, 5, 7-8, 10-13, 16-20 (there was a small typo in this rejection statement previously as claim 19 was clearly covered in the rejection), and 30-31 is/are rejected under 35 U.S.C. 103 as being unpatentable over Venkatesh et al. (US20050232988) and further in view of Khadka et al. (Asian J. of Pharm. Sci., 2014, 304-316, from IDS), WO02/20464 (‘464), US8580781 (‘0781).
Determination of the scope and content of the prior art
(MPEP 2141.01)
Regarding claims 1, 3, 5, 7-8, 10-13, 16, 20, and 30-31, Venkatesh teaches tablets for oral administration/pharmaceutical administration, specifically immediate release as Venkatesh teaches their formulations are bioequivalent to immediate release, comprising mannitol/sugar alcohol which reads on the claimed filler, and which comprises micronized drug, wherein the drug particles have an average particle diameter of less than 50 microns, preferably less than 25 microns, which reads on the claimed 5 microns to 80 microns as a d50 value and wherein the solid composition granules have an average particle size of 200 microns which read on the claimed 50 microns to 1mm d50 value, and wherein the micronized drug particles are blended with the binder, e.g. hydroxypropylmethylcellulose, which reads on new claims 30-31 and because they are blended with the binder the binder is present in an amount of greater than 0% (see [0014-0015]; [0002]; [0038]; [0020-0026]; [0028-0029]; claims).
Venkatesh teaches that their solid compositions which contain micronized drug which is not limited and includes any drug which can be administered orally and as such would broadly include the claimed tepotinib ([0025]).
Regarding claims 1, 17-19 (again limitations of claim 19 are clearly covered herein and 19 being missing from this claim statement is a typo), 20, 30-31, Venkatesh teaches that their solid compositions which contain micronized drug which is not limited and includes any drug which can be administered orally, and as such would broadly include the claimed tepotinib, and they teach wherein the drug is present in the tablets in amounts of about 0.01 to about 30% by weight based on the total weight of the tablet ([0025]), the claimed binder(s) which may be present (claims; [0014-0015]; [0002]; [0038]; [0020-0026]; [0028-0029]), the claimed fillers typically in amounts of about 30 to 70% by weight based on the total weight of the tablet ([0028]), can further comprise disintegrants, specifically the instantly claimed crospovidone, which is typically present in amounts of about 1 to 10% by weight based on the total tablet weight ([0029]). Venkatesh also teaches wherein a lubricating agent such as the claimed magnesium stearate is not typically added to the mix but, can be added as is conventional, but they prefer applying the lubricant to the tableting punches and dies are lubricated with the lubricants in a fine mist prior to tableting, thus placing trace amounts of lubricant on the tablet surface, which reads on the amounts of lubricant contained. Though Venkatesh clearly states that the act of blending the lubricant with the lubricant with the compression mix and tableting using a conventional tablet press is also an embodiment of their invention ([0030]).
Ascertainment of the difference between prior art and the claims
(MPEP 2141.02)
Regarding claims 1-3, 5, 7-8, 10-13, 16-18, 20, and 30-31, Venkatesh does not teach wherein the active agent is the specifically the claimed micronized tepotinib in the claimed salt forms. This deficiency in Venkatesh is addressed by ‘0781 and Khadka.
Khadka teaches that particle size reduction, specifically micronization is a conventional technique for particle size reduction that is commonly used to increase solubility of BCS class II drugs because it is a simple and safe method that leads to increasing the dissolution rate of drugs by increasing the surface area to drug ratio by which the active ingredient can dissolve or diffuse from the drug particles (see section 2.1; see section 2 conventional particle size reduction techniques: 1st paragraph). Khadka further teaches wherein BCS class IV drugs (includes tepotinib) have their solubilities improved by micronizing as is done for BCS class II drugs with the addition of absorption enhancers (see section 1.2 last complete paragraph).
‘0781 teaches that tepotinib, compound A257, specifically the claimed salts were known in the art, and were known to be formulated for oral delivery and could be formulated with binders, fillers, lubricants, disintegrants, etc. and that it was known to make the compound into a fine size (e.g. micronized) and mix with excipients such as mannitol, etc. (abstract; Col. 14, ln. 51-53; compound A257; Pharmacological Data section; claims; Col 15, ln. 59-Col. 16, ln. 17; Col. 16, ln. 18-Col. 17, ln. 3).
Regarding claim 19, Venkatesh does not teach wherein their composition comprises the claimed amount of lubricant/magnesium stearate. However, this deficiency is addressed by ‘464.
‘464 teaches that 0.5% of magnesium stearate is a known amount of lubricant to add to oral solid dosage formulations (See Example 4).
Finding of prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
It would have been obvious to one of ordinary skill in the art at the time of the instant filing to have formed the claimed solid composition and pharmaceutical composition(s) instantly claimed because Venkatesh teaches that it was known in the art to formulate solid compositions of poorly soluble drugs by micronizing them to the claimed particle size and combining them with binder and filler, specifically sugar alcohol fillers, such as mannitol to form granules of the claimed size. One of ordinary skill in the art would be motivated to use the claimed tepotinib as the micronized drug in the claimed amounts into the formulation of Venkatesh because Venkatesh teaches very similar solid compositions and pharmaceutical compositions which can comprise the micronized form of orally delivered drugs which are poorly soluble (and which are not limited) with the same excipients in overlapping amounts to those instantly claimed and it was known to micronize poorly soluble drugs in order to increase their solubility and mannitol is also known to help increase solubility of poorly soluble drugs and Khadka teaches that particle size reduction, specifically micronization is a conventional technique for particle size reduction that is commonly used to increase solubility of BCS class II drugs because it is a simple and safe method that leads to increasing the dissolution rate of drugs by increasing the surface area to drug ratio by which the active ingredient can dissolve or diffuse from the drug particles and Khadka teaches that this technique is also useful with BCS class IV drugs which include tepotinib, and ‘0781 teaches that it was known to make tepotinib into a fine size, e.g. micronize the drug as discussed above. Thus, it would be obvious to select tepotinib as the drug to be used in the formulation of Venkatesh and to micronize it to improve the solubility by increasing the surface area and formulating it with mannitol which is also known to help increase solubility of drugs in order to form a more soluble/effective tepotinib oral formulation because it was already known in the art to micronize poorly water soluble drugs which would include tepotinib to increase their solubility and it was known to formulate poorly soluble drugs in the same types of immediate release, etc. oral tablet formulations as claimed as taught by Venkatesh because one of ordinary skill in the art would have had a reasonable expectation that the formulation of Venkatesh containing the micronized tepotinib as taught by ‘0781 would improve/increase the solubility of tepotinib and allow for an effective immediate release oral tablet formulation of tepotinib based on the combined teachings of the prior art as discussed above.
Regarding claim 19, Venkatesh does not teach wherein the formulation comprises more than 30% drug or wherein the lubricant is present in the claimed amounts. However, it was known to use overlapping amounts of the claimed lubricants in oral formulations as is taught by ‘464. It also would have been obvious to optimize the amount of active drug, specifically the claimed tepotinib in the formulation of Vekatesh to read on the claimed amounts, e.g. 35% of tepotinib and 40% of filler, and to have from greater than 0% to 5% by weight binder because it was known in the art to optimize the amounts of active drug, fillers, and binder in oral formulations in order to form more/the most effective tepotinib oral formulations. “[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 reAller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Regarding the other claimed formulations, it would have been obvious to combine the claimed amounts of tepotinib with the claimed amounts of filler and claimed amounts of other components, e.g. the newly claimed amounts of greater than 0% to 10% of binder and/or greater than 0% to 5% of binder by weight, because as discussed above Venkatesh already teaches combining overlapping amounts of their poorly water soluble drug which is not limited with overlapping amounts to those instantly claimed of filler and it was known in the art to use overlapping amounts of the claimed lubricants in oral formulations as discussed above because it was known in the art to optimize the amounts of active drug and fillers, and other known excipients in oral formulations in order to form more/the most effective tepotinib oral formulations. “[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 reAller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the above claims would have been obvious to one of ordinary skill in the art within the meaning of 35 USC 103(a).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 29, and 32-35 is/are rejected under 35 U.S.C. 103 as being unpatentable over Venkatesh et al. (US20050232988) and further in view of Khadka et al. (Asian J. of Pharm. Sci., 2014, 304-316, from IDS), WO02/20464 (‘464), US8580781 (‘0781).
Determination of the scope and content of the prior art
(MPEP 2141.01)
Regarding claims 29, 32-33, and 35, Venkatesh teaches tablets for oral administration/pharmaceutical administration, specifically immediate release as Venkatesh teaches their formulations are bioequivalent to immediate release, comprising mannitol/sugar alcohol which reads on the claimed filler, and which comprises micronized drug, wherein the drug particles have an average particle diameter of less than 50 microns, preferably less than 25 microns, which reads on the claimed 5 microns to 80 microns as a d50 value and wherein the solid composition granules have an average particle size of 200 microns which read on the claimed 50 microns to 1mm d50 value, and wherein the micronized drug particles are blended with the binder, e.g. hydroxypropylmethylcellulose, which reads on new claims 32-33 (see [0014-0015]; [0002]; [0038]; [0020-0026]; [0028-0029]; claims).
Venkatesh teaches that their solid compositions which contain micronized drug which is not limited and includes any drug which can be administered orally and as such would broadly include the claimed tepotinib ([0025]).
Regarding claims 29, 32-33, and 35, Venkatesh teaches that their solid compositions which contain micronized drug which is not limited and includes any drug which can be administered orally, and as such would broadly include the claimed tepotinib, and they teach wherein the drug is present in the tablets in amounts of about 0.01 to about 30% by weight based on the total weight of the tablet ([0025]), the claimed binder(s) which may be present and as such when present would read on amounts of greater than 0 to 20% (claims; [0014-0015]; [0002]; [0038]; [0020-0026]; [0028-0029]), the claimed fillers typically in amounts of about 30 to 70% by weight based on the total weight of the tablet ([0028]), can further comprise disintegrants, specifically the instantly claimed crospovidone, which is typically present in amounts of about 1 to 10% by weight based on the total tablet weight ([0029]). Venkatesh also teaches wherein a lubricating agent such as the claimed magnesium stearate is not typically added to the mix but, can be added as is conventional, but they prefer applying the lubricant to the tableting punches and dies are lubricated with the lubricants in a fine mist prior to tableting, thus placing trace amounts of lubricant on the tablet surface, which reads on the amounts of lubricant. Though Venkatesh clearly states that the act of blending the lubricant with the lubricant with the compression mix and tableting using a conventional tablet press is also an embodiment of their invention ([0030]).
Ascertainment of the difference between prior art and the claims
(MPEP 2141.02)
Regarding claims 29, and 32-35, Venkatesh does not teach wherein the active agent is the specifically the claimed micronized tepotinib in the claimed salt forms or wherein the active agent is used in concentrations of greater than 30 wt%, specifically the now claimed 35 wt% of new claim 29. This deficiencies in Venkatesh are addressed by ‘0781 and Khadka.
Venkatesh does not teach wherein the formulation comprises more than 30% drug. It would have been obvious to optimize the amount of active drug, specifically the claimed tepotinib, in the formulation of Vekatesh to read on the claimed amounts, e.g. 35% of tepotinib because it was known in the art to optimize the amounts of active drug and fillers in pharmaceutical formulations in order to form more/the most effective tepotinib formulations. “[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 reAller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Khadka teaches that particle size reduction, specifically micronization is a conventional technique for particle size reduction that is commonly used to increase solubility of BCS class II drugs because it is a simple and safe method that leads to increasing the dissolution rate of drugs by increasing the surface area to drug ratio by which the active ingredient can dissolve or diffuse from the drug particles (see section 2.1; see section 2 conventional particle size reduction techniques: 1st paragraph). Khadka further teaches wherein BCS class IV drugs which include the claimed tepotinib also have their solubilities improved by micronizing as is done for BCS class II drugs with the addition of absorption enhancers (see section 1.2 last complete paragraph).
‘0781 teaches that tepotinib, compound A257, specifically that the i