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 .
Formal Matters
Applicant’s claim amendments and arguments in the reply filed on 21 November 2025 are acknowledged and have been fully considered. Claims 1-2, 4-6, 8-20, and 24-25 are pending. Claims 1-2, 4-6, and 8-19 are under consideration in the instant office action. Claims 20 and 24-25 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and/or species, there being no allowable generic or linking claims. Claims 3, 7, and 21-23 are canceled. Applicant’s claim amendments and arguments did not overcome the rejections set forth under 35 USC 103 in the previous office action for reasons set forth herein below.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d) and an updated bibliography data is attached acknowledging the receipt of the English translation of the foreign priority document.
Withdrawn Objections/Rejections
Rejections and/or objections not reiterated from the previous office actions are hereby withdrawn as are those rejections and/or objections expressly stated to be withdrawn.
Rejections Maintained
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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 under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
Claims 1-2, 4-6, 8, 10, 12, and 14-18 are rejected under 35 U.S.C. 103 as being unpatentable over Ding et al. (US 2017/0129909) in view of VERWIJS et al. (US 2018/0256610).
Applicant Claims
Applicants claim a pharmaceutical composition, comprising a spirocyclic aryl phosphorus oxide or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier, wherein, the spirocyclic aryl phosphorus oxide has the following structure:
PNG
media_image1.png
290
330
media_image1.png
Greyscale
the D90 of the spirocyclic aryl phosphorus oxide or a pharmaceutically acceptable salt
thereof is in a range of 40.3 mm to 79.6 mm.
Determination of the Scope and Content of the Prior Art (MPEP §2141.01)
Ding et al. teach anaplastic lymphoma kinase (ALK) is a part of the receptor tyrosine kinases (RTKs) protein family. ALK gene provides an instruction to make receptor tyrosine kinase protein transmit the signal from the surface of a cell to internal by a procedure of signal transmission. The procedure starts with stimulating the kinases of the cell surface and the dimerization of the kinases. After the dimerization, kinase was marked by a phosphate group, which is called phosphorylation. This process activates the kinases. The activated kinases can transfer the phosphate group to another protein in the cell, and further phosphorylate a series of downstream protein. This signal transmission pathway is very important to many cellular processes, such as cell growth and segmentation (proliferation) or cell maturation (differentiation) (see paragraph 0003). Ding et al. teach a spirocyclic aryl phosphorus oxide or sulfide as an ALK inhibitor, particularly, a compound represented by formula (I) as an ALK inhibitor or pharmaceutically acceptable salt thereof (see claim 1).
PNG
media_image2.png
231
300
media_image2.png
Greyscale
Ding et al. teach the claimed compound (compound 9) in a Markush list in claim 11
PNG
media_image3.png
276
322
media_image3.png
Greyscale
The term “pharmaceutically acceptable carrier” refers to any formulation or carrier medium that is capable of delivery of an effective amount of an active agent of the invention without toxic side effects on a host or patient. The term “excipients” conventionally means carriers, diluents and/or vehicles needed in formulating effective pharmaceutical compositions (paragraph 0062). Certain compounds of the invention can exist in unsolvated forms or solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and all are encompassed within the scope of the present invention. Certain compounds of the invention may exist in polycrystalline or amorphous forms (paragraph 0055).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.012)
Ding et al. do not specifically teach a D90 of the spirocyclic aryl phosphorus oxide or a pharmaceutically acceptable salt thereof is in a range of 40.3 mm to 79.6 mm and a D50 of the spirocyclic aryl phosphorus oxide or a pharmaceutically acceptable salt thereof is in a range of 13.0 mm to 23.8 mm or in a range of 13.0 mm to 18.2 mm as recited in claim 2. These deficiencies are cured by the teachings of VERWIJS et al.
VERWIJS et al. teach a pharmaceutical composition comprising 5-chloro-N4-[2- (dimethylphosphoryl)phenyl]-N2- {2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1- yl]phenyl}pyrimidine-2,4-diamine as the active pharmaceutical ingredient, and therapeutic uses of the pharmaceutical formulation. In particular, the invention is directed to tablets comprising the pharmaceutical composition, methods of preparing the tablets, and therapeutic uses thereof (see abstract). Brigatinib has the chemical formula C29H39CIN7O2P, which corresponds to a formula weight of 584.09 g/mol. Its chemical structure is shown below.
PNG
media_image4.png
138
330
media_image4.png
Greyscale
Brigatinib is a multi-targeted tyrosine-kinase inhibitor useful for the treatment of non-small cell lung cancer (NSCLC) and other diseases. It is a potent inhibitor of ALK (anaplastic lymphoma kinase) and is in clinical development for the treatment of adult patients with ALK-driven NSCLC. Crizotinib (XALKORI ®) is an FDA approved drug for first-line treatment of ALKpositive NSCLC, but as stated in Shaw et al., New Eng. J. Med. 370:1 189-97 2014 "Despite initial responses to crizotinib, the majority of patients have a relapse within 12 months, owing to the development of resistance." Brigatinib is thus a new and effective therapy for cancer patients with ALK-positive cancers (see paragraph 0004). Brigatinib is a structurally analogous ALK inhibitor like the sharing the identical 5-chloro-2,4-diaminopyrimidine core, 2-(dimethylphosphoryl)phenyl substituent at the 4-position, and 2-methoxy-4-(basic heterocyclic)phenyl substituent at the 2-position. The sole difference in the side chain is replacement of the 4-(4-methylpiperazin-1-yl)piperidin-1-yl group with the recited 9-methyl-3,9-diazaspiro[5.5]undecane-3-yl group, which is a minor variation as both are rigidified bis-nitrogenous heterocycles serving as basic appendages for kinase pocket engagement and solubility enhancement (see claim 11 of Ding et al. for different variants as equivalents for such purpose). VERWIJS et al. teach categories of excipients commonly used in the pharmaceutical industry for the preparation of solid dosage forms include fillers, binders, lubricants, glidants, disintegrants and preservatives. The choice of excipients within each category, the amounts thereof, and their degree of compatibility with the active pharmaceutical ingredient gives rise to an extremely wide range of possible formulations of widely varying properties (see paragraph 0042). The pharmaceutical composition of the first aspect of the invention preferably comprises one or more disintegrants. Disintegrants are substances that expand upon contact with moisture in the digestive tract and thus facilitate the disintegration of tablets and the release of the brigatinib active ingredient following ingestion. A preferred disintegrant is sodium starch glycolate Type A. Preferably, sodium starch glycolate Type A is present in an amount of from about 0.5 to about 5 wt% of the pharmaceutical composition. It has been found that the use of sodium starch glycolate Type A as a disintegrant results in improved stability of the brigatinib active ingredient when compared to other disintegrants that are available in the art (see paragraph 0053). The pharmaceutical composition of the first aspect of the invention preferably comprises one or more glidants. More preferably, the pharmaceutical composition of the first aspect of the invention comprises hydrophobic colloidal silica. Still more preferably, the pharmaceutical composition of the first aspect of the invention comprises about 0.2 to about 3 wt% of hydrophobic colloidal silica (see paragraph 0071). The pharmaceutical composition of the second aspect of the invention preferably comprises one or more fillers. More preferably, the pharmaceutical composition of the second aspect of the invention comprises one or more of lactose monohydrate and microcrystalline cellulose. Still more preferably, the pharmaceutical composition of the second aspect of the invention comprises about 20 to about 50 wt% of lactose monohydrate and about 15 to about 50 wt% of microcrystalline cellulose (see paragraph 0061). In order to enhance the manufacturability of solid dosage forms, particularly tablets, comprising the pharmaceutical composition, the composition of the first aspect of the invention preferably further comprises one or more lubricants. The use of lubricants prevents sticking of the pharmaceutical composition to die walls during compression and ejection of tablet cores. A preferred lubricant is magnesium stearate. Suitably, the magnesium stearate is present in an amount of from about 0.2 to about 3 wt%, for example from about 0.5 to about 2.5 wt%, from about 0.8 to about 2 wt% or from about 1 to about 1.8 wt% (see paragraph 0078). In accordance with the invention, the brigatinib particle size may be controlled in order to optimize the properties of solid oral dosage forms comprising the pharmaceutical composition of the invention. It has been found that increased hardness and reduced friability of tablet cores comprising the pharmaceutical composition are obtained when the brigatinib has a D50 particle size in the range of from about 5 to about 25 µm, preferably from about 6 to about 25 mm, preferably from about 8 to about 22 μm, more preferably from about 10 to about 20 µm (see page 13). The D90 particle size of the brigatinib particles is preferably no more than about 90 µm, more preferably no more than about 60 µm, more preferably no more than about 55 µm, more preferably no more than about 50 µm, more preferably no more than about 45 µm (see paragraphs 0125-0127).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the instant invention to modify the teachings of Ding et al. by utilizing the spirocyclic aryl phosphorus oxide or a pharmaceutically acceptable salt thereof with a D90 in a range of 40.3 mm to 79.6 mm and a D50 in a range of 13.0 mm to 23.8 mm or in a range of 13.0 mm to 18.2 mm because VERWIJS et al. teach a pharmaceutical composition comprising 5-chloro-N4-[2- (dimethylphosphoryl)phenyl]-N2- {2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1- yl]phenyl}pyrimidine-2,4-diamine as the active pharmaceutical ingredient, and therapeutic uses of the pharmaceutical formulation. In particular, the invention is directed to tablets comprising the pharmaceutical composition, methods of preparing the tablets, and therapeutic uses thereof (see abstract). Brigatinib has the chemical formula C29H39CIN7O2P, which corresponds to a formula weight of 584.09 g/mol. Its chemical structure is shown below.
PNG
media_image4.png
138
330
media_image4.png
Greyscale
Brigatinib is a multi-targeted tyrosine-kinase inhibitor useful for the treatment of non-small cell lung cancer (NSCLC) and other diseases. It is a potent inhibitor of ALK (anaplastic lymphoma kinase) and is in clinical development for the treatment of adult patients with ALK-driven NSCLC. Crizotinib (XALKORI ®) is an FDA approved drug for first-line treatment of ALKpositive NSCLC, but as stated in Shaw et al., New Eng. J. Med. 370:1 189-97 2014 "Despite initial responses to crizotinib, the majority of patients have a relapse within 12 months, owing to the development of resistance." Brigatinib is thus a new and effective therapy for cancer patients with ALK-positive cancers (see paragraph 0004). Brigatinib is a structurally analogous ALK inhibitor like the sharing the identical 5-chloro-2,4-diaminopyrimidine core, 2-(dimethylphosphoryl)phenyl substituent at the 4-position, and 2-methoxy-4-(basic heterocyclic)phenyl substituent at the 2-position. The sole difference in the side chain is replacement of the 4-(4-methylpiperazin-1-yl)piperidin-1-yl group with the recited 9-methyl-3,9-diazaspiro[5.5]undecane-3-yl group, which is a minor variation as both are rigidified bis-nitrogenous heterocycles serving as basic appendages for kinase pocket engagement and solubility enhancement (see claim 11 of Ding et al. for different variants as equivalents for such purpose). VERWIJS et al. teach categories of excipients commonly used in the pharmaceutical industry for the preparation of solid dosage forms include fillers, binders, lubricants, glidants, disintegrants and preservatives. The choice of excipients within each category, the amounts thereof, and their degree of compatibility with the active pharmaceutical ingredient gives rise to an extremely wide range of possible formulations of widely varying properties (see paragraph 0042). The pharmaceutical composition of the first aspect of the invention preferably comprises one or more disintegrants. Disintegrants are substances that expand upon contact with moisture in the digestive tract and thus facilitate the disintegration of tablets and the release of the brigatinib active ingredient following ingestion. A preferred disintegrant is sodium starch glycolate Type A. Preferably, sodium starch glycolate Type A is present in an amount of from about 0.5 to about 5 wt% of the pharmaceutical composition. It has been found that the use of sodium starch glycolate Type A as a disintegrant results in improved stability of the brigatinib active ingredient when compared to other disintegrants that are available in the art (see paragraph 0053). The pharmaceutical composition of the first aspect of the invention preferably comprises one or more glidants. More preferably, the pharmaceutical composition of the first aspect of the invention comprises hydrophobic colloidal silica. Still more preferably, the pharmaceutical composition of the first aspect of the invention comprises about 0.2 to about 3 wt% of hydrophobic colloidal silica (see paragraph 0071). The pharmaceutical composition of the second aspect of the invention preferably comprises one or more fillers. More preferably, the pharmaceutical composition of the second aspect of the invention comprises one or more of lactose monohydrate and microcrystalline cellulose. Still more preferably, the pharmaceutical composition of the second aspect of the invention comprises about 20 to about 50 wt% of lactose monohydrate and about 15 to about 50 wt% of microcrystalline cellulose (see paragraph 0061). In order to enhance the manufacturability of solid dosage forms, particularly tablets, comprising the pharmaceutical composition, the composition of the first aspect of the invention preferably further comprises one or more lubricants. The use of lubricants prevents sticking of the pharmaceutical composition to die walls during compression and ejection of tablet cores. A preferred lubricant is magnesium stearate. Suitably, the magnesium stearate is present in an amount of from about 0.2 to about 3 wt%, for example from about 0.5 to about 2.5 wt%, from about 0.8 to about 2 wt% or from about 1 to about 1.8 wt% (see paragraph 0078). One of ordinary skill in the art would have been motivated to do so because VERWIJS et al. teach that, the brigatinib particle size may be controlled in order to optimize the properties of solid oral dosage forms comprising the pharmaceutical composition of the invention. It has been found that increased hardness and reduced friability of tablet cores comprising the pharmaceutical composition are obtained when the brigatinib has a D50 particle size in the range of from about 5 to about 25 µm, preferably from about 6 to about 25 mm, preferably from about 8 to about 22 μm, more preferably from about 10 to about 20 µm (see page 13). The D90 particle size of the brigatinib particles is preferably no more than about 90 µm, more preferably no more than about 60 µm, more preferably no more than about 55 µm, more preferably no more than about 50 µm, more preferably no more than about 45 µm (see paragraphs 0125-0127). Furthermore, in the case where the claimed ranges for amounts of ingredients and particle sizes “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). Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985). Furthermore, differences in concentration or particle size will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration 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). Thus, an ordinary skilled artisan would have had a reasonable expectation of success upon combination of the Ding et al. and VERWIJS et al. because both references teach pharmaceutical compositions comprising a structurally related spirocyclic aryl phosphorus oxide or a pharmaceutically acceptable salt thereof.
In light of the forgoing discussion, one of ordinary skill in the art would have concluded that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim(s) 9, 11, 13, and 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ding et al. (US2017/0129909) in view of VERWIJS et al. (US 2018/0256610) as applied to claims 1-2, 4-6, 8, 10, 12, and 14-18 above, and further in view of Wang et al. (WO 2006/000137, machine English translation provided).
Applicant Claims
Applicants claim a pharmaceutical composition, comprising a spirocyclic aryl phosphorus oxide or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier, wherein, the spirocyclic aryl phosphorus oxide has the following structure:
PNG
media_image1.png
290
330
media_image1.png
Greyscale
the D90 of the spirocyclic aryl phosphorus oxide or a pharmaceutically acceptable salt
thereof is in a range of 40.3 mm to 79.6 mm. Dependent claims 9 and 13 recite a specific type of disintegrant sodium carboxymethyl starch and a specific type of glidant micronized silica gel. Dependent claim 19 recites specific ingredients and their amounts.
Determination of the Scope and Content of the Prior Art (MPEP §2141.01)
The teachings of Ding et al. and VERWIJS et al. are described in detail above and are incorporated herein by reference.
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.012)
Ding et al. and VERWIJS et al. do not specifically teach sodium carboxymethyl starch as disintegrant type; micronized silica gel as a glidant type; hydroxypropyl methyl cellulose as adhesive or binder type; and the respective amounts of the ingredients in the composition as recited in claim 19. These deficiencies are cured by the teachings of Wang et al.
Wang et al. teach a panax notoginsenoside orally disintegrating tablet for treating cardiovascular and cerebrovascular diseases, the prescription composition comprising panax notoginseng saponins, a binder, a coating material, a filler, a disintegrating agent, a flavoring agent, Grafting agent, lubricant and other raw materials, the weight of each raw material is as follows: Panax notoginseng saponin 10% ~ 50%, binder 0~5%, coating material 0-40%, filler 20 %~80%. , disintegrant 2%~30%. , flavoring agent 1%~30%, effervescent agent 0~30%, glidant 0.01%~5 %, and lubricant 0.3%~3% (see claim 1). The panax notoginsenoside orally disintegrating tablet according to claim 1, wherein the binder is selected from the group consisting of starch, pregelatinized starch, dextrin, maltodextrin, sucrose, gum arabic, methylcellulose, Carboxymethylcellulose, ethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone (PVP), alginic acid, alginate, xanthan gum, hydroxypropyl methylcellulose (HPMC), can be used alone or combination thereof (see claim 2). The panax notoginsenoside orally disintegrating tablet according to claim 1, wherein the filler is selected from the group consisting of mannitol, microcrystalline cellulose, dextrin, lactose, starch, xylitol, sorbitol, erythritol , glucose, polymeric sugar, SMCC, pregelatinized starch, etc., or any combination thereof (see claim 4). The panax notoginsenoside orally disintegrating tablet according to claim 1, wherein the disintegrant is selected from the group consisting of crosslinked polyvinylpyrrolidone (PPVP), sodium carboxymethyl starch (CMS-Na), and low-substituted hydroxypropyl Methyl cellulose (L-HPC), croscarmellose Sodium (CCNa) or the like may be used singly or in combination (see claim 5). The panax notoginsenoside orally disintegrating tablet according to claim 1, wherein the glidant is selected from the group consisting of micronized silica gel, talc, Cab-Os i K Aros i K hydrated sodium aluminosilicate, or the like. Combination (see claim 8).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the instant invention to modify the teachings of Ding et al. and VERWIJS et al. by utilizing sodium carboxymethyl starch as disintegrant type and micronized silica gel as a glidant type and their respective amounts in the composition as recited in claim 19 because Wang et al. teach a panax notoginsenoside orally disintegrating tablet for treating cardiovascular and cerebrovascular diseases, the prescription composition comprising panax notoginseng saponins, a binder, a coating material, a filler, a disintegrating agent, a flavoring agent, Grafting agent, lubricant and other raw materials, the weight of each raw material is as follows: Panax notoginseng saponin 10% ~ 50%, binder 0~5%, coating material 0-40%, filler 20 %~80%. , disintegrant 2%~30%. , flavoring agent 1%~30%, effervescent agent 0~30%, glidant 0.01%~5 %, and lubricant 0.3%~3% (see claim 1). The panax notoginsenoside orally disintegrating tablet according to claim 1, wherein the binder is selected from the group consisting of starch, pregelatinized starch, dextrin, maltodextrin, sucrose, gum arabic, methylcellulose, Carboxymethylcellulose, ethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone (PVP), alginic acid, alginate, xanthan gum, hydroxypropyl methylcellulose (HPMC), can be used alone or combination thereof (see claim 2). The panax notoginsenoside orally disintegrating tablet according to claim 1, wherein the filler is selected from the group consisting of mannitol, microcrystalline cellulose, dextrin, lactose, starch, xylitol, sorbitol, erythritol , glucose, polymeric sugar, SMCC, pregelatinized starch, etc., or any combination thereof (see claim 4). The panax notoginsenoside orally disintegrating tablet according to claim 1, wherein the disintegrant is selected from the group consisting of crosslinked polyvinylpyrrolidone (PPVP), sodium carboxymethyl starch (CMS-Na), and low-substituted hydroxypropyl Methyl cellulose (L-HPC), croscarmellose Sodium (CCNa) or the like may be used singly or in combination (see claim 5). The panax notoginsenoside orally disintegrating tablet according to claim 1, wherein the glidant is selected from the group consisting of micronized silica gel, talc, Cab-Os i K Aros i K hydrated sodium aluminosilicate, or the like. Combination (see claim 8). One of ordinary skill in the art would have been motivated to utilize sodium carboxymethyl starch as disintegrant type and micronized silica gel as a glidant type and their respective amounts in the composition as recited in claim 19 because the ingredients are functionally equivalent disintegrants and glidants as the ones taught by Ding et al. and VERWIJS et al. One of ordinary skill in the art would have been motivated to utilize binders like HPMC because the adhesives or binders in the pharmaceutical industry as conventionally known and recognized by VERWIJS et al. and Wang et al., binders are essential excipients that hold active pharmaceutical ingredients (APIs) and other excipients together to form granules and tablets. They provide mechanical strength for manufacturing and handling, ensure tablets maintain their integrity, and prevent fragmentation during transport. Substituting one disintegrant, filler, binder, lubricant, etc., with another is prima facie obvious. The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945) (Claims to a printing ink comprising a solvent having the vapor pressure characteristics of butyl carbitol so that the ink would not dry at room temperature but would dry quickly upon heating were held invalid over a reference teaching a printing ink made with a different solvent that was nonvolatile at room temperature but highly volatile when heated in view of an article which taught the desired boiling point and vapor pressure characteristics of a solvent for printing inks and a catalog teaching the boiling point and vapor pressure characteristics of butyl carbitol.) Furthermore, in the case where the claimed ranges for amounts of ingredients “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). Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985). Furthermore, differences in concentration or particle size will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration 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). Thus, an ordinary skilled artisan would have had a reasonable expectation of success upon combination of the Ding et al., VERWIJS et al., and Wang et al. because all of the references teach pharmaceutical compositions comprising pharmaceutically acceptable excipients such as disintegrants, glidant, lubricants, fillers, etc., in order to formulate poorly soluble drugs into acceptable dosage forms such as granules and tablets.
In light of the forgoing discussion, one of ordinary skill in the art would have concluded that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 21 November 2025 have been fully considered but they are not persuasive.
Applicant argues “The experimental data as shown in Tables 5 and 6 of Applicant's specification demonstrate that, compared with dissolution data of other particle sizes, spirocyclic aryl phosphorus oxides with D90 in the range of 40.3 µm to 79.6 µm and D50 in the range of 13.0 µm to 23.8 µm are dissolved out most rapidly from pharmaceutical compositions. When the particle size of D90 is less than 40.3 µm or D50 is less than 13.0 µm, the dissolution gradually becomes slower, and when D90 is more than 79.6 µm or D50 is more than 23.8 µm, the dissolution is also slower. In addition, the pharmaceutical compositions of the present invention were taken for clinical trials. The result as shown in Table 9 of Applicant's specification demonstrates good bioavailability.”
The above assertions are not found persuasive because the examiner does acknowledge that the recited D90 and D50 particle size distribution ranges demonstrate criticality to a specific formulation disclosed in Table 3 through varying the particle size distributions as disclosed in Table 2. Tables 2 and 3 disclose as follows:
PNG
media_image5.png
682
910
media_image5.png
Greyscale
However, the examiner would like to remind applicant that the above formulation contains specific ingredients at specific amounts which is a single point data whereas claim one is drawn to pharmaceutical composition comprising the recited active with D90 and D50 values as recited and any pharmaceutically acceptable carrier at any amounts. The data is not commensurate in scope with the claims. Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (Claims were directed to a process for removing corrosion at "elevated temperatures" using a certain ion exchange resin (with the exception of claim 8 which recited a temperature in excess of 100°C). Appellant demonstrated unexpected results via comparative tests with the prior art ion exchange resin at 110°C and 130°C. The court affirmed the rejection of claims 1-7 and 9-10 because the term "elevated temperatures" encompassed temperatures as low as 60°C where the prior art ion exchange resin was known to perform well. The rejection of claim 8, directed to a temperature in excess of 100°C, was reversed.). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003) (data showing improved alloy strength with the addition of 2% rhenium did not evidence unexpected results for the entire claimed range of about 1-3% rhenium); In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983) (Claims were directed to certain catalysts containing an alkali metal. Evidence presented to rebut an obviousness rejection compared catalysts containing sodium with the prior art. The court held this evidence insufficient to rebut the prima facie case because experiments limited to sodium were not commensurate in scope with the claims.).
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TIGABU KASSA whose telephone number is (571)270-5867. The examiner can normally be reached on 8 AM-5 PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, David Blanchard can be reached on 571-272-0827. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/TIGABU KASSA/
Primary Examiner, Art Unit 1619
Prosecution Insights