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 .
DETAILED ACTION
Response to Amendment
The amendment filed 4/14/2025 has been entered. Newly amended Claims 1-2, 5, 7, 9, 12, 19-21, 26, 41, and 50-61 are pending in the application.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied and constitute the complete set presently being applied to the instant application.
Claims 54-57 and 60-61 are withdrawn as being directed to compositions not encompassing that which was elected by applicant in the response filed 10/11/2024:
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. Claims 1-2, 5, 7, 9, 12, 19-21, 26, 41, 50-53, and 58-59 read on the above species of API and excipients and are examined herein.
For applicant’s benefit, it is noted that withdrawn Claim 61 is dependent on Claim 58; however, Claim 58 does not recite TPGS as the surfactant. Rather, Claim 60 lists TPGS as a surfactant.
Response to Applicant’s Arguments
Applicant argues regarding the 35 USC 103 rejection over Chen alone is overcome by incorporating the limitations of Claim 17 into independent Claim 1. Applicant’s argument is fully considered and persuasive because Chen does not teach or fairly suggest the claimed amounts of particular ingredients in the composition of Claim 1 as amended. The rejection is withdrawn.
Regarding the 103 rejection over Chen in view of Birtalan, applicant argues the solid dispersions as claimed have superior PK profiles as compared to Examples 25 and 30 which possess a higher percentage of API and lower percentage of carrier. Applicant argues the cited references do not suggest that the superior PK profiles as characterized by greater AUC would result from the amounts of the composition as claimed. This argument is fully considered but not persuasive. First, applicant refers to Page 356 of the specification which refers to 81 examples and only generally concludes that Examples 7-24 and 26-29 have superior PK profiles. However, no specific data or table demonstrating the results is supplied or referenced by applicant. Applicant does not offer specific evidence in the specification, arguments, or evidentiary declaration so as to support the assertion that certain examples have “superior PK profiles”. It is also noted that there is no comparison to suggest that the results are significant and surprising or unexpected. Second, Birtalan teaches that analogous BCL-2 inhibitors with polymeric carriers and surfactants, in amounts within those claimed ranges, yield AUC values 23.3, 36.3, and 76 hr*ug/ml which vary and also encompass those values listed on Page 356 of applicant’s specification: 30, 40, and 50 hr*ug/ml (Pages 160-164; specifically, Page 160, Example 12; Page 161, Para 1461; and Page 164, Table 16). AUC variable in response to changes in amounts of excipients within the scope of amended Claim 1 and not unexpected in view of the Birtalan compositions. Therefore, this argument is not persuasive because the results and conclusions drawn therefrom by applicant are not substantiated by the specification nor by a declaration nor are the results surprising in view of the Birtalan data. It is further noted, that the examples which were not noted by applicant as having superior AUC values are also encompassed by Claim 1; e.g., 37 on Page 343. Applicant suggests such a composition encompassed within Claim 1 does not possess the “surprising result”. Therefore, applicant’s arguments are not commensurate in scope with the amended independent claim and not persuasive on this basis alone.
Regarding the same rejection, applicant submits that the compounds of Formula I of Birtalan and Formula A of Claim 1 are distinct in that the former comprises a bicycle bound through O and the latter comprises a tricycle bound through N:
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Applicant’s argument is fully considered but not persuasive. Although, the compounds are not the same, examiner relies on Chen not Birtalan to teach the particular BCL-2 inhibitor compound (NFR: Page 5 and 7). Examiner also explains that the core of the Birtalan compounds is analogous to that of the Chen compounds, both compounds comprising the core are BCL-2 modulators (NFR: Page 7). The compounds are similar in that both comprise a polyheterocycle bound to a phenyl-cyclohexenyl-piperazinyl-phenyl-amido-sulfone-phenyl core. Both are also known in the art to serve as BCL-2 inhibitors which can be formulated through hot melt extrusion. Again, examiner does not suggest the modification of Formula I compounds to those of Formula A but describes the structural similarities between Formula I and the compounds of Chen to suggest that the Chen compound could be formulated with the excipients of Birtalan. One of skill in the art would expect the formulation to yield a suitable pharmaceutical dosage form because of the close structural similarity of the prior art compounds. Therefore, the rejection remains as amended hereinbelow.
Applicant argues the nonstatutory double patenting rejections are moot resulting from the incorporation of the limitations of Claim 17 into Claim 1. The rejections are amended and reissued below as a result of applicant’s amendments.
Applicant separately argues that App. No. 18641869 is abandoned and the rejection is moot. The rejection thereover is withdrawn.
App. No. 17269004 has matured into Patent No. 12220419. The rejection is amended appropriately.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 26 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 26 recites “the API is the compound selected from”. There is insufficient antecedent basis for “the compound” in the claim because no compound is described previously in Claim 26 or Claim 1 upon which Claim 26 depends.
Claim 26 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor regards as the invention. The claim refers to “Examples 7-24 and 26-29” of the specification. Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993). See MPEP 2173.05 (s).
Claim 26, in its reference to Examples of the specification, contains the trademark/trade name “TweenTM 80” for example in Example 5 of Page 329. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a brand of polysorbate and, accordingly, the identification/description is indefinite.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 1-2, 5, 7, 9, 12, 19-21, 26, 41, 50-53, and 58-59 are rejected under 35 U.S.C. 103 as being unpatentable over Chen (WO2019040573, published 2/28/2019, claiming priority through US provisional applications 62/615,007 and 62/549,081 filed 1/09/2018 and 8/23/2017, respectively, cited in 12/09/2022 IDS) in view of Birtalan (US20120108590, published 5/03/2012).
Chen teaches Example 10, (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-l-yl)-2-(3-methyl-2,3-dihydropyrrolo[3',2':5,6] pyrido[2,3-b][l,4]oxazinl(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl) amino)phenyl)sulfonyl)benzamide, the elected species, as a BCL-2 inhibitor (Pages 85-86, Example 10), reading on the elected compound as recited by instant claims 1-2, 5, and 58. The compound can be formulated as an orally-administered solid dispersion or hot melt extrusion to increase bioavailability of the compound as claimed in Claims 26, 41, and 53 (Page 39, Para 1; Page 43, Para 2). Regarding Claims 9, 12, 19, and 50-52, the composition can also comprise antioxidants like ascorbic acid, glidants like silicon dioxide, disintegrants like croscarmellose sodium, and surfactants like 1-10% polysorbate 80 (aka Tween 80) (Page 37, Last Para; Page 38, Last Para). Regarding Claim 7, compositions can be comprised of inert polymer carriers like dextran, a polysaccharide, or polyoxyethylene (Page 37, Para 2).
Chen fails to teach the use of the elected copovidone polymer carrier to be used in the solid dispersion or specific percentages of ingredients (aside from surfactant).
Regarding claim 20, as discussed above, Chen teaches the elected species of (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-l-yl)-2-(3-methyl-2,3-dihydropyrrolo[3',2':5,6] pyrido[2,3-b][l,4]oxazinl(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl) amino)phenyl)sulfonyl)benzamide.
Birtalan teaches copovidone as a polymeric carrier suitable for solid dispersions comprising analogues to the Chen compound, BCL-2 inhibitors of a genus of Formula I with a phenyl-cyclohexenyl-piperazinyl-phenyl-amido-sulfone-phenyl core (encircled below) like that of the elected species taught in Chen (Para 1250; Abstract; Para 29):
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Birtalan reports several successful examples of HME formulations comprising 80% copovidone with different surfactants, disintegrants, and other excipients:
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(Pages 160-164; Page 160, Example 1, Formulation 1). Alternative glidants to aerosol like colloidal silicon dioxide are taught and may be used in place of aerosol (Para 1283). Copovidone can be used to control the drug release rate (Para 1310). Specifically, Kollidon VA64 is taught as elected by applicant (Para 1308) and reads on claim 21.
Regarding the specific quantities of each ingredient in Claim 1 and Claim 59, the API can be 5-40%, optimally 10-15%, and the polymer carrier 40-85%, preferably 78-82%, of the formulation (Para 1246 and 1308; Para 1267 and 1308). The remaining antioxidant and glidant may comprise up to 2% of the remaining formulation, or 1% of each, falling within the claimed ranges:
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Further, In the case where the claimed ranges or values "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05 I. The MPEP also teaches differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." See MPEP 2144.05 II (A). The claimed ranges of concentrations and AUC are not shown by applicant to be critical or result in unexpected properties which would support a finding of nonobviousness.
An artisan of ordinary skill in the art seeking to form a bioavailable dose of the Chen compound would, following the guidance provided by Chen, formulate a solid dispersion and hot melt extrusion comprising the Chen API as well as the acceptable excipients above for their respective purposes. One of skill in the art seeking to form an HME solid dispersion comprising the elected species as taught in Chen with a controlled release to achieve optimal PK properties such as AUC, would find it obvious to further formulate a composition and choose copovidone as a carrier which can serve to regulate release rate as taught by Birtalan. The same artisan would use the concentrations of excipients well known in the art as taught by Birtalan to form a solid dispersion with increased bioavailability as well as suitable “manufacturability and quality of the extrudates” (Para 1308). Such a formulation would be expected to yield a bioavailable solid dispersion over which control of the BCL-2 inhibitor release rate may be exerted for more precise and lasting doses. The same artisan would expect success in the formulation of said solid dispersion because Chen provides details the acceptable excipients to be used in the formulation of the claimed dosage form and an analogous compound to those taught in Birtalan.
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.
PROVISIONAL
1. Claims 1-2, 5, 7, 9, 12, 19-21, 26, 41, 50-53, and 58-59 are provisionally rejected on the grounds of nonstatutory double patenting as being unpatentable over Claims 1-17 of copending Application No. 17764285 (hereinafter referred to as Newave) in view of Chen (WO2019040573, published 2/28/2019, claiming priority through US provisional applications 62/615,007 and 62/549,081 filed 1/09/2018 and 8/23/2017, respectively, IDS) and Birtalan (US20120108590, published 5/03/2012).
Although the claims at issue are not identical, they are not patentably distinct from each other because both applications are directed to a pharmaceutical composition of overlapping genera of Bcl-2 inhibitors.
For example, Newave teaches the following compound in Claim 15: (S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[ 1,1'-biphenyl]-2-yl)methyl)piperazin- 1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(3-(1,1,1- trifluoro-2-methylpropan-2-yl)-2,3 -dihydropyrrolo[3',2': 5,6]pyrido[2,3 -b][1,4]oxazin-1(6H)- yl)benzamide, in which the following examined definitions of Formula (A) apply: R1 is Cl and m is 1; R2 is alkyl, methyl, and n is 2; R7 is H and g is 3; L is -L1-L2- wherein L1 is a bond and L2 is an alkyl, methylene; R9 is a heterocycloalkyl; f is 0; R10 is alkyl, trifluoro-tert-butyl.
Newave is also directed to methods of using the inhibitor. However, the methods described in Newave require the existence of the compounds which render obvious the claims of the copending application.
Newave is silent as to the formation of a specific composition in the form of a hot melt extrusion solid dispersion with the claimed excipients.
Chen teaches Example 10, (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-l-yl)-2-(3-methyl-2,3-dihydropyrrolo[3',2':5,6] pyrido[2,3-b][l,4]oxazinl(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl) amino)phenyl)sulfonyl)benzamide (Left), as a BCL-2 inhibitor, which is similar to the above Newave species (Right), in that both share a common ((chlorophenyl-dimethyl-tetrahydro-biphenyl)- methyl-piperazinyl)-N-(nitro-pyranyl)methyl)amino)phenyl)sulfonyl)benzamide core (Pages 85-86, Example 10):
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The compound can be formulated as an orally-administered solid dispersion or hot melt extrusion to increase bioavailability of the compound as claimed in Claims 26, 41, and 53 (Page 39, Para 1; Page 43, Para 2). Regarding Claims 9, 12, 19, and 50-52, the composition can also comprise antioxidants like ascorbic acid, glidants like silicon dioxide, disintegrants like croscarmellose sodium, and surfactants like 1-10% polysorbate 80 (aka Tween 80) (Page 37, Last Para; Page 38, Last Para). Regarding Claim 7, compositions can be comprised of inert polymer carriers like dextran, a polysaccharide, or polyoxyethylene (Page 37, Para 2).
Chen fails to teach the use of the elected copovidone polymer carrier to be used in the solid dispersion or specific percentages of ingredients (aside from surfactant).
Regarding claim 20, as discussed above, Chen teaches the elected species of (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-l-yl)-2-(3-methyl-2,3-dihydropyrrolo[3',2':5,6] pyrido[2,3-b][l,4]oxazinl(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl) amino)phenyl)sulfonyl)benzamide.
Birtalan teaches copovidone as a polymeric carrier suitable for solid dispersions comprising analogues to the Chen compound, BCL-2 inhibitors of a genus of Formula I with a phenyl-cyclohexenyl-piperazinyl-phenyl-amido-sulfone-phenyl core (encircled below) like that of the elected species taught in Chen (Para 1250; Abstract; Para 29):
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Birtalan reports several successful examples of HME formulations comprising 80% copovidone with different surfactants, disintegrants, and other excipients:
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(Pages 160-164; Page 160, Example 1, Formulation 1). Alternative glidants to aerosol like colloidal silicon dioxide are taught and may be used in place of aerosol (Para 1283). Copovidone can be used to control the drug release rate (Para 1310). Specifically, Kollidon VA64 is taught as elected by applicant (Para 1308) and reads on claim 21.
Regarding the specific quantities of each ingredient in Claim 1 and Claim 59, the API can be 5-40%, optimally 10-15%, and the polymer carrier 40-85%, preferably 78-82%, of the formulation (Para 1246 and 1308; Para 1267 and 1308). The remaining antioxidant and glidant may comprise up to 2% of the remaining formulation, or 1% of each, falling within the claimed ranges:
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Further, In the case where the claimed ranges or values "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05 I. The MPEP also teaches differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." See MPEP 2144.05 II (A). The claimed ranges of concentrations and AUC are not shown by applicant to be critical or result in unexpected properties which would support a finding of nonobviousness.
An artisan of ordinary skill in the art seeking to form a bioavailable dose of the Chen compound would, following the guidance provided by Chen, formulate a solid dispersion and hot melt extrusion comprising the Chen API as well as the acceptable excipients above for their respective purposes. One of skill in the art seeking to form an HME solid dispersion comprising the elected species as taught in Chen with a controlled release to achieve optimal PK properties such as AUC, would find it obvious to further formulate a composition and choose copovidone as a carrier which can serve to regulate release rate as taught by Birtalan. The same artisan would use the concentrations of excipients well known in the art as taught by Birtalan to form a solid dispersion with increased bioavailability as well as suitable “manufacturability and quality of the extrudates” (Para 1308). Such a formulation would be expected to yield a bioavailable solid dispersion over which control of the BCL-2 inhibitor release rate may be exerted for more precise and lasting doses. The same artisan would expect success in the formulation of said solid dispersion because Chen provides details the acceptable excipients to be used in the formulation of the claimed dosage form and an analogous compound to those taught in Birtalan.
Since both applications teach pharmaceutical compositions comprising the same Bcl-2 inhibitors, the examiner maintains that the aforementioned claims of the instant application are substantially overlapping in scope as discussed hereinabove and are prima facie obvious over the cited claims of Newave.
This is a provisional nonstatutory double patenting rejection.
2. Claims 1-2, 5, 7, 9, 12, 19-21, 26, 41, 50-53, and 58-59 are provisionally rejected on the grounds of nonstatutory double patenting as being unpatentable over Claims 21-25 and 27-31 of copending Application No. 18142842 (hereinafter referred to as Newave) in view of Chen (WO2019040573, published 2/28/2019, claiming priority through US provisional applications 62/615,007 and 62/549,081 filed 1/09/2018 and 8/23/2017, respectively, IDS) and Birtalan (US20120108590, published 5/03/2012).
Although the claims at issue are not identical, they are not patentably distinct from each other because both applications are directed to a pharmaceutical composition comprising the same Bcl-2 inhibitors, namely 4-(4-((4'-chloro-5, 5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin- l-yl)- 2-(3,4-dihydro-2H-pyrrolo[3',2': 5,6]pyrido[2,3 -b][1,4]oxazepin-1(7H)-yl)-N-((3 -nitro-4- (((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide. (Other similar compounds are listed in copending Claims 21 and 23-26.)
Newave is silent as to the formation of a specific composition in the form of a hot melt extrusion solid dispersion with the claimed excipients.
Chen teaches Example 10, (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-l-yl)-2-(3-methyl-2,3-dihydropyrrolo[3',2':5,6] pyrido[2,3-b][l,4]oxazinl(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl) amino)phenyl)sulfonyl)benzamide (Left), as a BCL-2 inhibitor, which is similar to the above Newave species (Right), in that both share a common ((chlorophenyl-dimethyl-tetrahydro-biphenyl)- methyl-piperazinyl)-N-(nitro-pyranyl)methyl)amino)phenyl)sulfonyl)benzamide core (Pages 85-86, Example 10):
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The compound can be formulated as an orally-administered solid dispersion or hot melt extrusion to increase bioavailability of the compound as claimed in Claims 26, 41, and 53 (Page 39, Para 1; Page 43, Para 2). Regarding Claims 9, 12, 19, and 50-52, the composition can also comprise antioxidants like ascorbic acid, glidants like silicon dioxide, disintegrants like croscarmellose sodium, and surfactants like 1-10% polysorbate 80 (aka Tween 80) (Page 37, Last Para; Page 38, Last Para). Regarding Claim 7, compositions can be comprised of inert polymer carriers like dextran, a polysaccharide, or polyoxyethylene (Page 37, Para 2).
Chen fails to teach the use of the elected copovidone polymer carrier to be used in the solid dispersion or specific percentages of ingredients (aside from surfactant).
Regarding claim 20, as discussed above, Chen teaches the elected species of (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-l-yl)-2-(3-methyl-2,3-dihydropyrrolo[3',2':5,6] pyrido[2,3-b][l,4]oxazinl(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl) amino)phenyl)sulfonyl)benzamide.
Birtalan teaches copovidone as a polymeric carrier suitable for solid dispersions comprising analogues to the Chen compound, BCL-2 inhibitors of a genus of Formula I with a phenyl-cyclohexenyl-piperazinyl-phenyl-amido-sulfone-phenyl core (encircled below) like that of the elected species taught in Chen (Para 1250; Abstract; Para 29):
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Birtalan reports several successful examples of HME formulations comprising 80% copovidone with different surfactants, disintegrants, and other excipients:
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(Pages 160-164; Page 160, Example 1, Formulation 1). Alternative glidants to aerosol like colloidal silicon dioxide are taught and may be used in place of aerosol (Para 1283). Copovidone can be used to control the drug release rate (Para 1310). Specifically, Kollidon VA64 is taught as elected by applicant (Para 1308) and reads on claim 21.
Regarding the specific quantities of each ingredient in Claim 1 and Claim 59, the API can be 5-40%, optimally 10-15%, and the polymer carrier 40-85%, preferably 78-82%, of the formulation (Para 1246 and 1308; Para 1267 and 1308). The remaining antioxidant and glidant may comprise up to 2% of the remaining formulation, or 1% of each, falling within the claimed ranges:
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t
=
2
%
A
n
t
i
o
x
i
d
a
n
t
+
G
l
i
d
a
n
t
.
Further, In the case where the claimed ranges or values "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05 I. The MPEP also teaches differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." See MPEP 2144.05 II (A). The claimed ranges of concentrations and AUC are not shown by applicant to be critical or result in unexpected properties which would support a finding of nonobviousness.
An artisan of ordinary skill in the art seeking to form a bioavailable dose of the Chen compound would, following the guidance provided by Chen, formulate a solid dispersion and hot melt extrusion comprising the Chen API as well as the acceptable excipients above for their respective purposes. One of skill in the art seeking to form an HME solid dispersion comprising the elected species as taught in Chen with a controlled release to achieve optimal PK properties such as AUC, would find it obvious to further formulate a composition and choose copovidone as a carrier which can serve to regulate release rate as taught by Birtalan. The same artisan would use the concentrations of excipients well known in the art as taught by Birtalan to form a solid dispersion with increased bioavailability as well as suitable “manufacturability and quality of the extrudates” (Para 1308). Such a formulation would be expected to yield a bioavailable solid dispersion over which control of the BCL-2 inhibitor release rate may be exerted for more precise and lasting doses. The same artisan would expect success in the formulation of said solid dispersion because Chen provides details the acceptable excipients to be used in the formulation of the claimed dosage form and an analogous compound to those taught in Birtalan.
Since both applications teach pharmaceutical compositions comprising the same Bcl-2 inhibitors, the examiner maintains that the aforementioned claims of the instant application are substantially overlapping in scope as discussed hereinabove and are prima facie obvious over the cited claims of Newave.
This is a provisional nonstatutory double patenting rejection.
NONPROVISIONAL
1. Claims 1-2, 5, 7, 9, 12, 19-21, 26, 41, 50-53, and 58-59 are rejected on the grounds of nonstatutory double patenting as being unpatentable over Claims 1-21 of U.S. Patent No. 11279711 (hereinafter referred to as Newave) in view of Chen (WO2019040573, published 2/28/2019, claiming priority through US provisional applications 62/615,007 and 62/549,081 filed 1/09/2018 and 8/23/2017, respectively, IDS) and Birtalan (US20120108590, published 5/03/2012).
Although the claims at issue are not identical, they are not patentably distinct from each other because both applications are directed to a pharmaceutical composition comprising the same Bcl-2 inhibitors, namely 4-(4-((4'-chloro-5, 5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin- l-yl)- 2-(3,4-dihydro-2H-pyrrolo[3',2': 5,6]pyrido[2,3 -b][1,4]oxazepin-1(7H)-yl)-N-((3 -nitro-4- (((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide. (Other similar compounds are listed in copending Claims 21 and 23-26.)
Newave is also directed to methods of using the inhibitor. However, the methods described in Newave require the existence of the compounds which render obvious the claims of the copending application.
Newave is silent as to the formation of a specific composition in the form of a hot melt extrusion solid dispersion with the claimed excipients.
Chen teaches Example 10, (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-l-yl)-2-(3-methyl-2,3-dihydropyrrolo[3',2':5,6] pyrido[2,3-b][l,4]oxazinl(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl) amino)phenyl)sulfonyl)benzamide (Left), as a BCL-2 inhibitor, which is similar to the above Newave species (Right), in that both share a common ((chlorophenyl-dimethyl-tetrahydro-biphenyl)- methyl-piperazinyl)-N-(nitro-pyranyl)methyl)amino)phenyl)sulfonyl)benzamide core (Pages 85-86, Example 10):
PNG
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369
597
media_image5.png
Greyscale
vs.
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358
729
media_image7.png
Greyscale
.
The compound can be formulated as an orally-administered solid dispersion or hot melt extrusion to increase bioavailability of the compound as claimed in Claims 26, 41, and 53 (Page 39, Para 1; Page 43, Para 2). Regarding Claims 9, 12, 19, and 50-52, the composition can also comprise antioxidants like ascorbic acid, glidants like silicon dioxide, disintegrants like croscarmellose sodium, and surfactants like 1-10% polysorbate 80 (aka Tween 80) (Page 37, Last Para; Page 38, Last Para). Regarding Claim 7, compositions can be comprised of inert polymer carriers like dextran, a polysaccharide, or polyoxyethylene (Page 37, Para 2).
Chen fails to teach the use of the elected copovidone polymer carrier to be used in the solid dispersion or specific percentages of ingredients (aside from surfactant).
Regarding claim 20, as discussed above, Chen teaches the elected species of (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-l-yl)-2-(3-methyl-2,3-dihydropyrrolo[3',2':5,6] pyrido[2,3-b][l,4]oxazinl(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl) amino)phenyl)sulfonyl)benzamide.
Birtalan teaches copovidone as a polymeric carrier suitable for solid dispersions comprising analogues to the Chen compound, BCL-2 inhibitors of a genus of Formula I with a phenyl-cyclohexenyl-piperazinyl-phenyl-amido-sulfone-phenyl core (encircled below) like that of the elected species taught in Chen (Para 1250; Abstract; Para 29):
PNG
media_image3.png
188
49
media_image3.png
Greyscale
.
Birtalan reports several successful examples of HME formulations comprising 80% copovidone with different surfactants, disintegrants, and other excipients:
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34
347
media_image4.png
Greyscale
(Pages 160-164; Page 160, Example 1, Formulation 1). Alternative glidants to aerosol like colloidal silicon dioxide are taught and may be used in place of aerosol (Para 1283). Copovidone can be used to control the drug release rate (Para 1310). Specifically, Kollidon VA64 is taught as elected by applicant (Para 1308) and reads on claim 21.
Regarding the specific quantities of each ingredient in Claim 1 and Claim 59, the API can be 5-40%, optimally 10-15%, and the polymer carrier 40-85%, preferably 78-82%, of the formulation (Para 1246 and 1308; Para 1267 and 1308). The remaining antioxidant and glidant may comprise up to 2% of the remaining formulation, or 1% of each, falling within the claimed ranges:
100
%
D
o
s
a
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e
F
o
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m
-
10
%
A
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I
-
78
%
P
o
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e
r
-
10
%
S
u
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a
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2
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A
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o
x
i
d
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n
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+
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l
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d
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n
t
.
Further, In the case where the claimed ranges or values "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05 I. The MPEP also teaches differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." See MPEP 2144.05 II (A). The claimed ranges of concentrations and AUC are not shown by applicant to be critical or result in unexpected properties which would support a finding of nonobviousness.
An artisan of ordinary skill in the art seeking to form a bioavailable dose of the Chen compound would, following the guidance provided by Chen, formulate a solid dispersion and hot melt extrusion comprising the Chen API as well as the acceptable excipients above for their respective purposes. One of skill in the art seeking to form an HME solid dispersion comprising the elected species as taught in Chen with a controlled release to achieve optimal PK properties such as AUC, would find it obvious to further formulate a composition and choose copovidone as a carrier which can serve to regulate release rate as taught by Birtalan. The same artisan would use the concentrations of excipients well known in the art as taught by Birtalan to form a solid dispersion with increased bioavailability as well as suitable “manufacturability and quality of the extrudates” (Para 1308). Such a formulation would be expected to yield a bioavailable solid dispersion over which control of the BCL-2 inhibitor release rate may be exerted for more precise and lasting doses. The same artisan would expect success in the formulation of said solid dispersion because Chen provides details the acceptable excipients to be used in the formulation of the claimed dosage form and an analogous compound to those taught in Birtalan.
Since both claim sets teach a pharmaceutical composition comprising the same species of Bcl-2 inhibitors, the examiner maintains that the aforementioned claims of the instant application are substantially overlapping in scope as discussed hereinabove and are prima facie obvious over the cited claims of Newave.
2. Claims 1-2, 5, 7, 9, 12, 19-21, 26, 41, 50-53, and 58-59 are rejected on the grounds of nonstatutory double patenting as being unpatentable over Claims 1-30 of U.S. Patent No. 11365206 (hereinafter referred to as Newave) in view of Chen (WO2019040573, published 2/28/2019, claiming priority through US provisional applications 62/615,007 and 62/549,081 filed 1/09/2018 and 8/23/2017, respectively, IDS) and Birtalan (US20120108590, published 5/03/2012).
Although the claims at issue are not identical, they are not patentably distinct from each other because both applications are directed to a pharmaceutical composition comprising the elected species: (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-l-yl)-2-(3-methyl-2,3-dihydropyrrolo[3',2':5,6] pyrido[2,3-b][l,4]oxazinl(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl) amino)phenyl)sulfonyl)benzamide.
Newave is also directed to methods of using the inhibitor. However, the methods described in Newave require the existence of the compounds which render obvious the claims of the copending application.
Newave is silent as to the formation of a specific composition in the form of a hot melt extrusion solid dispersion with the claimed excipients.
Chen teaches Example 10, (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-l-yl)-2-(3-methyl-2,3-dihydropyrrolo[3',2':5,6] pyrido[2,3-b][l,4]oxazinl(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl) amino)phenyl)sulfonyl)benzamide, as a BCL-2 inhibitor, which is the same as applicant’s elected species and the Newave compound (Pages 85-86, Example 10). The compound can be formulated as an orally-administered solid dispersion or hot melt extrusion to increase bioavailability of the compound as claimed in Claims 26, 41, and 53 (Page 39, Para 1; Page 43, Para 2). Regarding Claims 9, 12, 19, and 50-52, the composition can also comprise antioxidants like ascorbic acid, glidants like silicon dioxide, disintegrants like croscarmellose sodium, and surfactants like 1-10% polysorbate 80 (aka Tween 80) (Page 37, Last Para; Page 38, Last Para). Regarding Claim 7, compositions can be comprised of inert polymer carriers like dextran, a polysaccharide, or polyoxyethylene (Page 37, Para 2).
Chen fails to teach the use of the elected copovidone polymer carrier to be used in the solid dispersion or specific percentages of ingredients (aside from surfactant).
Regarding claim 20, as discussed above, Chen teaches the elected species of (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-l-yl)-2-(3-methyl-2,3-dihydropyrrolo[3',2':5,6] pyrido[2,3-b][l,4]oxazinl(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl) amino)phenyl)sulfonyl)benzamide.
Birtalan teaches copovidone as a polymeric carrier suitable for solid dispersions comprising analogues to the Chen compound, BCL-2 inhibitors of a genus of Formula I with a phenyl-cyclohexenyl-piperazinyl-phenyl-amido-sulfone-phenyl core (encircled below) like that of the elected species taught in Chen (Para 1250; Abstract; Para 29):
PNG
media_image3.png
188
49
media_image3.png
Greyscale
.
Birtalan reports several successful examples of HME formulations comprising 80% copovidone with different surfactants, disintegrants, and other excipients:
PNG
media_image4.png
34
347
media_image4.png
Greyscale
(Pages 160-164; Page 160, Example 1, Formulation 1). Alternative glidants to aerosol like colloidal silicon dioxide are taught and may be used in place of aerosol (Para 1283). Copovidone can be used to control the drug release rate (Para 1310). Specifically, Kollidon VA64 is taught as elected by applicant (Para 1308) and reads on claim 21.
Regarding the specific quantities of each ingredient in Claim 1 and Claim 59, the API can be 5-40%, optimally 10-15%, and the polymer carrier 40-85%, preferably 78-82%, of the formulation (Para 1246 and 1308; Para 1267 and 1308). The remaining antioxidant and glidant may comprise up to 2% of the remaining formulation, or 1% of each, falling within the claimed ranges:
100
%
D
o
s
a
g
e
F
o
r
m
-
10
%
A
P
I
-
78
%
P
o
l
y
m
e
r
-
10
%
S
u
r
f
a
c
t
a
n
t
=
2
%
A
n
t
i
o
x
i
d
a
n
t
+
G
l
i
d
a
n
t
.
Further, In the case where the claimed ranges or values "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05 I. The MPEP also teaches differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating suc