DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . 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 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.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 09/10/2025 and 08/13/2025 have been considered by the examiner.
Status of the Claims
The response filed 09/10/2025 is acknowledged.
Claims 1-3, 5-16, 20-23, 26-29, 31, 35-37, 41-42, 44 and 46-54 are pending.
Claims 1-3, 5-16, 20, and 47-53 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 09/29/2020.
Claims 21-23, 26-29, 31, 35-37, 41-42, 44, 46 and 54 are treated on the merits in this action.
The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application. Rejections not reiterated herein have been withdrawn.
Withdrawn
The provisional rejection of claim(s) 21-23, 26-29, 31, 35-37, 41-42, 44, 46, and 54 on the ground of nonstatutory double patenting as being unpatentable over claim(s) 1-53, 55-57, 59-62, 64-76 of US Application No. 16185333 in view of Brough, US 20090303630 A1 has been withdrawn because 16185333 was abandoned.
Response to Arguments
Applicant's arguments filed 09/10/2025 have been fully considered but they are not persuasive.
With respect to the rejection of claims 21, 22, 23, 26-29, 31, 35, 36, 37, 41, 42, 44, 46, and 54 under 35 U.S.C. 103 as being unpatentable over Cao, J. Kor. Pharm. Sci., 33, 1, 2003 in view of Brough, US 20090053315 and CN 104434809 A (Zou).
1. Cao, Brough, and Zou
Applicant argues the Action's assertions in response to Applicant's arguments submitted in the previous response filed October 25, 2024, collectively hinge on the notion that the Action's cited art (Cao, Brough, Zou, and Lundbeck) teaches or suggests incorporating insoluble lubricants such as magnesium stearate (MgSt) or sodium stearyl fumarate (SSF) into single-phase solid amorphous dispersions for enhanced dissolution, stability, or bioavailability. However, Applicant respectfully submits that the Action's assertions are flawed, at least for the following reasons: (1) the cited art lacks express or inherent disclosure of the claimed single-phase structure comprising the recited lubricants; (2) substitution to include the recited lubricants in a single-phase structure is counterintuitive, at odds with the knowledge in the art as of the priority date, and changes the cited references' principles of operation; (3) the Action's assumptions of inherent disclosure or expectation lack evidentiary support and are at odds with the knowledge in the art; and (4) Applicant's unexpected results rebut any prima facie case. Applicant argues these deficiencies in the Action's assertions clearly demonstrate non-obviousness of the pharmaceutical composition recited in the pending claims. Applicant addresses each of the Action's assertions in turn, below.
In response:
Applicant’s argument (1) that the cited art lacks express or inherent disclosure of the claimed single-phase structure comprising the recited lubricants is unpersuasive.
It is acknowledged no single reference of record teaches a single phase solid amorphous dispersion comprising an amorphous API, an excipient, and either magnesium stearate or sodium stearyl fumarate. However, the rejections are not based on a single reference.
Cao teaches solid amorphous dispersions containing sodium lauryl sulfate, an amorphous API, and a polymer.
Sodium lauryl sulfate is a lubricant named in Zou as an alternative for magnesium stearate and/or sodium stearyl fumarate. Zou teaches the addition of sodium stearyl fumarate, magnesium stearate, and/or sodium lauryl sulfate improves dissolution of the amorphous API from the dispersion by stabilizing the amorphous form of the API in the dispersion, i.e., the lubricant prevents crystallization of the amorphized API in the dispersion.
Zou and Lundbeck clearly teach the recited lubricants (magnesium stearate and sodium stearyl fumarate) in solid amorphous dispersion comprising an amorphous API and additional excipients.
Brough clearly teaches that their disclosure is focused on the use of thermokinetic compounding (TKC) for the production of amorphous solid dispersion systems (Brough, e.g., 0182), including single phase composites (Brough, e.g., 0100), and exemplifies the production of single-phase amorphous composites (Brough 0153), including single phase ternary (API and two polymers) solid amorphous dispersions which were not a single phase when processed using (HME) hot melt extrusion (Brough, e.g., 0179-0180).
Brough teaches composites which are single phase, miscible composites of two or more pharmaceutical materials previously considered to be immiscible (Brough, e.g., 0100). Thus, the skilled artisan would have understood Brough’s excipients for preparing composites in ¶ 0018, which names magnesium stearate, as applicable to amorphous composites and single-phase miscible composites.
Thus, the combined teachings of the cited prior art suggest modifying single phase, solid amorphous dispersions comprising an API and excipients with a named lubricant for improved drug dissolution.
Applicant’s argument that (2) substitution to include the recited lubricants in a single-phase structure was counterintuitive, was at odds with the knowledge in the art as of the priority date, and changes the cited references' principles of operation is unpersuasive.
Cao does not expressly teach the use of magnesium stearate in the solid amorphous dispersion, but does teach the use of magnesium stearate as an excipient with the solid dispersion (Cao, entire document, e.g., Table 1 and pg. 9: preparation of capsules containing solid dispersion).
Brough clearly teaches single phase, solid amorphous dispersions containing an amorphous API, and one or more excipients (Brough, e.g., 0100; claim 20, single glass transition temperature; Brough, e.g., 0153: single glass transition temperature indicating the composition is a single phase), including lubricants (Brough, e.g., claims 1, 6, and 7). Stearates are named in claim 14. Brough names magnesium stearate (Brough, e.g., 0018).
Zou expressly teaches the addition of lubricant to the API polymer dispersion results in an amorphous dispersion which is as stable or more stable than an amorphous dispersion which contains only the API and the polymer (Zou, e.g., pg. 2/5, Invention Content, ¶ 2). Lubricants include magnesium stearate, sodium stearyl fumarate, and sodium lauryl sulfate (Zou, e.g., pg. 2, Invention Content).
Thus, Zou expressly teaches incorporating magnesium stearate and/or sodium stearyl fumarate in a solid amorphous dispersion containing an amorphous drug and a polymer excipient.
It is also noted that Brough amorphous dispersion composites may include magnesium stearate (Brough, e.g., 0018). Further, Brough expressly claims a method of making a pharmaceutical composition comprising one or more APIs with one or more pharmaceutically acceptable excipients, wherein the composition containing the API and excipients further comprises a processing agent such as a lubricant (Brough, e.g., claims 1, 6, and 7). Stearates are named in Brough, e.g., claim 14. From claims 1, 6, 7, and 14 it is clear that Brough teaches including processing agents such as lubricants in the same phase with the API and excipients and therefore in the final dosage forms containing them.
It is also noted that Lundbeck teaches amorphous dispersions containing sodium stearyl fumarate, e.g., Lundbeck’s dispersions also contain sodium stearyl fumarate which is a claimed lubricant (Lundbeck, e.g., Table 1).
Thus, Lundbeck expressly teaches solid amorphous dispersions containing a named lubricant, i.e., sodium stearyl fumarate, and notes the improved solubility relative to formulations not containing sodium stearyl fumarate in the amorphous dispersion phase (Lundbeck, e.g., pg. 34:3-13).
Each of Brough, Zou, and Lundbeck, independently, clearly teach or suggest adding magnesium stearate or sodium stearyl fumarate to a solid amorphous dispersion containing an amorphous drug dispersed in a polymer with a goal to improve dissolution.
Therefore, the cited prior art shows that the inclusion of magnesium stearate or sodium stearyl fumarate in a single phase solid amorphous dispersion as claimed was not counterintuitive, not at odds with the knowledge in the art as of the priority date since there were express suggestions to make this modification (Zou and Lundbeck), and the modification does not change the cited references' principles of operation since Zou teaches the modification results in the desired improvement to drug dissolution by stabilizing the amorphous form of the drug in the solid dispersion.
Applicant’s argument (3) that the Action's assumptions of inherent disclosure or expectation lack evidentiary support and are at odds with the knowledge in the art is unpersuasive.
At least the teachings of Brough provide clear evidentiary support that, prior to the filing date of the presently claimed invention, known techniques, such as thermokinetic compounding, were effective to prepare single phase solid amorphous dispersions which comprise API in an amorphous state, and one or more excipients, even for combinations of two or more pharmaceutical materials previously considered to be immiscible (Brough, e.g., 0100 and Example 5, 0179-0180).
Brough teaches their disclosure is focused on the use of thermokinetic compounding (TKC) for the production of amorphous solid dispersion systems (Brough, e.g., 0182), including single phase composites (Brough, e.g., 0100), and exemplifies the production of single-phase amorphous composites (Brough 0153), including single phase ternary (API and two polymers) solid amorphous dispersions which were not a single phase when processed using hot melt extrusion (Brough, e.g., 0179-0180).
Further, Brough teaches composites which are single phase, miscible composites of two or more pharmaceutical materials previously considered to be immiscible (Brough, e.g., 0100). Thus, the skilled artisan would have understood Brough’s excipients for preparing composites in ¶ 0018, as applicable to amorphous composites and single-phase miscible composites.
Brough exemplifies formation of a single phase solid amorphous dispersion characterized as having a single Tg using mDSC (Brough, e.g., 0153 and Fig. 10).
Applicant’s argument (4) that unexpected results rebut any prima facie case is unpersuasive for the reasons set forth under (F.) below.
In the remarks, pg. 12:
1. Cao, Brough, and Zou:
Applicant aruges the Action appears to be improperly conflating the terms "solid dispersion" with "single phase" which is absolutely incorrect and indefensible from a scientific standpoint. Applicant argues it is well known in pharmaceutical chemistry that a "solid dispersion" is generic term that says absolutely nothing about the number of phases, much less whether the contents of one or more phases are amorphous or crystalline. Applicant argues the Action at times appears to argue that the term "solid dispersion" is sufficient to meet the limitation of applicant's "single-phase solid amorphous dispersion" feature. Applicant request that if the Examiner truly argues this to be the case, a clear statement on the record - supported by clear evidence and not merely personal opinion - is required to establish the fact that solid dispersion can be understood as irrefutably as meaning "single-phase solid amorphous dispersion" and nothing more. Applicant argues that in the absence of such evidence, the Examiner should desist from making any such indefensible arguments and acknowledge on the record that Cao in fact does not teach such a composition based purely on the existence of the language "solid dispersion."
In response:
It is noted that the office action does not assert that all solid dispersions are single phase, amorphous solid dispersions. Further, the office action does not assert Cao teaches a single phase, amorphous solid dispersions based purely on the existence of the language “solid dispersion” in the Cao reference. Rather, the Office action concludes that the skilled artisan would have understood that Cao teaches single phase, amorphous solid dispersions based on the evidence in Cao found in the reference, and the fact that Brough defines amorphous solid dispersions which exhibit a single Tg (as shown in Cao, Fig. 5) as having only a “single phase” (Brough, e.g., 0153). That is, because Cao teaches solid dispersions which have an amorphous drug as evident from the x-ray diffraction data in Fig. 4, and because Cao teaches solid dispersions which having a single Tg as evident from the DSC thermograms of Fig. 5, the skilled artisan would have understood that the term “solid dispersion,” as used in the Cao reference, refers to a single phase amorphous solid dispersion.
That is, the skilled artisan would have understood that Cao teaches single phase amorphous solid dispersions because compositions referred to in Cao using the phrase “solid dispersion” have amorphous drug and are shown to exhibit a single glass transition temperature (Tg).
Cao, pg. 11, Fig. 4 shows the amorphous nature of the Cao’s solid dispersion (F1) labeled as (c):
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Cao, Fig. 5 shows a solid dispersion system (F1) having a single Tg at 71.58 °C:
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The skilled artisan would have considered Cao’s amorphous solid dispersion (simply referred to as a solid dispersion in Cao, e.g. in Fig. 4 above) to be a single phase amorphous solid dispersion based on the definition in Brough, US 20090053315, ¶ 0153:
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As evident from Brough, 0153, compositions which contain an amorphous drug and exhibit only a single glass transition temperature are considered to have only a single phase.
In light of Brough’s definition of a single phase solid amorphous dispersion characterized as having a single glass transition temperature, the skilled artisan would have understood that when Cao uses the term solid dispersion, Cao means a solid dispersion in which the drug is amorphous, and that the solid dispersion has a single Tg, i.e., is a single phase, amorphous solid dispersion. See Office action dated 04/10/2025, e.g., pg. 18, ¶s 1 and 3.
The skilled artisan would have recognized that at least formulation F1 in Cao is a single phase solid amorphous dispersion based on the lack of crystalline peaks as evident from the x-ray data in Fig. 4 and the single Tg as evident from Fig. 5.
It was acknowledged that Cao does not expressly teach single phase solid amorphous dispersions containing magnesium stearate or sodium stearyl fumarate. However, Zou teaches adding lubricants including magnesium stearate and/or sodium stearyl fumarate to solid amorphous dispersions to stabilize the amorphous form of the drug contained therein.
The office action further found that the Cao reference prepares their solid amorphous dispersions in the same way proposed by the present application, i.e., using solvent evaporation (Office action dated 04/10/2025, ¶ spanning pp. 18-19).
The Office action further noted that even if evidence was presented showing Cao’s amorphous solid dispersions containing additional excipients, e.g., sodium lauryl sulfate (Cao, e.g., pg. 8, Table 1, F2-F4) do not have a single phase, it would have been obvious to formulate Cao’s amorphous solid dispersions as a single phase amorphous solid dispersion since Brough teaches single phase solid dispersions are desirable for improving dissolution, bioavailability, and solubility of active pharmaceutical agents (Office action dated 04/10/205, pg. 19, 3rd ¶).
A. Applicant argues Cao does not disclose, teach, or suggest "...wherein the nonpolymeric lubricant is an agent selected from the group consisting of magnesium stearate and sodium stearyl fumarate..." as recited in claim 21 and the deficiency is not remedied by Brough or Zou, alone or in combination
Applicant argues that while Zou lists MgSt and SSF among possible lubricants (claims 1-2; page 2), Zou does not "clearly teach incorporating" them into a single-phase solid amorphous dispersion as claimed.
This argument is unpersuasive. It was acknowledged that Zou does not teach a single phase amorphous solid dispersion. Brough was cited for teaching single phase solid amorphous dispersions. Zou does clearly teach incorporating lubricants such as magnesium stearate and sodium stearyl fumarate in solid dispersions containing drug in an amorphous form dispersed in a polymeric excipient (amorphous solid dispersion). Zou teaches the addition of lubricant to the API polymer dispersion results in an amorphous dispersion which is as stable or more stable than an amorphous dispersion which contains only the API and the polymer (Zou, e.g., pg. 2/5, Invention Content, ¶ 2). Lubricants include magnesium stearate, sodium stearyl fumarate, and sodium lauryl sulfate (Zou, e.g., pg. 2, Invention Content).
Applicant argues Zou focuses on stability enhancement by adding lubricants to form "solid dispersion particles agent" or tablets/granules, but embodiments (e.g., Embodiment 6) show lubricants such as MgSt added after forming the solid dispersion (which includes olaparib and povidone), not as part of the amorphous phase. Applicant acknowledges claims 1-2 of Zou suggest adding a lubricant partially during hot melt extrusion processing ("part of the lubricant agent"), but Zou provides no evidence of single-phase formation (e.g., no Tg or XRD data).
This argument is unpersuasive. It is noted that Applicant acknowledges Zou teaches adding lubricant to the amorphous solid dispersion phase resulting from hot melt extrusion. However, Applicant dismisses this teaching because Zou does not teach a single phase amorphous solid dispersion. It is agreed that Zou does not expressly teach a single phase amorphous solid dispersion - the teachings of Brough cures this deficiency. Zou does teach “lubricants” such as sodium lauryl sulfate, magnesium stearate, and sodium stearyl fumarate will stabilize the amorphous form of the drug in an amorphous solid dispersion to which the lubricant is added.
Zou teaches improved dissolution of the drug in amorphous solid dispersions containing lubricants. For example, Zou concludes the addition of lubricants, such as magnesium stearate or sodium stearyl fumarate are effective to stabilize the amorphous form of the drug (unformed) in the solid dispersion even after six months under accelerated storage conditions because the amorphous solid dispersions exhibit improved dissolution rate even after six months under accelerated storage conditions.
See Zou, e.g., pg. 3/5:
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See also Zou, e.g., pg. 5/5:
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The improved stability of the unformed (amorphous form) of the drug is evidenced in Zou based on the observed improved dissolution rate of the drug from the amorphous solid dispersions containing lubricant. At pg. 5/5, Zou characterizes prior art amorphous dispersions lacking a lubricant as having reduced dissolution rate after three months noting the decline in dissolution rate is a result of crystal formation of the drug in the amorphous dispersion after three months accelerated storage conditions. The skilled artisan understood that Zou teaches the improvement in dissolution after six months accelerated storage conditions is attributed to the stabilization of the amorphous form of the drug due to the presence of the lubricant.
Thus, Zou does not just relate to stability, and clearly teaches the addition of lubricants including magnesium stearate and/or sodium stearyl fumarate to solid amorphous dispersions for improved drug dissolution, even after exposure to accelerated storage testing compared to solid amorphous dispersions lacking lubricants, because – as stated in Zou – the addition of the lubricant stabilizes the more soluble amorphous form of the drug present in the solid amorphous dispersion.
Applicant argues substituting Cao's water-soluble surfactants (e.g., SLS) with insoluble MgSt/SSF would change Cao's principle of operation (solubilization via surfactants; p. 7-8, 13).
This argument is unpersuasive because, as enumerated above, Zou teaches the addition of lubricants including magnesium stearate and/or sodium stearyl fumarate to the solid amorphous dispersion improves drug dissolution after exposure to accelerated storage testing compared to solid amorphous dispersions lacking lubricants. See Zou, e.g., pg. 5, 2. Accelerated test result of table. Zou and Cao are modifying the solid amorphous dispersions for express purpose of improving solubility of the drug using similar techniques based on dispersing the drug in a solid polymer excipient to stabilize the amorphous form of the drug with the intent of preventing drug crystallization within the dispersion.
Applicant has argued Brough ([0018]) generically lists MgSt as an excipient for composites, but not in a single- phase amorphous dispersion.
This argument is unpersuasive.
Brough teaches their disclosure is focused on the use of thermokinetic compounding (TKC) for the production of amorphous solid dispersion systems (Brough, e.g., 0182), including single phase composites (Brough, e.g., 0100), and exemplifies the production of single-phase amorphous composites (Brough 0153), including single phase ternary (API and two polymers) solid amorphous dispersions which were not a single phase when processed using hot melt extrusion (Brough, e.g., 0179-0180).
Amorphous composites are named in Brough 0023. Further, Brough teaches composites which are single phase, miscible composites of two or more pharmaceutical materials previously considered to be immiscible (Brough, e.g., 0100). Thus, the skilled artisan would have understood Brough’s excipients for preparing composites in ¶ 0018, as applicable to amorphous composites and single-phase miscible composites. Further, Zou teaches lubricants are excipients which may be used in solid amorphous dispersions. Thus, Brough, 0018, is not the only cited art suggesting the use of magnesium stearate to formulate solid amorphous dispersions of drugs.
Applicant again argues Brough teaches lubricants as "processing agents" ([0011], [0144]). As Applicant explained in the response filed April 11, 2024, persons of ordinary skill in the art would have understood "processing agent" to refer to components that are used in the manufacture of the drug product but do not appear in the finished drug product except at residual levels.
This argument is unpersuasive. Processing agents are pharmaceutical excipients. There is nothing in Brough suggesting processing agents do not appear in finished drug products. In contrast, Brough teaches processing agents may be included with the dispersion phase with the API and excipients (Brough, e.g., 0054). Brough teaches an amorphous composite may be prepared with or without a processing agent (Brough, e.g., 0011). Brough exemplifies processing agents integral with a single amorphous phase, e.g., a plasticizer in an amorphous drug dispersion with a polymer (TEC, see Fig., 17 DSC analysis).
The skilled artisan would have considered processing agents as materials which are in the same phase as the API and excipients based on Brough’s disclosure.
Further still, Brough expressly claims a method of making a pharmaceutical composition comprising one or more APIs with one or more pharmaceutically acceptable excipients, wherein the composition containing the API and excipients further comprises a processing agent such as a lubricant (Brough, e.g., claims 1, 6, and 7). Stearates are named in claim 14. From claims 1, 6, 7, and 14 it is clear that Brough teaches including processing agents, such as lubricants, are present in the same phase with the API and excipients and therefore in the final dosage forms containing them.
Applicant argues substituting Cao's water-soluble surfactants with insoluble non-polymeric lubricants is counterintuitive in view of teachings against incorporating MgSt/SSF in Ansel (page 208: MgSt retards dissolution) and Louw (pages. 4-6, Fig. 4.18: lubricants MgSt/SSF decrease dissolution rate).
This argument is unpersuasive. Zou expressly teaches the addition of lubricant to the API polymer dispersion results in an amorphous dispersion which is as stable or more stable than an amorphous dispersion which contains only the API and the polymer (Zou, e.g., pg. 2/5, Invention Content, ¶ 2). Lubricants include magnesium stearate, sodium stearyl fumarate, and sodium lauryl sulfate (Zou, e.g., pg. 2, Invention Content). It is also noted that Brough suggests amorphous dispersion composites may include magnesium stearate (Brough, e.g., 0018). It is also noted that Lundbeck teaches amorphous dispersions containing sodium stearyl fumarate, e.g., Lundbeck’s dispersions also contain sodium stearyl fumarate which is a claimed lubricant (Lundbeck, e.g., Table 1).
Each of Brough, Zou, and Lundbeck, independently, clearly suggest adding magnesium stearate or sodium stearyl fumarate to a solid amorphous dispersion containing an amorphous drug dispersed in a polymer with the goal of improving drug dissolution.
The reference “Ansel’s” has been given full consideration. However, Ansel’s relates to the use of magnesium stearate as a lubricant.
Even though Cao is concerned with drug dissolution, Cao uses magnesium stearate with each formulation (Cao, e.g., pg. 8, Table 1 and pg. 9).
The reference “Louw” has been given full consideration. However, Louw relates to the use of magnesium stearate as a lubricant, specifically a lubricant coating (Louw, pg. 5 cited in the remarks, 10/25/2024, pg. 6).
Cao is concerned with drug dissolution, yet Cao uses magnesium stearate with each formulation (Cao, e.g., pg. 8, Table 1, and pg. 9).
Neither Ansel’s, nor Louw appear to directly comment on the use of magnesium stearate as an additive in a single-phase amorphous solid dispersion, or a single-phase solid solution.
However, Zou, Brough, and Lundbeck are directly related to solid amorphous dispersions of APIs and represent a clear teaching which would have prompted the skilled artisan to modify single phase solid amorphous dispersions of APIs (Brough) with a lubricant such as magnesium stearate and/or sodium stearyl fumarate (Zou or Lundbeck). Further, Brough clearly suggests single phase amorphous dispersions may contain stearates, e.g., magnesium stearate, and enable the production of single-phase dispersions (miscible composites) previously considered to be immiscible (citations above).
If it were counter intuitive to include stearates, magnesium stearates and/or sodium stearyl fumarate in an amorphous solid dispersion phase before the filing date of the presently claimed invention, then neither Zou nor Lundbeck would have done so. Likewise, if it were counter intuitive to include stearates, magnesium stearates and/or sodium stearyl fumarate to formulate an amorphous solid dispersion phase before the filing date of the presently claimed invention, then Cao would not have used magnesium stearate to formulate the solid dispersions as found on pg. 8, table 1 and pg. 9. The fact that that both Zou and Lundbeck demonstrate the inclusion of insoluble excipients magnesium stearate and/or sodium stearyl fumarate directly in a solid amorphous dispersion is more relevant than references which do not directly address the preparation of amorphous solid dispersions.
B. Skilled persons would not have been motivated to substitute the soluble agents of Cao (oleic acid, TWEEN 80, and/or sodium lauryl sulfate) with insoluble or poorly soluble non-polymeric lubricants of Brough or Zou, such as sodium stearyl fumarate or magnesium stearate, to enhance dissolution of poorly soluble active ingredients
Applicant argues Zou's stability teaching (page 2/5, 2) does not motivate inclusion of insoluble lubricants in a single-phase solid amorphous dispersion to improve solubility. Applicant argues stability is Zou's focus, whereas solubility is the focus of Cao. Applicant argues no motivation exists to substitute the insoluble lubricants of Zou (e.g., insoluble MgSt/SSF) for Cao's water-soluble surfactants (e.g., SLS) at least because to do so would change the principle of operation of Cao and would have been expected to render the formulation of Cao unsuitable for its intended purpose of improved solubilization. MPEP §2143.01V and §2143.01VI. Applicant argues Zou teaches the use of SLS (soluble surfactant) or MgSt/SSF (insoluble lubricants) for the purpose of improved stability, but Zou does not suggest insoluble lubricants improve dissolution like Cao's surfactants. Applicant argues that instead, substitution of the soluble surfactants of Cao with insoluble lubricants MgSt/SSF would have been expected to hinder Cao's solubilization (pages 7-8).
This argument is unpersuasive at least because Zou desires stability of the drug’s amorphous form for the express purpose of improved drug dissolution.
Despite that fact that lubricants such as magnesium stearate or sodium stearyl fumarate may have been expected to retard drug dissolution, Zou suggests that is not the case for solid amorphous dispersions because the lubricants incorporated in the solid dispersion phase prevents the formation of insoluble crystalline drug in the solid dispersion relative to solid dispersions not containing a lubricant.
As enumerated above, Zou teaches the addition of lubricants including magnesium stearate and/or sodium stearyl fumarate to the solid amorphous dispersion improves drug dissolution after exposure to accelerated storage testing compared to solid amorphous dispersions lacking lubricants because – as stated in Zou – the addition of the lubricant stabilizes the more soluble unformed (amorphous) form of the drug present in the solid amorphous dispersion. See Zou, e.g., pg. 5, 2. Accelerated test result of table.
Zou and Cao are modifying the solid amorphous dispersions for express purpose of improving solubility of the drug using similar techniques based on dispersing the drug in a solid polymer excipient and additional excipients which stabilize the amorphous form of the drug with the intent of improving drug dissolution, e.g., by preventing drug crystallization within the dispersion (Zou).
Thus, modifying single phase solid amorphous dispersions known from the combined teachings of Cao and Brough with magnesium stearate or sodium stearyl fumarate as suggested in Zou would not change the principle of operation of Cao’s solid dispersions because of the improved dissolution observed by Zou.
Applicant argues that to improve stability Zou teaches adding lubricants at least partly post-dispersion; the teaching of Zou to add lubricants post-dispersion is clearly at odds with including the lubricants in a single-phase amorphous solid dispersion as recited in the pending claims, which achieves improved dissolution without adding lubricants post-dispersion. Applicant argues persons of ordinary skill in the art would have understood that Zou's teaching of adding insoluble lubricants (at least partly post-dispersion) such as MgSt or SSF would have been a trade-off that could improve stability, at the expense of decreasing solubility.
This argument is unpersuasive.
Cao also teaches the adding lubricant (magnesium stearate) to the solid amorphous dispersion powder post dispersion formation (Cao, e.g., Table 1 and pg. 9: preparation of capsules containing solid dispersion). This is done despite the possibility of decreased solubility. Even if magnesium stearate was expected to decrease drug solubility, Cao formulates solid amorphous dispersions with magnesium stearate.
Zou teaches the addition of lubricants including magnesium stearate and/or sodium stearyl fumarate to the solid amorphous dispersion phase improves drug dissolution after exposure to accelerated storage testing compared to solid amorphous dispersions lacking lubricants because – as stated in Zou – the addition of the lubricant stabilizes the more soluble unformed (amorphous) form of the drug present in the solid amorphous dispersion. See Zou, e.g., pg. 5, 2. Accelerated test result of table.
Applicant has argued persons of ordinary skill in the art would understand that an insoluble lubricant that is known to "retard release of the drug" would not be expected to provide a "gain" in "dissolution". Applicant argues the Action does not point to any teaching in Zou to support the Action's assertion that "preserving the stability" would provide such a "gain" in "dissolution". As shown for example in Louw, addition of insoluble lubricants such as MgSt and SSF to example compositions decreased dissolution.
This argument is unpersuasive.
Zou teaches the addition of lubricants including magnesium stearate and/or sodium stearyl fumarate to the solid amorphous dispersion improves drug dissolution after exposure to accelerated storage testing compared to solid amorphous dispersions lacking lubricants because the addition of the lubricant stabilizes the more soluble unformed (amorphous) form of the drug present in the solid amorphous dispersion. See Zou, e.g., pg. 5, 2. Accelerated test result of table.
Under the heading “2. Accelerated test result of table” Zou expressly teaches that amorphous dispersions lacking lubricant suffer crystal formation under conditions of accelerated storage which results in serious decline of drug dissolution when compared to solid dispersions containing amorphous drug stabilized with a lubricant because the unformed state of the drug is maintained by the presence of the lubricant within the solid amorphous dispersion.
Therefore, the skilled artisan would have clearly understood from Zou that preserving the stability of the amorphous drug in the dispersion using a lubricant means preventing crystallization, and this improved amorphous state stability of the API results in improved dissolution relative to amorphous dispersions lacking a lubricant.
C. Applicant argues Cao provides no evidence that the solid dispersions of Cao prepared using solubilizers (oleic acid, sodium lauryl sulfate, and/or TWEEN 80), are "[a] pharmaceutical composition comprising a single-phase solid amorphous dispersion of (a) an active pharmaceutical ingredient, (b) one or more pharmaceutically acceptable excipients, and (c) a non-polymeric lubricant..." as recited in pending independent claim 21.
It is noted that Cao was not cited as an anticipatory reference. It is acknowledged in the obviousness rejection that Cao does not expressly teach the named magnesium stearate or sodium stearyl fumarate in a single phase solid amorphous dispersion.
Applicant argues those of ordinary skill in the art would understand that Fig. 5 of Cao does not provide any evidence that F1 is a single-phase amorphous solid dispersion. Applicant argues Fig. 5 of Cao presents only conventional DSC heat flow thermograms, without modulation or reverse heat flow, and thus does not establish that formulation F1 is a single-phase amorphous solid dispersion. Applicant argues For example, Applicant provides herewith a book chapter by Xiangyu Ma, Daniel Ellenberger, Kevin P. O'Donnell, and Robert O. Williams III, entitled "Optimizing the Formulation of Poorly Water-Soluble Drugs" which is chapter 2 of R. O. Williams III et al. (eds.), Formulating Poorly Water Soluble Drugs, published in 2002 in AAPS Advances in the Pharmaceutical Sciences Series 50 (hereinafter "Ma"). As explained in Section 2.2.1 at page 44 of Ma, "analysis of the reversing heat flow obtained through mDSC [modulated DSC] provides the best visualization of the Tg event," and mDSC uniquely enables "increased limit of detection and sensitivity, trustable interpretation, [and] accurate quantification of amorphous phases". Section 2.2.1 at page 47 of Ma also emphasizes that "upon formation of a solid dispersion, the drug and polymer are intimately mixed such that the system...will have a single intermediate Tg," and that observation of multiple or poorly defined Tg's indicates incomplete mixing or phase separation.
This argument is unpersuasive. The art cited by Applicant, “Ma,” agrees with the art cited by the Examiner, e.g., Brough, i.e., a single Tg as shown in Fig. 5 of Cao is indicative of a single-phase dispersion. Brough teaches formation of a single phase solid amorphous dispersion characterized as having a single Tg using mDSC (Brough, e.g., 0153 and Fig. 10). Accordingly, the skilled artisan would have understood that Cao, Fig. 5 shows a single phase solid amorphous dispersion of amorphous drug and an excipient polymer as evidenced by Brough.
Sodium lauryl sulfate (Cao, formulationsF2-F4) is recognized in Zou as a lubricant. This was pointed out in the previous Office action.
Applicant has provided no mDSC evidence which contradicts the finding that Cao’s F1 formulation is a single phase solid amorphous dispersion. Applicant has provided no mDSC evidence which contradicts the finding that Cao’s F2-F11 are likely to be single-phase solid amorphous dispersions based on Cao’s characterization of F1.
Brough teaches techniques (thermokinetic compounding – TKC) enabling the formation of a single-phase solid amorphous dispersion even for immiscible excipients, and provides direct evidence of single-phase solid amorphous dispersions using mDSC characterization (Brough, e.g., 0153 and Fig. 10).
None of Applicant’s exemplified compositions are characterized by mDSC evidence showing a single-phase solid amorphous dispersion.
“As a practical matter, the Patent Office is not equipped to manufacture products by the myriad of processes put before it and then obtain prior art products and make physical comparisons therewith.” MPEP 2113 It is noted that In re Best (195 USPQ 430) and In re Fitzgerald (205 USPQ 594) discuss the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions that are newly cited or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to "prove that subject matter shown to be in the prior art does not possess characteristic relied on" (205 USPQ 594, second column, first full paragraph).
Here, the solid amorphous dispersion composition of both the claims and the cited prior art contains an active pharmaceutical agent, a pharmaceutical excipient, and a lubricant. Further, the prior art composition appears to be a single phase, amorphous solid dispersion based on the data presented in Cao at Figs. 4 (X-ray diffraction) and 5 (DSC thermogram). Cao offers no reason, like separate terminology, to believe the lubricant containing compositions (F2-F11) exhibit X-ray diffraction or DSC thermograms different from those shown for F1. Further, Cao’s lubricant containing solid dispersions (F2-F11) show enhanced dissolution profiles, which are even superior to the single-phase amorphous solid dispersion formulation F1 (Cao, e.g., Fig. 7). These findings support the conclusion that the DSC and X-ray diffraction patterns of formulations F2-F11, which contain lubricant in the solid amorphous dispersion referenced by the previous office action, are solid dispersions having the recited properties of being a single phase and amorphous as claimed.
Furthermore, the present specification indicates the single phase solid amorphous dispersions may be prepared by solvent evaporation (Specification, e.g., pg. 3:1-14; pg. 7:16-25; and ¶ spanning pp. 8-9). Cao teaches preparing the solid amorphous dispersion comprising drug, polymer, and lubricant using solvent evaporation (Cao, e.g., pg. 8, c2: PREPARATION OF SOLID DISPERSION). The prior art composition is made in the same way proposed by the present specification and appears to be a single phase based on DSC as evident from Cao, e.g., pg. 12, fig. 5.
Further still, even if evidence were presented showing Cao’s formulations are not a single phase, the skilled artisan would have been motivated by Zou to incorporate magnesium stearate and/or sodium stearyl fumarate in Cao’s solid dispersions for improved stability of the amorphous form of the LOS drug, and would have been motivated by Brough to formulate the modified dispersion as a single-phase amorphous dispersion characterized by mDSC.
Applicant argues formation of amorphous solid dispersions using solvent evaporation processes that include a solubilizer such as sodium lauryl sulfate or Tween 80 during the process does not necessarily result in incorporation of the solubilizer into a single phase with the drug and polymer in the amorphous solid dispersion. Applicant argues that in some instances, the additives can partition to the surface of amorphous solid dispersion particles. Applicant provides herewith for the Examiner’s reference a review article by Zhang et al. entitled “Impact of Surfactants as Formulation Additives and Media Components on the Performance of Amorphous Solid Dispersions”, published in Crystal Growth & Design, 2025, 25, pp 5562-5573 (hereinafter, “Zhang”). Applicant argues Zhang describes a study in which amorphous solid dispersions were prepared using a solvent evaporation process with surfactants such as sodium lauryl sulfate (SLS) and d-a- tocopherol polyethylene glycol 1000 succinate (TPGS). SLS was found to be largely present on the particle surface rather than molecularly dispersed within the ASD matrix, enhancing wetting but indicating separation from the bulk amorphous phase.
This argument is unpersuasive. The Zhang reference is post-dated art which is not indicative of the state of the art before the filing date of the presently claimed invention. To the extent that Zhang is relied upon to allegedly show inherent features of Cao’s solid dispersions, it is noted that none of the formulations in Zhang appear to contain an amorphous dispersion of lovastatin (LOS), PVP, and SLS as reported in Cao. It is additionally noted that none of the formulations in Zhang appear to contain a ternary amorphous dispersion of lovastatin, PVP, and SLS made using a mixed acetone:ethanol solvent system employed by Cao, e.g., pg. 8: Preparation of solid dispersion.
Applicant has provided no mDSC evidence showing formulations F2-F11 lack the single-phase limitation.
Even if Cao’s formulations alone, or further comprising magnesium stearate as motivated by Zou, are shown to contain more than one phase, formulation techniques were known from Brough which enable the formation of a single-phase miscible composite of two or more pharmaceutical materials previously considered to be immiscible (Brough, e.g., 0100). Brough demonstrates techniques were known, e.g., thermokinetic compounding (TKC), and effective to form a single-phase composition of a ternary mixture of drug and pharmaceutical excipients which exhibit two discrete phases when prepared using other methods, e.g., hot melt extrusion (Brough, e.g., 0179).
Consequently, even if the skilled artisan found Cao’s F2-F11 formulations or Cao’s formulations containing magnesium stearate and/or sodium stearyl fumarate as motivated by Zou to contain more than one phase, the skilled artisan had a reasonable expectation of successfully preparing a single-phase solid amorphous dispersion containing drug, polymer, and magnesium stearate as motivated by Zou using techniques known from Brough such as thermokinetic compounding. Since Brough was able to successfully formulate a ternary formulation containing a drug and two polymers as a single-phase – even though this was not possible using other techniques – the skilled artisan would have had a reasonable expectation of successfully forming a single phase amorphous solid dispersion with a drug, polymer and magnesium stearate or sodium stearyl fumarate using techniques known from Brough.
D. Applicant argues Brough does not remedy the deficiencies of Cao
Applicant argues Brough ([0153]) teaches that a single Tg indicates a single-phase but doesn't motivate modifying Cao to arrive at a single-phase amorphous solid dispersion that includes insoluble lubricants such as MgSt/SSF, which, as already explained, would have been counterintuitive in view of Ansel (page 208) and Louw (p. 121, Fig. 4.18).
This argument is unpersuasive. Brough was not cited for teaching an embodiment containing a single phase solid amorphous dispersion of an active pharmaceutical ingredient, one or more pharmaceutically acceptable excipients, and a nonpolymeric lubricant, wherein the non-polymeric lubricant is magnesium stearate or sodium stearyl fumarate since that would be an anticipatory reference. Brough was cited for teaching the desirability of a single phase amorphous solid dispersion, e.g., to maximize surface area of the drug within the dispersion based on the known direct correlation between surface area and drug solubility, and techniques which enable the production of single phase solid amorphous dispersion which contain mixtures of drug and excipients previously considered to be immiscible (Brough, e.g., 0100), e.g., excipients including magnesium stearate (Brough, e.g., 0018) or stearates (Brough, e.g., claim 14). Zou was cited for teaching the technique of incorporating lubricants including magnesium stearate and/or sodium stearyl fumarate into solid amorphous dispersions to stabilize the amorphous form of the drug.
Further, it is maintained that the skilled artisan would not have found it counterintuitive to include insoluble lubricants such as magnesium stearate and/or sodium stearyl fumarate in a single phase solid amorphous dispersion as taught by the combined teachings of Cao and Brough because of the express teaching in Zou that such a modification would be effective to stabilize the amorphous form of the drug, and because both Cao and Zou teach further formulating the solid amorphous dispersions with magnesium stearate after the dispersion is formed (Zou, e.g., pg. 3: Olaparib, povidone and partial lubrication agent are mixed, solid dispersions are prepared by melt extrusion method, so Disintegrant, diluent and rest lubricant mixed pressuring plate are added afterwards, obtain the tablet).
Applicant argues Brough [0100] merely refers to "[p]roducing single phase, miscible composites of two or more pharmaceutical materials previously considered to be immiscible for utilization in a secondary processing step, e.g., melt extrusion, film coating, tableting and granulation." Applicant argues Brough [0013], [0118] lists stearates generically as excipients, not in single-phase solid amorphous dispersions. Applicant argues Brough [0107] is a general description of experiments using thermokinetic compounding of drugs and polymeric excipients and does not exemplify lubricants in single-phase dispersions. Applicant argues Brough [0153], [0173] and [0179]-[0180] merely refer to composites of drugs and polymer excipients and also doesn't exemplify inclusion of lubricants in single-phase solid amorphous dispersions. Applicant argues those of ordinary skill in the art, aware of lubricants' negative impacts (Ansel/Louw), would avoid this modification.
These arguments are unpersuasive.
It is not clear why Applicant dismisses Brough 0100 since the present application contains the same teaching (Spec., e.g., pg. 24:3-6).
Regarding processing agents, Applicant’s argument that Brough, 0114 and claim 7 mentions lubricants as processing agents, not as integral components to a single amorphous phase is unpersuasive: it is noted that Brough exemplifies processing agents integral with a single amorphous phase, e.g., a plasticizer in an amorphous drug dispersion with a polymer (TEC, see Fig., 17 DSC analysis).
Applicant dismisses Brough’s clear teaching, exemplification, and characterization of single phase solid amorphous dispersions (Brough [0153], [0173] and [0179]-[0180]) because the cited paragraphs do not exemplify lubricants. This argument ignores the teachings of Zou which expressly teaches incorporating lubricants, e.g., magnesium stearate, in a solid amorphous dispersion to stabilize the amorphous state of the drug in the dispersion.
Applicant argues the Action’s assertions overlooks Brough’s core principle: using thermokinetic mixing to form a single-phase amorphous composite that enhance API dissolution and bioavailability often without processing agents (Remarks, pp. 25-26).
This argument is unpersuasive because Brough teaching processing agents are not required to prepare a single phase solid amorphous dispersion is simply a statement that processing agents are optional. Brough, ¶ 0066-0077 does not list various excipients which should be avoided. Brough, e.g., 0066 lists excipients and adjuvants [which] may be used to enhance the efficacy and efficiency of the APIs. This includes ingredients which control or delay release of the API (Brough, e.g., 0066). Brough teaches excipients which begin release after the expiration of a delay period (lag time) after administration (Brough, e.g., 0076) or which slows release of the drug over a period of time, e.g., 3 hours to 2 weeks for example (Brough, e.g., 0077). The skilled artisan would understand that Brough, e.g., 0076-0077, teaches that agents which delay or slow dissolution are desirable depending on the desired release profile of the formulation. Even if lubricants were expected to retard dissolution, Brough teaches the formulations may include retardants (Brough, e.g., 0070).
Moreover, despite the understanding that lubricants may retard dissolution, Zou teaches incorporating lubricants into the solid amorphous dispersion phase improved dissolution by delaying crystallization of the amorphous drug in the dispersion. See Zou, e.g., pg. 3/5:
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See also Zou, e.g., pg. 5/5:
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The improved stability of the unformed (amorphous form) is based on the observed improvement to dissolution rate of the drug from the amorphous solid dispersions containing lubricant even after storage. At pg. 5/5, Zou characterizes prior art amorphous dispersions lacking a lubricant as having reduced dissolution rate after three months noting the decline in dissolution rate is a result of crystal formation of the drug in the amorphous dispersion after three months accelerated storage conditions. The skilled artisan would have understood that Zou teaches the improvement in dissolution after six months accelerated storage conditions is attributed to the stabilization of the amorphous form of the drug due to the presence of the lubricant.
E. Applicant argues Zou does not remedy the deficiencies of Cao.
This is unpersuasive because Zou remedies any deficiency in the combined teachings of Cao and Brough with respect to incorporating magnesium stearate into a single phase solid amorphous dispersion. See Office action dated 04/10/2025, pg. 24:
It would have been obvious before the effective filing date of the presently claimed invention to modify a single phase solid amorphous dispersion comprising an API, one or more pharmaceutically acceptable excipients (PVP), and a lubricant, e.g., sodium lauryl sulfate, as known from Cao and Brough by including magnesium stearate and/or sodium stearyl fumarate in the single phase solid amorphous dispersion as suggested by Zou using techniques for preparing single phase solid dispersions known in the art from Brough with a reasonable expectation of success.
Applicant has argued:
In response to Applicant's arguments submitted in the previous response filed October 25, 2024, the Action at page 11 asserts:
"Zou very clearly teaches solid dispersions comprising a lubricant (Zou, e.g., claim 1). In fact, Zou very clearly teaches adding lubricants during the production of the solid dispersion (Zou, e.g., claim 2). It is noted that Zou teaches two alternatives for preparing a solid dispersion as seen from Zou, claim 2"
and
"In the first preparation, part of the lubricant is clearly added to the solid dispersion and the remainder of the lubricant is added after the solid dispersion is formed. In the alternative preparation, the lubricant is added after the formation of the solid dispersion. Applicant's arguments focus on the second embodiment, while the Office action relies on the first embodiment."
A machine translation of claim 2 of Zou is provided immediately below, in which the "first embodiment" referred to in the Action is underlined (emphasis added):
"2. the preparation method of granule described in claim 1, which is characterized in that by olaparib, povidone and partial lubrication agent Mixing prepares solid dispersions by melt extrusion method, then adds rest lubricant and obtains the granule; or Olaparib and povidone are dissolved in organic solvent, solid point is prepared by solvent evaporated method or spray drying process Granular media obtains the granule after adding lubricant;
In parts by weight, each parts by weight of raw materials is 25-100 parts of olaparibs, 50-250 parts of povidone and 2-6 parts of lubricants;
The lubricant is selected from two kinds of lauryl sodium sulfate and magnesium stearate; Two kinds of lauryl sodium sulfate and talcum powder; Two Two [sic.] kinds of silica and magnesium stearate; Or three kinds of lauryl sodium sulfate, silica and magnesium stearate."
Applicant argues there is no express disclosure in Zou that the "first embodiment" in claim 2 of Zou results in successful formation of a single phase amorphous solid dispersion including the lubricants referred to in claim 2 of Zou. Applicant argues that to the extent the Action takes the position that the "first embodiment" in claim 2 of Zou inherently discloses a single phase amorphous solid dispersion including "a lubricant is selected from two kinds of lauryl sodium sulfate and magnesium stearate; Two kinds of lauryl sodium sulfate and talcum powder; Two Two [sic.] kinds of silica and magnesium stearate; Or three kinds of lauryl sodium sulfate, silica and magnesium stearate." the burden is on the examiner to provide a basis in fact or evidence to reasonably support the determination that the allegedly inherent characteristic is necessarily present. MPEP §2112 IV.
This argument is unpersuasive. Applicant’s argument acknowledges that Zou teaches adding magnesium stearate to a solid dispersion comprising an amorphous drug and a polymer excipient. However, Applicant dismisses Zou’s teaching because the cited passage does not teach a single phase. Zou was not cited for teaching a single phase solid amorphous dispersion. Brough was cited for teaching single phase solid amorphous dispersions.
Applicant provides herewith for the Examiner's reference an article by Alhijjaj et al. entitled "Creating Drug Solubilization Compartments via Phase Separation in Multicomponent Buccal Patches Prepared by Direct Hot Melt Extrusion Injection Molding", published in Mol. Pharmaceutics 2015, 12, 4349-4362 (hereinafter, "Alhijjaj").
The teachings of Alhijjaj have been considered but are unpersuasive. Zou was not cited for teaching a single phase solid amorphous dispersion. The relevance of Alhijjaj to Zou is not clear since Alhijjaj does not appear to discuss magnesium stearate in a solid dispersion. The relevance of Alhijjaj to a single phase solid amorphous dispersion is not clear since it appears Aljijjaj purposefully prepared a solid dispersion having multiple phases to improve drug dissolution.
It not surprising that the teachings of Alhijjaj indicate hot melt extrusion does not necessarily result in a single phase because Alhjjaj was studying the formulation strategy of forming multiple phase compositions comprising phase separated compartments to improve the bioavailability of poorly water-soluble drugs from solid dispersions (Alhijjaj, e.g., pg. 4361, Conclusion). Alhijjaj purposely selected excipients with different solubility in each other and the model drug to create separated phases in the solid dispersion by design (Alhijjaj, e.g., Abstract).
Applicant provides herewith for the Examiner's reference an article by Biedrzycka et al. entitled "The Use of Hot Melt Extrusion to Prepare a Solid Dispersion of Ibuprofen in a Polymer Matrix", published in Polymers 2023, 15, 2912 (hereinafter, "Biedrzycka"). Biedrzycka describes the formation of an amorphous solid dispersion using hot melt extrusion incorporating a lubricant during the process, where the lubricant forms a separate phase in the final amorphous solid dispersion. In particular, in Biedrzycka, ternary amorphous solid dispersions were prepared using hot melt extrusion with ibuprofen (drug), Eudragit EPO (polymer), and Compritol 888 ATO (glyceryl dibehenate, a lubricant). The Compritol was added during extrusion but exhibited partial insolubility with the drug-polymer matrix, resulting in phase separation as confirmed by differential scanning calorimetry (DSC; showing two glass transition temperatures and a melting peak for Compritol) and X-ray powder diffraction (XRPD; indicating a crystalline Compritol peak). The ibuprofen-polymer remained amorphous, while the lubricant formed a distinct crystalline phase. See, e.g., Biedrzycka at pages 6-7 and Figures 4 and 5 ("Extrudates containing Eudragit EPO and ibuprofen have only one Tg, which appears around 15 °C (Figure 4). [] In addition, there is no melting peak of ibuprofen on the thermograms, which proves that the drug is completely dissolved in the matrix. [] In contrast, materials consisting of Eudragit EPO, ibuprofen, and COM 888 ATO show two Tg (Figure 5). The first Tg occurs around 10 °C and the second Tg around 45 °C. In addition, the thermograms show a melting peak at a temperature of about 66 °C, which indicates a partial content of the plasticizer COM in the crystalline form."). Applicant argues Biedrzycka provides evidence that single phase amorphous solid dispersions containing a lubricant or a solubilizer are not necessarily formed when a lubricant or a solubilizer is included in a hot melt extrusion process.
The teachings of Biedrzycka have been considered but are unpersuasive.
Zou was not cited for teaching a single phase solid amorphous dispersion as stated above. The relevance of Biedrzycka to Zou is not clear since Biedrzycka does not appear to discuss magnesium stearate in a solid dispersion.
Biedrzycka is a postdated reference, and as such does not represent the understanding of those skilled in the art before the filing date of the presently claimed invention.
It is acknowledged that hot melt extrusion does not necessarily result in a single-phase composition as this fact is evident from Brough. For example, Brough, e.g., example 5, 0179, teaches a multicomponent solid amorphous dispersion of itraconazole, EUDRAGIT L100-55, and carbomer 974p produced two discrete phases. Nonetheless, the use of the TKC processing technique on the same combination of API and excipients results in single phase ternary (API and two polymers) solid amorphous dispersions which were not a single phase when processed using hot melt extrusion (Brough, e.g., 0179-0180).
Consequently, even if hot-melt extrusion does not necessarily result in a single-phase solid amorphous dispersion, Brough enabled the production of single phase solid amorphous dispersions of two or more pharmaceutical materials previously considered to be immiscible (Brough, e.g., 0018, 0023, and 0100) before the filing date of the presently claimed invention.
Applicant has argued Zou is focused on improving stability and lists alternatives but equates soluble sodium lauryl sulfate with insoluble MgSt/SSF without motivating substitution in Cao’s surfactant-based system. Applicant argues the proposed modification changes Cao’s principle of operation (solubilization), is counterintuitive in view of Ansel/Lou, Zou’s stability focus doesn’t motivate for Cao’s dissolution focus and expectation of success is low due to expected dissolution hinderance.
These arguments are unpersuasive and have been addressed above. Zou and Cao are not at odds because they both are trying to solve problems associated with improving the solubility of poorly soluble drugs using similar techniques, i.e., amorphous solid dispersions. Zou is not focused solely on stability at the expense of dissolution since Zou teaches that incorporating magnesium stearate in a solid amorphous dispersion improves dissolution by inhibiting crystallization of the amorphous drug in the dispersion. Zou teaches a solid amorphous dispersion containing a drug, polymer, and lubricant shows increased dissolution relative to similar solid amorphous dispersions not containing a lubricant, because the lubricant inhibits crystallization of the amorphous drug dispersed in the polymer. Thus, the skilled artisan would have had a reasonable expectation of successfully modifying single-phase solid amorphous dispersions with a lubricant named in Zou, e.g., magnesium stearate and/or sodium stearyl fumarate, to achieve similar dissolution benefits.
F. Surprising results
Applicant submits that the subject matter recited in the pending claims is not obvious over the cited references, at least because of unexpected solubility and bioavailability enhancements identified by the Applicant, as described in the instant application as filed
This argument is unpersuasive.
It is not clear where the specification shows evidence that lubricants could be made to supersaturate aqueous media and once in solution provide superior stabilization of supersaturated drug solutions.
Lundbeck clearly teaches sodium stearyl fumarate in a solid amorphous dispersion phase with a drug and pharmaceutical excipients (Lundbeck, e.g., claim 12-13, pg. 11:17-24, pp. 26-28, example 3, Table 1). Lundbeck reports this technique provides a prolonged absorption phase with reduced Cmax and increased absorption in the intestinal environment compared to known modified release formulations while also providing an AUC corresponding to an immediate release formulation (Lundbeck, e.g., pg. 1: Field of the invention).
Applicant states each of the examples of this disclosure show superior performance of solid amorphous dispersions that contain non-polymeric lubricants. However, this argument is unpersuasive at least because the claimed invention is not commensurate in scope with the evidence presented in the specification.
The specification (pg., 31, Example 1, lines 2-7) indicates specific combinations of the drug vemurafenib, the polymer hypromellose acetate succinate, and sodium stearyl fumarate showed solubility performance improvement.
The specification also presents data for deferasirox (deferasirox in Example 1 and Fig. 1). The specification reports that in a pk dog model, Deferasirox showed significant improvement in bioavailability for compositions containing magnesium stearate inside the amorphous dispersion relative to the same compositions not containing magnesium stearate in the amorphous solid dispersion (Specification, e.g., Table 2 and Fig. 1).
In contrast, the specification, examples 2 and 3, formulate a solid amorphous dispersion with a drug, polymer and each of the named lubricants (magnesium stearate and sodium stearyl fumarate), and report in vitro dissolution results did not show performance enhancement with the inclusion of magnesium stearate or sodium stearyl fumarate in the solid amorphous dispersion phase. Thus, performance enhancement has not been shown for each example of the disclosure as clearly explained in the specification on pg. 34.
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Based on the statements made on pg. 34 of the Specification, it does not appear the skilled artisan would be able to extrapolate the improvements reported for specific embodiments containing vemurafenib and deferasirox over the full scope of the invention as presently claimed which encompasses any drug in combination with any excipient, in combination with magnesium stearate or sodium stearyl fumarate. As seen from pg. 34, the specification reports that the properties of a lubricant that lead to solubility/dissolution enhancement of the drug cannot be determined a priori. As seen from Examples 2-3, the claimed lubricants, magnesium stearate or sodium stearyl fumarate do not improve dissolution of itraconazole when present in the amorphous solid dispersion as tested by Applicant.
It is additionally noted that none of the examples in the disclosure are described as a single phase. Applicant has indicated it is improper to assume a solid amorphous dispersion is a single phase since the term solid dispersion does not say anything about the number of phases in the dispersion (Remarks, 09/10/2025, pg. 12). It is not clear that Examples 1, 2 and 3 are single phase solid amorphous dispersions since there is no evidence showing they are a single phase, e.g., mDSC data, characterizing the exemplified compositions.
It is additionally noted that there is no evidence of unexpected results comparing the performance of a single phase solid amorphous dispersion containing a named lubricant vs a solid amorphous dispersion containing a named lubricant (sodium stearyl fumarate) which is not necessarily a single phase as found in Lundbeck, e.g., pp. 26-27, example 3, table 1.
2. Lundbeck and Brough
Applicant has argued there is nothing in the disclosure of Brough to suggest the successful formation of "... a single-phase solid amorphous dispersion of (a) an active pharmaceutical ingredient, (b) one or more pharmaceutically acceptable excipients, and (c) a non-polymeric lubricant..." as recited in amended claim 21. Applicant has argued that to the extent lubricants are used in Brough, the lubricants are referred to as "processing agents." Applicant has argued there is no disclosure, teaching, or suggestion in Brough of the successful formation of a single-phase solid amorphous dispersion of an API, an excipient, and a lubricant, wherein all three of these components form a single-phase solid amorphous dispersion.
These arguments are unpersuasive for the reasons set forth above with respect to Brough in the previous rejection.
Regarding processing agents, Applicant’s argument that Brough, 0114 and claim 7 mentions lubricants as processing agents, not as integral components to a single amorphous phase is unpersuasive: it is noted that Brough exemplifies processing agents integral with a single amorphous phase, e.g., a plasticizer in an amorphous drug dispersion with a polymer (TEC, see Fig., 17 DSC analysis).
Applicant dismisses Brough’s clear teaching, exemplification, and characterization of single phase solid amorphous dispersions (Brough [0153], [0173] and [0179]-[0180]) because the cited paragraphs of Brough do not exemplify lubricants. This argument ignores the teachings of Lundbeck which expressly teaches incorporating lubricants, e.g., sodium stearyl fumarate, in a solid amorphous dispersion (Lundbeck, e.g., pg. 27, table 1). Lundbeck teaches incorporating a lubricant directly in the solid amorphous dispersion phase which is prepared using Brough’s thermokinetic compounding technique (Lundbeck, e.g., pg. 26, example 3, lines 2-12 referencing US 20090053315)
Maintained Rejections
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 21, 22, 23, 26-29, 31, 35, 36, 37, 41, 42, 44, 46, and 54 are rejected under 35 U.S.C. 103 as being unpatentable over Cao, J. Kor. Pharm. Sci., 33, 1, 2003 in view of Brough, US 20090053315 and CN 104434809 A (Zou).
Cao teaches a solid dispersion comprising a pharmaceutically active agent (API), an excipient, e.g., polyvinylpyrrolidone (PVP), and an additional excipient, i.e., oleic acid (OA), tween 80 (TW 80) and/or sodium lauryl sulfate (SA). See Cao, entire document, e.g., Abstract and pg. 8, Table 1. Oleic acid, TWEEN 80 and sodium lauryl sulfate are exemplified in combination with API and PVP both individually or in combination (Cao, e.g., pg. 8, table 1).
Solid dispersions are prepared by fully dissolving the API, PVP and solubilizer (Cao, e.g., pg. 8, c2: PREPARATION OF SOLID DISPERSION).
Cao teaches the API and the entire composition is amorphous (Cao, e.g., pg. 11, Fig. 4). Solid dispersions appear to be amorphous by x-ray diffraction (Cao, e.g., pg. 11, Fig. 4). Thus, Cao teaches a solid amorphous dispersion of an active pharmaceutical ingredient, pharmaceutically acceptable excipient (PVP), and oleic acid, sodium lauryl sulfate, and/or TWEEN 80.
Cao does not use the term “single phase.” However, Cao teaches single phase solid amorphous dispersions based on the data found in Cao. Cao’s solid dispersions appear to be a single phase because, e.g., the solid dispersion shows a single broad Tg peak, similar to PVP alone, and lacking a sharp (Tg) peak for the API (Cao, e.g., pg. 12, Fig. 5).
Brough teaches compositions similar to those of Cao, wherein a drug substance is formulated as an amorphous solid dispersion (Brough, e.g., Example 1, 0107), which is a composite composition in the form of a single-phase miscible composition of two or more pharmaceutical materials (Brough, e.g., 0100), wherein the amorphous carrier character improves the dissolution rate, bioavailability, and solubility characteristics of the API-polymer composite (Brough, e.g., 0090, 0102, and 0110). Brough teaches techniques which enable the formation of a miscible composite (single phase) of one or more pharmaceutical materials even if previously considered immiscible (Brough, e.g., 0100). Brough teaches polymeric carriers provide a stabilizing effect on supersaturated API solutions which improves the dissolution properties of poorly water-soluble drugs (Brough, e.g., 0110). Brough teaches the stabilizing carrier further comprising various functional excipients, e.g., surfactant, stabilizing agent, retardant or similar functional excipient (Brough, e.g., 0070). Brough teaches stearates may be included in the composite (Brough, e.g., 0013 claim 14). Brough clearly suggests the composites may include magnesium stearate (Brough, e.g., 0018).
Brough clearly suggests composites, e.g., single phase composite compositions may include excipients such as magnesium stearate (Brough, e.g., 0018). Brough teaches techniques which enable the production of a single phase, miscible composite of two or more pharmaceutical materials previously considered to be immiscible for utilization in a secondary processing step (Brough, e.g., 0100). Known techniques enable the formation of a single-phase composite with a variety of known pharmaceutical excipients including stearates (including magnesium stearate) and polymeric materials (Brough, e.g., 0013 and 0118). Brough teaches known techniques for preparing solid dispersions and single-phase materials include melt extrusion and thermokinetic compounding (Brough, e.g., 0107). Brough teaches single phase composites obtained using hot melt extrusion or thermokinetic processing as evidenced by a single Tg (Brough, e.g., 0153 and 0179-0180). Single glass transition is also indicative of amorphous solid solutions (single phase amorphous solid dispersions). See Brough, e.g., 0173. The skilled artisan would have recognized that Brough teaches techniques which enable the formulation of single phase solid amorphous dispersion composites comprising a drug and multiple excipients including polymers and stearates.
Brough teaches compositions exhibiting a single glass transition phase are single phase compositions (Brough, e.g., 0153). Cao, e.g., pg. 12, Fig. 5, shows solid amorphous dispersions exhibiting a single glass transition phase. Thus, Cao appears to teach a single phase solid amorphous dispersion as claimed as evidenced by Brough.
Furthermore, the present specification indicates the single phase solid amorphous dispersions may be prepared by solvent evaporation (Specification, e.g., pg. 3:1-14; pg. 7:16-25; and ¶ spanning pp. 8-9). Cao teaches preparing the solid amorphous dispersion using solvent evaporation (Cao, e.g., pg. 8, c2: PREPARATION OF SOLID DISPERSION). The prior art composition is made in the same way proposed by the present specification and appears to be a single phase based on DSC as evident from Cao, e.g., pg. 12, fig. 5.
However, in the event Applicant can show Cao’s compositions are not a single phase, Brough teaches the formation of a solid solution (single phase solid amorphous dispersion) represents the limit of particle size reduction which maximizes the total surface area of the drug in the excipient carrier (Brough, e.g., 0109). Maximizing drug surface area is expected to maximize drug dissolution because the effective surface area is directly proportional to the rate of solute dissolution dC/dt (Brough, e.g., 0108). Thus, the skilled artisan understood the formation of a solid solution corresponding to the claimed feature of a single phase solid amorphous dispersion was desirable for maximizing the effective surface area of the drug and therefore maximizing the rate of dissolution of the drug from the dispersion contributed by the effective surface area of the drug molecules.
It would have been obvious before the effective filing date of the presently claimed invention to formulate Cao’s amorphous dispersions as a single phase solid amorphous solid dispersion since Brough teaches single phase compositions are desirable for improving dissolution, bioavailability, and solubility of active pharmaceutical agents. The skilled artisan would have seen this modification as the use of a known technique to improve similar solid dispersions in the same way. The skilled artisan would have had a reasonable expectation of success because Brough teaches techniques which enable the formation of a miscible composite (single phase) of one or more pharmaceutical materials even if previously considered immiscible.
Cao does not use the term “lubricant” in reference to oleic acid, TWEEN 80 and sodium lauryl sulfate. However, at least sodium lauryl sulphate was an art recognized lubricant before the effective filing date of the presently claimed invention as evident from Zou (Zou, e.g., claims 1-2). Consequently, Cao as evidenced by Brough or the combined teachings of Cao and Brough teach a single phase, solid amorphous dispersion comprising an API, an excipient (polymer), and a lubricant (sodium lauryl sulfate) as evidenced by Zou, e.g., claim 1.
While the combined teachings of Cao and Brough teach a single phase solid amorphous solid dispersion comprising an API and excipients, the combined teachings of Cao and Brough do not expressly teach the single phase solid amorphous dispersion comprising magnesium stearate or sodium stearyl fumarate.
Zou provides an express suggestion which would have prompted one skilled in the art to modify a single phase, amorphous, solid solution known from the combined teachings of Cao and Brough by including a named lubricant, i.e., magnesium stearate as recited in claim 21 with a reasonable expectation of success.
Zou teaches the addition of lubricant to the API polymer dispersion results in an amorphous dispersion which is as stable or more stable than an amorphous dispersion which contains only the API and the polymer (Zou, e.g., pg. 2/5, Invention Content, ¶ 2). Lubricants include magnesium stearate, sodium stearyl fumarate, and sodium lauryl sulfate (Zou, e.g., pg. 2, Invention Content).
Zou teaches solid dispersions comprising a lubricant (Zou, e.g., claim 1), wherein the lubricant is combinations of lauryl sodium sulfate, magnesium stearate, talc, or silica (Zou, e.g., claim 1).
Zou clearly teaches the lubricant is incorporated within the solid dispersion (Zou, e.g., claim 2):
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This means the lubricant is in the amorphous solid dispersion. Zou uses the term unformed state (amorphous) to characterize the dispersion under accelerated testing conditions (Zou, e.g., pg. 2/25, ¶ 23 and pg. 5, final ¶).
Zou also clearly teaches the lubricant added to the solid dispersion on pg. 3:
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Zou very clearly teaches solid dispersions comprising a lubricant (Zou, e.g., claim 1).
Zou very clearly teaches adding lubricants during the production of the solid dispersion. See Zou, e.g., claim 2:
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It is clearly seen that Zou expressly teaches part of the lubricant is added to the solid dispersion and the remainder of the lubricant is added after the solid dispersion is formed.
Zou exemplifies the addition of lubricant to prepare the solid dispersion. See Zou, e.g., pg. 5, embodiment 5:
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Zou expressly teaches the lubricant magnesium stearate may be used with the lubricant silica, or as an alternative to the lubricant silica, or as an alternative to the lubricant sodium lauryl sulfate as employed by Cao, or in combination with the lubricant sodium lauryl sulfate as employed by Cao. See Zou, e.g., claim 1:
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Additionally, Zou expressly teaches the lubricant sodium stearyl fumarate may be used as an alternative to the lubricant magnesium stearate. See Zou, e.g., pg. 2:
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It would have been obvious before the effective filing date of the presently claimed invention to modify a single phase solid amorphous dispersion comprising an API, one or more pharmaceutically acceptable excipients (PVP), and a lubricant, e.g., sodium lauryl sulfate, as known from Cao and Brough by including magnesium stearate and/or sodium stearyl fumarate in the single phase solid amorphous dispersion as suggested by Zou using techniques for preparing single phase solid dispersions known in the art from Brough with a reasonable expectation of success. The skilled artisan would have been motivated to make this modification to improve the stability of the amorphous API in the composition during storage in the same way suggested by Zou with a reasonable expectation of success. Given the effort required to prepare an amorphous solid dispersion including solid solutions for increased drug dissolution as reported in Brough, the skilled artisan would have used Zou’s technique of adding lubricants such as magnesium stearate to the amorphous dispersion to preserve the amorphous nature of the drug in the same way reported by Zou. The skilled artisan would have had a reasonable expectation of success because Cao teaches compositions comprising combinations of excipients including polymers and lubricants such as sodium lauryl sulfate, because Brough suggests a variety of pharmaceutical excipients are useful for preparing amorphous dispersions including stearates and magnesium stearate, and because Zou suggests lubricants including magnesium stearate, and sodium stearyl fumarate were known and used for the purpose of improving the stability of the amorphous character of poorly water-soluble drugs in similar amorphous dispersion pharmaceutical compositions.
Applicable to claim 22: Brough teaches wherein the solid dispersion composition may include one or more active pharmaceutical ingredients (Brough, e.g., 0089-0091), Examples include antineoplastic agents, cardiovascular agents, etc. (Brough, e.g., 0058). It would have been obvious before the effective filing date of the presently claimed invention to modify compositions suggested by Cao, Brough, and Zou by including additional active agents, such as additional cardiovascular agents with a reasonable expectation of success. the skilled artisan would have viewed this modification as combining known API useful for, e.g., cardiovascular treatment, to arrive at a third composition useful for the same purpose.
Applicable to claim 23, povidone is a pharmaceutical polymer. See Cao, entire document, e.g., Abstract and pg. 8, Table 1 PVP.
Applicable to claims 26, 27, and 28: povidone is poly(vinylpyrrolidone) as recited by instant claims 26 and 27 and 28. Notably, Cao teaches the single phase amorphous solid dispersion comprising povidone and sodium lauryl sulfate, aka, sodium dodecyl sulfate as named in claim 28.
Applicable to claim 29, Cao does not teach a plasticizer. Brough teaches processing agents, including plasticizers are optional (Brough, e.g., 0011 and 0025).
Applicable to claim 31: Cao teaches API to polymer ratio of 1:9 (Cao, e.g., Table 1). Cao does not expressly teach the ratios recited in claim 31. However, Brough teaches API to polymer ratio may be 1:2 or 1:4 (Brough, e.g., 0122, 0138, 0146, 0179). Brough teaches the amount of polymeric carrier is a result effective parameter the skilled artisan would have routinely optimized to achieve an amorphous dispersion depending on the nature of the API in the composition. For example, for the same drug, a ratio of 1:4 drug to polymer results in a fully amorphous dispersion, while a ratio of 1:2 results in a slight amount of crystalline drug (Brough, e.g., 0139). The ratio of 1:4 is a clearly disclosed value recited in claim 31 which is reported in Brough as effective for producing an amorphous dispersion of a poorly water-soluble drug.
Applicable to claim 36: Brough teaches the excipient may include a thermolabile polymeric excipient (Brough, e.g., 0013 and 0093 and 0105 and 0107, 0137, 0140 and 0144 and 0182 and claim 13).
Applicable to claims 37, 41-42 and 54: Cao teaches the composition in a capsule for oral administration (Cao, e.g., pg. 12: Figs. 5-7). Claims 37 and 41 refer to properties of the composition of claim 21. Cao suggests the pharmaceutical compositions have improved dissolution (Cao, e.g., pg. 12, Figs. 6-7). Brough teaches the amorphous carrier character improves the dissolution rate, bioavailability, and solubility characteristics of the API-polymer composite (Brough, e.g., 0090, 0102, and 0110). Since the composition of the cited prior art meets the structural limitations of claim 21, it is assumed properties recited in the present claims are necessarily present. See MPEP 2112.01, I-II. Here, the prior art teaches a specific pharmaceutical composition having each of the elements generically recited in claim 21 arranged in a single-phase amorphous, solid solution. Consequently, the structure taught by the prior art falls within the scope claimed and is presumed to have the same properties observed by Applicant.
Applicable to claim 44: Cao does not teach vemurafenib.
Applicable to claim 46: The combined teachings of Cao, Brough, and Zou teach the same lubricants named by the presently claimed invention. Consequently, the lubricant in the prior art composition would appear meet the limitations of poorly water soluble or water insoluble, and/or crystalline prior to compounding with said active pharmaceutical ingredient to the extent that this product by process limitation limits the subject matter of claim 46. The product by process limitation does not appear to imply any structural difference over the cited prior art since, e.g., the prior art teaches entirely amorphous single phase solid dispersions containing the recited elements.
Accordingly, the subject matter of claims 21-23, 26-29, 31, 35-37, 41-42, 44, 46, and 54 would have been prima facie obvious before the effective filing date of the presently claimed invention, absent evidence to the contrary.
Claims 21, 22, 23, 26-29, 31, 35, 36, 37, 41, 42, 44, 46, and 54 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2015175505 (Lundbeck) in view of Brough, US 20090053315.
Lundbeck teaches formulations comprising an amorphous solid dispersion (Lundbeck, abstract, claims). The solid dispersion comprises API in an amorphous form (Lundbeck, e.g., claim 1). The solid dispersion further comprises a polymer or a combination of at least two polymers (Lundbeck, e.g., claim 4). The solid dispersion further comprises a lubricant, e.g., sodium stearyl fumarate (Lundbeck, e.g., claim 12-13, pg. 11:17-24, pp. 26-28, example 3, Table 1). Hypromellose is a lubricant (Lundbeck, e.g., pg. 32-34). Lundbeck’s solid dispersions contain hypromellose (Lundbeck, e.g., Table 1). Lundbeck’s dispersions also contain sodium stearyl fumarate which is a claimed lubricant (Lundbeck, e.g., Table 1). Dispersions are in the form of an oral dosage form, e.g., capsule or tablet (Lundbeck, e.g., claim 77). Hypromellose is the pharmaceutical polymer hydroxypropyl methylcellulose (Lundbeck, e.g., pg. 9:32-34). Hydroxypropyl methylcellulose is named in claims 26, 27, and 28). Lundbeck teaches the ratio between hypromellose and API is about 1:4 (Lundbeck, e.g., table 1).
Lundbeck teaches the solid dispersion comprising sodium stearyl fumarate which is a named lubricant in claim 21 as amended.
Lundbeck does not expressly teach the solid amorphous dispersion is a single phase.
Brough cures this deficiency.
Brough teaches solid amorphous dispersions similar to those of Lundbeck, wherein a drug substance is formulated as an amorphous solid dispersion (Brough, e.g., Example 1, 0107), which is a composite composition in the form of a single-phase miscible composition of two or more pharmaceutical materials (Brough, e.g., 0100 and 0153), wherein the amorphous carrier character improves the dissolution rate, bioavailability, and solubility characteristics of the API-polymer composite (Brough, e.g., 0090, 0102, and 0110). Brough teaches techniques which enable the formation of a miscible composite (single phase) of one or more pharmaceutical materials even if previously considered immiscible (Brough, e.g., 0100). Brough teaches polymeric carries provide a stabilizing effect on supersaturated API solutions (Brough, e.g., 0110). Brough teaches the stabilizing carrier further comprising a surfactant (Brough, e.g., 0070). Brough teaches the formation of a solid solution (single phase solid amorphous dispersion) represents the limit of particle size reduction which maximizes the total surface area of the drug in the excipient carrier (Brough, e.g., 0109). Maximizing drug surface area is expected to maximize drug dissolution because the effective surface area is directly proportional to the rate of solute dissolution dC/dt (Brough, e.g., 0108). Thus, the skilled artisan understood the formation of a solid solution corresponding to the claimed feature of a single phase solid amorphous dispersion was desirable for maximizing the effective surface area of the drug and therefore maximizing the rate of dissolution of the drug from the dispersion contributed by the effective surface area of the drug molecules.
It would have been obvious before the effective filing date of the presently claimed invention to formulate Lundbeck’s amorphous dispersions as a single phase solid amorphous dispersion, e.g., a solid solution, since Brough teaches single phase compositions are desirable for improving dissolution, bioavailability, and solubility of active pharmaceutical agents. The skilled would have seen this modification as the use of a known technique to improve similar solid dispersions in the same way. Alternatively, the skilled artisan would have seen this modification as a substitution of one known solid amorphous dispersion for another where each dispersion was known and used for improving solubility, dissolution, and bioavailability of poorly soluble active pharmaceutical compounds. The skilled artisan would have had a reasonable expectation of success because Brough teaches techniques which enable the formation of a miscible composite (single phase) of one or more pharmaceutical materials even if previously considered immiscible.
Applicable to claim 22: Brough teaches wherein the solid dispersion composition may include one or more active pharmaceutical ingredients (Brough, e.g., 0089-0091). It would have been obvious before the effective filing date of the presently claimed invention to modify compositions suggested by Lundbeck by including additional active agents, such as additional agents effective for treating movement disorders with a reasonable expectation of success. The skilled artisan would have viewed this modification as combining known API useful for, e.g., movement disorders, to arrive at a third composition useful for the same purpose.
Applicable to claim 29, Lundbeck does not teach a plasticizer. Brough teaches processing agents, including plasticizers are optional (Brough, e.g., 0011 and 0025).
Applicable to claim 31: Lundbeck teaches API to polymer ratio of about 1:4 (Lundbeck, e.g., pg. 27, Table 1). Brough teaches API to polymer ratio may be 1:2 or 1:4 (Brough, e.g., 0122, 0138, 0146, 0179). Brough teaches the amount of polymeric carrier is a result effective parameter the skilled artisan would have routinely optimized to achieve an amorphous dispersion depending on the nature of the API in the composition. For example, for the same drug, a ratio of 1:4 drug to polymer results in a fully amorphous dispersion, while a ratio of 1:2 results in a slight amount of crystalline drug (Brough, e.g., 0139). The ratio of 1:4 is a clearly disclosed value recited in claim 31 which is reported in Brough as effective for producing an amorphous dispersion of a poorly water-soluble drug.
Applicable to claim 36: Brough teaches the excipient may include a thermolabile polymeric excipient (Brough, e.g., 0013 and 0093 and 0105 and 0107, 0137, 0140 and 0144 and 0182 and claim 13).
Claims 37 and 41 refer to properties of the composition of claim 21. Lundbeck suggests the pharmaceutical compositions have enhanced dissolution (Lundbeck, e.g., pg. 10:5-9). Brough teaches the amorphous carrier character improves the dissolution rate, bioavailability, and solubility characteristics of the API-polymer composite (Brough, e.g., 0090, 0102, and 0110). Since the composition of the cited prior art meets the structural limitations of claim 21, it is assumed properties recited in the present claims are necessarily present. See MPEP 2112.01, I-II. Here, the prior art teaches a specific pharmaceutical composition having each of the elements generically recited in claim 21 arranged in a single-phase amorphous, solid solution. Consequently, the structure taught by the prior art falls within the scope claimed and is presumed to have the same properties observed by Applicant.
Applicable to claim 44: Lundbeck does not teach vemurafenib.
Applicable to claim 46: The combined teachings of Lundbeck and Brough teach the same lubricants named by the presently claimed invention. Consequently, the lubricant in the prior art composition would appear meet the limitations of poorly water soluble or water insoluble, and/or crystalline prior to compounding with said active pharmaceutical ingredient to the extent that this product by process limitation limits the subject matter of claim 46. The product by process limitation does not appear to imply any structural difference over the cited prior art since, e.g., the prior art teaches entirely amorphous single phase solid dispersions containing the recited elements.
Accordingly, the subject matter of claims 21-23, 26-29, 31, 35-37, 41-42, 44, 46, and 54 would have been prima facie obvious before the effective filing date of the presently claimed invention, absent evidence to the contrary.
Claims 21, 22, 23, 26-29, 31, 35, 36, 37, 41, 42, 44, 46, and 54 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2015175505 (Lundbeck) in view of Brough, US 20090053315 and CN 104434809 A (Zou).
The combined teachings of Lundbeck and Brough enumerated above with respect to claims 21, 22, 23, 26-29, 31, 35, 36, 37, 41, 42, 44, 46, and 54 are reiterated here. This rejection is made because while Lundbeck and Brough clearly teach a single phase amorphous solid dispersion containing an API, a polymer, and a lubricant such as sodium stearyl fumarate, the combined teachings Lundbeck and Brough do not expressly teach a single phase amorphous solid dispersion containing an API, a polymer, and magnesium stearate.
Brough clearly suggests composites, e.g., single phase composite compositions may include excipients such as magnesium stearate (Brough, e.g., 0018). Brough teaches techniques which enable the production of a single phase, miscible composite of two or more pharmaceutical materials previously considered to be immiscible for utilization in a secondary processing step (Brough, e.g., 0100). Known techniques enable the formation of a single-phase composite with a variety of known pharmaceutical excipients including stearates (including magnesium stearate) and polymeric materials (Brough, e.g., 0013 and 0118). Brough teaches known techniques for preparing solid dispersions and single-phase materials include melt extrusion and thermokinetic compounding (Brough, e.g., 0107). Brough teaches single phase composites can be obtained using hot melt extrusion or thermokinetic processing as evidenced by a single Tg (Brough, e.g., 0153 and 0179-0180). Single glass transition is also indicative of amorphous solid solutions (single phase amorphous solid dispersions). See Brough, e.g., 0173. The skilled artisan would have recognized that Brough teaches techniques which enable the formulation of single phase solid amorphous dispersion composites comprising a drug and multiple excipients including polymers and stearates.
Zou clearly shows the skilled artisan considered magnesium stearate and sodium stearyl fumarate to be art recognized equivalent lubricants which may be added to solid dispersions to improve stability of non-crystalline forms of the drug in the dispersion. Zou teaches the addition of lubricant to the API polymer dispersion results in an amorphous dispersion which is as stable or more stable than an amorphous dispersion which contains only the API and the polymer (Zou, e.g., pg. 2/5, Invention Content, ¶ 2). Lubricants include magnesium stearate, sodium stearyl fumarate, and sodium lauryl sulfate (Zou, e.g., pg. 2, Invention Content).
It would have been obvious before the effective filing date of the presently claimed invention to modify a single phase solid amorphous dispersion comprising an API, one or more pharmaceutically acceptable excipients (PVP), and a lubricant, e.g., sodium stearyl fumarate, as taught by Lundbeck and Brough by including magnesium stearate as suggested by Zou using techniques for preparing single phase solid dispersions known in the art from Brough with a reasonable expectation of success. The skilled artisan would have been motivated to make this modification to improve the stability of the amorphous API in the composition during storage in the same way suggested by Zou with a reasonable expectation of success. The skilled artisan may have seen this modification as a combination of two known lubricants clearly identified in the prior art as useful for stabilizing amorphous dispersions. Alternatively, the skilled artisan may have seen this modification as a substitution of one known lubricant for another where each were known and suggested as useful for stabilizing amorphous dispersions. The substitution or combination of art recognized equivalents is prima facie obvious. See MPEP 2144.06. The skilled artisan would have had a reasonable expectation of success because Lundbeck teaches compositions comprising combinations of excipients including polymers and lubricants such as sodium stearyl fumarate, because Brough suggests a variety of pharmaceutical excipients are useful for preparing amorphous dispersions including stearates and magnesium stearate, and because Zou suggests lubricants magnesium stearate and sodium stearyl fumarate were known and used for the purpose of improving the stability of the amorphous character of poorly water-soluble drugs in similar amorphous dispersion pharmaceutical compositions. Given the effort required to prepare an amorphous solid dispersion including solid solutions for increased drug dissolution as reported in Brough, the skilled artisan would have used Zou’s technique of adding lubricants such as magnesium stearate to the amorphous dispersion to preserve the amorphous nature of the drug in the same way reported by Zou.
Accordingly, the subject matter of claims 21, 22, 23, 26-29, 31, 35, 36, 37, 41, 42, 44, 46, and 54 would have been prima facie obvious before the effective filing date of the presently claimed invention, absent evidence to the contrary.
Conclusion
No claim is 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.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to WILLIAM A CRAIGO whose telephone number is (571)270-1347. The examiner can normally be reached on Monday - Friday, 9am - 6pm, PDT.
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/WILLIAM CRAIGO/Examiner, Art Unit 1615
/SUSAN T TRAN/Primary Examiner, Art Unit 1615
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