Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Response to Amendment
Acknowledgment is made of the receipt and entry of the amendment filed on 11/19/2025, wherein independent claim 1 is amended, and new claim 36 is added.
Independent claim 1 is amended to remove limitation “wherein the apilimod salt is in a ratio (w/w) of apilimod salt to gelatin of 3 to 12.5:1”, which broadens the scope of claim 1. New claim 36 recites limitation “wherein the apilimod salt is in a ratio (w/w) of apilimod salt to gelatin of 3 to 12.5:1”, which was previously presented in independent claim 1 .
Election/Restrictions
Applicant affirmed the election of Group I, apilimod composition in reply dated 09/16/2024 without traverse.
Claims 17-20 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected election.
Status of Claims
Claims 1, 3-4, 11-14, 17-20, 23, and 26-36 are pending in the instant application.
Claims 17-20 remain withdrawn.
Claims 1, 3-4, 11-14, 23, and 26-36 are under examination in this office action.
Action Summary
Applicant’s Remarks filed 11/19/2025 have been fully considered, but they are NOT persuasive to overcome rejections under 35 USC §103 and double patenting rejections on the record. Independent claim 1 is amended to remove the limitation “wherein the apilimod salt is in a ratio (w/w) of apilimod salt to gelatin of 3 to 12.5:1”, which broadens the scope of instant claim 1. Claims 1, 3-4, 11-14, 23, and 26-36 remain rejected under 35 USC § 103 as being unpatentable over, i) Lichenstein’ 884 in view of Sugimoto, Jones (2011) and Green; ii) Beeharry’ 439 in view of Sugimoto, Jones and Green. Applicant’s argument against individual reference on the record are addressed accordingly.
As noted in previous office action, instant disclosed dissolution profile of apilimod hydrochloride, malonate, and tartrate salt form in combination with fish gelatin and mannitol at specific concentration/ratio do not necessarily represent/predict embodiment genus of apilimod salt in combination with different excipient, at different concentration and at different ratio thereof encompassed by claim 1 that could achieve instantly claimed dissolution profile. In other words, instantly claimed unexpected/unpredictable superior dissolution profiles of apilimod salts do not commensurate with the scope of claim 1 and instant disclosure. Applicant is advised to further amend claims with limitation that are critical/essential to achieve the intended dissolution profile ( at least 80% after 20mins at pH 1-2) , for example. the concentration/amount of apilimod salt as recited in claims 33-36, in combination with the amount/ratio of apilimod salt/fish gelatin as recited in claims 26-28, concentration/amount of mannitol as recited in claim 23, water content as recited in claims 30-32, and/or other pharmaceutical acceptable excipients that have sufficient support by instant specification.
Response to Declaration
The Declaration under 37 CFR 1.132 by Dr. Keith Fandrick filed 11/19/2025 is fully considered.
Fandrick Declaration focused on dissolution profile of instantly amended orally disintegrating tablet (ODT). Fandrick Declaration argues the dissolution profile of an orally disintegrating tablet (ODT) has been closely linked to the intrinsic dissolution rate (IDR) of its active pharmaceutical ingredient (API)…and instantly claimed invention provides ODTs of specific apilimod salts (i.e., hydrochloride, malonate, and L-tartrate) that exhibit unexpectedly superior dissolution profiles compared to both the apilimod free base and other apilimod salts, including those with higher intrinsic dissolution rates (IDRs)(Declaration, para 3- 7).
RESPONSE: The examiner does not dispute intrinsic dissolution rate (IDR) is a key factor closely linked to dissolution profile of ODT formulation and instantly claimed apilimod salts exhibit better dissolution profile than free amine as presented by Fandrick Declaration. However, Sugimoto teaches intraorally rapidly disintegrating tablet comprising acid salt of a medicinal substance is preferably applicable to the free form in terms of taste, stability or operability . Sugimoto teaches dissolution test wherein samples were evaluated at 2, 5, 10, 15, 20, 25 and 30 minutes and the drug dissolution rate is preferably 80% and over for initial 30 minutes(See Col. 8, lines 53-54; Col. 22, Experiment 5). A skilled artisan would have reasonable expectation that micronized salt form (e.g. hydrochloride) of basic active ingredients (e.g. apilimod) would have better dissolution file under acidic conditions of pH at about 1- 2 based on the prior art and general knowledge of ODT formulation. It's noted Fandrick Declaration argument about the solubility of apilimod salts at non-acidic conditions(Declaration, para 11) is not a claimed technical feature of instantly apilimod salts ODT nor disclosed by instant specification. Sugimoto teaches property of oral disintegrating tablet which disintegration time in the oral cavity is within 60 seconds, preferably 45 seconds, and more preferably 30 seconds wherein the oral cavity is considered as non-acidic condition.
The examiner agrees the dissolution profile of an orally disintegrating tablet (ODT) is the intrinsic property of orally disintegrating tablet (ODT). Orally disintegrating tablet (ODT) is a well-known oral dosage form in the pharmaceutical industry that has several advantages over conventional tablets, e.g. rapid disintegration, rapid onset of action, and improved patient compliance. Once the solid oral dosage of apilimod is formulated, the dissolution profile could be measured by a skilled artisan through routine experiment. The characterization and measurement of dissolution profile do not necessarily contribute to the structural limitation of the apilimod composition.
As argued in Fandrick Declaration, different salt form of active ingredients would have different chemical/physical properties, different solubility, different dissolution profile, etc. The dissolution profile of active ingredients are also affected by a variety of factor, e.g. concentration of active ingredients and inactive ingredients (e.g. excipients, disintegrant, etc.) and ratio thereof, etc. Independent claim 1 is amended to remove the limitation “wherein the apilimod salt is in a ratio (w/w) of apilimod salt to gelatin of 3 to 12.5:1”, which broadens the scope of instant claim 1. Instant claim 1 recites orally disintegrating tablet (ODT) comprising apilimod salt ( hydrochloride, malonate, or L- tartrate salt) in combination of gelatin and one or more pharmaceutically acceptable excipients for desired dissolution profile without any limitation of dose amount and/or ratio of the active and inactive ingredient. Instant specification only disclosed dissolution profile of working example, e.g. apilimod hydrochloride, malonate, tartrate (50mg or 125mg) in combination with specific excipient (e.g. fish gelatin and mannitol) at specific concentration and ratio, which display various mean dispersion time (See Table 6, FIGs 4-7). Instant specification does not disclose any other concentration of apilimod salt >125mg (e.g. 200mg, 500mg,etc.), in combination with any other excipients at different ratios and dissolution profile thereof.
As such, instant disclosed dissolution profile of apilimod hydrochloride, malonate, and tartrate salt form in combination with fish gelatin and mannitol at specific concentration/ratio do not necessarily represent/predict embodiment genus of apilimod salt in combination with any excipient, at any concentration and at different ratio thereof encompassed by claim 1 that could achieve instantly claimed dissolution profile. In other words, instantly claimed unpredictable superior dissolution profiles of apilimod salts do not commensurate with the scope of claim 1.
Applicant is advised to further amend claims with limitation that are critical/essential to achieve the intended dissolution profile of apilimod( at least 80% after 20mins at pH 1-2).
Fandrick Declaration argues unexpected reversal between IDR and actual dissolution performance are not taught by prior art, Lichenstein , in view of Sugimoto, Jones and Green would not lead to the claimed invention with a reasonable expectation of success due to the unpredictable and counterintuitive dissolution behavior of the salts (IDRs) and their low solubility in non-acidic conditions (Declaration, para 9-10 and 12).
RESPONSE: As stated in MPEP 2144.08 II, obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g., In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988). Orally disintegrating tablet (ODT) is a well-known oral dosage form in the pharmaceutical industry that has several advantages over conventional tablets, e.g. rapid disintegration, rapid onset of action, and improved patient compliance, especially for pediatric, geriatric, psychiatric patients, etc. as taught by Sugimoto, Jones and Green. Jones on the record teaches “gelatin and mannitol are both excipients which are used in the formulation of freeze-dried ODTs, Ghourichay ( 2021) on the record reviews the benefit/advantage of Orally disintegrating tablets (ODTs), commercial ODT formulation on the market (See Table 1), approved excipient used in ODT formulation (See Table 2) and ODT formulation techniques (See Figure 1). Ghourichay teaches lyophilization platforms for ODT formulation comprising gelatin and mannitol (See page 5, left column) : “Zydis process starts with forming an aqueous bulk liquid constituted of gelatin as polymeric binder and mannitol as a mechanical booster. Gelatin acts as a glue to retain API and filler particles together in the final ODT. Furthermore, the presence of a hydrophilic filler (highly soluble in water) such as mannitol can promote disintegration. Thus, orally disintegrating tablets (ODTs) comprising gelatin and mannitol via Zydis platform is considered as general knowledge to a skilled artisan in the art of pharmaceutical formulation. A POSA would reasonably expect orally disintegrating tablets (ODTs) comprising apilimod salts and gelatin would provide reasonable dissolution profile as taught by Sugimoto. More importantly, instantly claimed unpredictable superior dissolution profiles of apilimod salts do not commensurate with the scope of claim 1 and instant disclosure.
Priority
The instant application 18/416,608 filed on 01/11/2024, is a continuation application of U.S. Application Serial No. 18/528,630 which is a USC §371 National Stage application of International Application No. PCT/US2022/033107 filed June 10, 2022, which claims the benefit under 35 USC §119(e) to U.S. Application Serial No. 63/202,438 filed June 11, 2021. It’s noted Example 2 “ ORALLY DISINTEGRATING TABLETS OF THE APILIMOD SALTS” starting [117], wherein micronized apilimod salts were incorporated into orally disintegrating tablets, and experimental data thereof , were not disclosed in U.S. provisional application No. 63/202,438.
Information Disclosure Statement
The information disclosure statement filed on 02/23/2026 is in compliance with the provisions of 37 CFR1.97. Accordingly, the reference listed in IDS are being considered by the Examiner.
Claim Rejections - 35 USC § 103
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.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3-4, 11-14, 23, and 26-36 are rejected under 35 U.S.C. 103 as being unpatentable over Lichenstein et al (US 20170020884 A1, hereafter Lichenstein’ 884), in view of Sugimoto et al. (US 7,927,623 B2), Jones et al. (Pharmaceutics 2011, 3, 440-457; doi:10.3390/pharmaceutics3030440, “The Influence of Formulation and Manufacturing Process Parameters on the Characteristics of Lyophilized Orally Disintegrating Tablets”), and Green et al.(US 9,192,580 B2)(maintained and reiterated as necessitated by amendment).
Claim interpretation: The limitation “dissolves at least 80% under acidic conditions of pH at about 1- 2 after 20 minutes of administration” recited in amended claim 1 and its dependent claims, is construed as property and/or intended result of the claimed apilimod composition which do not necessarily contribute to the structural limitation of composition product. Stability and dissolution profile are the property/direct result of composition once orally disintegrating tablet of apilimod salt is formulated and could be measured by a skilled artisan.
Regarding the active ingredient apilimod and salt thereof, Lichenstein’ 884 teaches pharmaceutical composition comprising apilimod and pharmaceutical salt thereof, for treating cancer( See abstract, [0035]-[0036]). Lichenstein’ 884 teaches exemplary pharmaceutically acceptable salt of apilimod, such as chloride, tartrate, maleate, etc. (See [0039]).
Lichenstein’ 884 teaches apilimod composition can be in the form of an orally acceptable dosage form including capsules, tablets, soft gelatin capsule, etc., wherein pharmaceutical excipients (e. g. gelatin, mannitol etc.) are used(See [0102]-[0106]).
Lichenstein’ 884 teaches unit dosage form comprises 25, 50, 75, 100, 200, or 300 milligrams of the active pharmaceutical ingredient, e.g., apilimod free base or apilimod dimesylate, in the form of a tablet or capsule for oral delivery (See [0099]-[0101]) (which reads on the dosage limitation of instant claims 12-14).
Lichenstein’ 884 collectively teaches solid oral dosage form (e.g. tablet, capsule) of apilimod, comprising apilimod salt (chloride, tartrate, etc.) and pharmaceutically acceptable excipients(e.g. gelatin, mannitol, etc.) at claimed range of unit dosage form.
Lichenstein’ 884 is silent about orally rapidly disintegrating tablet and the stability profile and dissolution profile thereof. Orally disintegrating tablet (ODT) is a well-known oral dosage form in the pharmaceutical industry that has several advantages over conventional tablets, e.g. rapid disintegration, rapid onset of action, and improved patient compliance, especially for patients having difficulty in swallowing, e.g. pediatric, geriatric, psychiatric, and bedridden patients, etc. Please note stability and dissolution profile are the property/direct result of composition once orally disintegrating tablet of apilimod is formulated and measured by a skilled artisan. The characterization and measurement of stability and dissolution profile do not necessarily contribute to the structural limitation of the apilimod composition.
Sugimoto teaches orally rapidly disintegrating tablets for poorly water-soluble drug under neutral or alkaline conditions which are converted into acid salts for the purpose of achieving rapid dissolution, improved bioavailability and early onset of efficacy thereof(See abstract, Col. 2, lines 28-34, 51-65; Col. 3, lines 1-59, claims 1-2, 4-5). Sugimoto teaches intraorally rapidly disintegrating tablet comprising acid salt of a medicinal substance is preferably applicable to the free form in terms of taste, stability or operability( See Col. 7, lines 28-33). Sugimoto teaches exemplary acids include organic acids having pKa of 4 or below, such as fumaric acid, tartaric acid, etc.(See Col. 4, lines 50-54)(which reads on salt form of instant claims 1). Sugimoto teaches embodiments of active ingredients which solubility under acid conditions (e.g. pH 1-2) is 10-fold or 100-fold compared with the solubility in water at pH 7, wherein higher solubility might lead to higher dissolution under acidic conditions (See Col. 4, lines 39-45).
Sugimoto teaches preparation of oral disintegrating tablet comprises process of granulation, spraying, etc. which is construed as micronization (See Col. 9 and 10, Examples 1-5). Sugimoto teaches embodiments with the mean particle diameter within the range of 30 to 500um, preferably 50 to 300 um, more preferably 100 to 200 um(See Col 4. lines 31-34)(which reads on “micronized” limitation).
Regarding limitation of mannitol recited in instant claims 3 and 23, Sugimoto teaches mannitol is water-soluble saccharide which furnishes the tablet with good solubility and sweetness and further teaches orally rapidly disintegrating tablets comprising active ingredients and various amount of mannitol(See Examples 1, 2, 5).
Regarding the limitation of claims 33-35, Sugimoto teaches the oral disintegrating tablet dosage unit at 300 mg/unit wherein the content of active ingredients at the preferred range of 10-30% w/w (See Col. 8, line 27; See Example 1)(which overlaps with range of claims 33-35).
Sugimoto teaches property of oral disintegrating tablet which disintegration time in the oral cavity is within 60 seconds, preferably 45 seconds, and more preferably 30 seconds(See Col. 8, lines 36-37; Col. 21, Experiment 3; claim 2). Sugimoto also teaches dissolution test wherein samples were evaluated at 2, 5, 10, 15, 20, 25 and 30 minutes and the drug dissolution rate is 70% and over, preferably 80% and over for initial 30 minutes(See Col. 8, lines 53-54; Col. 22, Experiment ).
Sugimoto teaches gelatin as one or more pharmaceutical excipient that can be mixed with active ingredients (See Col. 4, line 29; Col 25, line51; claims 1 and 7).
Jones teaches gelatin is a principal excipient used as a binder in the formulation of lyophilized orally disintegrating tablets(which reads on instant claim 29). Jones teaches “gelatin and mannitol are both excipients which are used in the formulation of freeze-dried ODTs. These materials are responsible for forming the highly porous matrix structure of the dosage form. Gelatin, a protein, which acts as a glassy amorphous compound, provides structural strength, whilst mannitol (a sugar alcohol) provides crystallinity, hardness and elegance. Water is used as a manufacturing process media, which induces the porous structure upon sublimation during the freeze drying stage” (See page 441, Introduction). Jones teaches various embodiments comprising gelatin and mannitol ( e.g. 9% w/w gelatin and 30% w/w mannitol ), and explores the effect of various process parameters on the dissolution profile, e.g. pH, ionic strength, reducing particle size by ball milling, etc. (See page 442, Experimental Section; page 446, Results and Discussion). Please note reduced particle size by micro-ball milling also read on instant “micronized” limitation.
Sugimoto and Jones are silent about the fish gelatin limitation of claim 4.
Green teaches preparation of fast-dispersing dosage form using fish gelatin by freeze-drying or lyophilizing a combination of the active ingredient and fish gelatin (e.g. non-gelling fish gelatin)(See abstract; Col. 3, lines 30-67; Examples 3-5; claims 1-5). Green teaches benefit of no-gelling, non-hydrolyzed fish gelatin in preparing rapidly dispersing dosage forms using, which releases the active ingredient rapidly on contact with a fluid(e.g. saliva), in terms of processing parameters and product qualities (See Col. 3, lines 30-55;). Green teaches oral disintegrating solid dosage form containing fish gelatin “have a faster disintegration time, a better taste and a better mouth feel than dosage forms containing mammalian derived gelatin. Moreover, there is no need for sweeteners and flavors to be added to mask the taste or smell of the gelatin since fish gelatin has an acceptable taste and smell …greatly reduced with attendant cost benefits. … In addition, since fish gelatin is soluble in cold water, the heating step, which is required when mammalian derived gelatin is used, can be omitted thereby producing cost savings in heating costs and shorter mixing times.” (See Col. 11, lines 26-46).
Regarding the water content limitation recited in claims 30-32, Green teaches various amount of water content prior to lyophilization, e.g. about 91- 93% (See Example 3-5).
Regarding the amount/concentration limitation of active ingredient recited in instant claims 33-35, Green teaches the quantity of active ingredient vary according to the particular drug selected and the patient’s needs. The active ingredient can be generally present in an amount from about 0.2% to about 95%, typically from about 1% to about 20%, by weight of the composition of the dried dosage form(See Col. 9, lines 12-7; Example 3).Green explicitly teaches embodiments comprising 1.5% of active ingredients(salt form), 4.0% of fish gelatin, 3.0% of mannitol, and 90.9% of water with disintegration time of 0.78 seconds (See Example 3)(which reads on instantly claimed range of fish gelatin, mannitol).
Regarding the limitation of the ratio of apilimod salt to gelatin, the ratio of active ingredient to fish gelatin in Example 3 is calculated to be 15:40. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. MPEP 2144.05. For example, for embodiments comprising 20% of active ingredient and 4.0% of fish gelatin, the ratio of active ingredient to fish gelatin could be calculated as 5:1 (which would read on instantly claimed 3 to 12.5:1).
It would have been obvious to one of the ordinary skilled in the art before the effective filing date of instantly claimed invention to explore dosage form of apilimod composition taught by Lichenstein’ 884 with the teaching of oral disintegrating tablet taught by Sugimoto, Jones and Green, together with experimentation/ optimization based on general knowledge of apilimod and solid oral formulation, and arrive at the instantly claimed invention with reasonable expectation of success. Before the effective filing date of instant claimed invention, it was already known apilimod solid oral dosage form (e.g. tablet, capsule) comprising apilimod salt (chloride, tartrate, etc.) and pharmaceutically acceptable excipients(e.g. gelatin, mannitol, etc.) could be made as taught by Lichenstein’ 884. It was also known orally rapidly disintegrating tablets comprising acid salts of poorly water-soluble drug under neutral or alkaline conditions in combination with pharmaceutically acceptable excipients(e.g. gelatin, mannitol, etc.) could be made for the purpose of achieving rapid dissolution as taught by Sugimoto, Jones and Green. Jones teaches gelatin and mannitol are both excipients which are commonly used in the formulation of freeze-dried ODTs.
Orally disintegrating tablet (ODT) is a well-known oral dosage form in the pharmaceutical industry that has several advantages over conventional tablets, e.g. rapid disintegration, rapid onset of action, and improved patient compliance. The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to further explore dosage form for apilimod for better disintegrating profile, and bioavailability, etc. A skilled artisan would be motivated to combine the teachings of Lichenstein’ 884, Sugimoto, Jones and Green because Sugimoto explicitly teaches orally rapidly disintegrating tablets comprising acid salts of poorly water-soluble drug under neutral or alkaline conditions have benefit of rapid dissolution, improved bioavailability and early onset of efficacy. Green teaches the benefit of preparing oral rapidly dispersing dosage forms using no-gelling, non-hydrolyzed fish gelatin, which has better taste, simplified process step and lower preparation cost, etc. Further exploration the dosage amount/ratio based on the teachings of prior art and routine optimization based on general knowledge of apilimod and solid oral formulation is within the knowledge of a skilled artisan. The combined teachings of prior art and experimentation/ optimization based on general knowledge of apilimod and solid oral formulation would provide a new dosage form of apilimod salt in oral disintegrating tablet with rapid dissolution profile, improved taste and bioavailability and less cost for cancer treatment.
One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on the combined teachings of prior art and general knowledge of apilimod and solid oral formulation. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant’s argument based on the unpredictable dissolution behavior of apilimod salt is similar to Dr. Frandrick Declaration. Please see Response to Frandrick Declaration. Despite IDR of an API is a key factor of the dissolution of ODT containing API, there are other factors, e.g. different excipients, amount/ratio and combination thereof that would contribute to the final dissolution of ODT formulation. As noted in previous office action and reiterated above, instantly claimed unpredictable superior dissolution profiles of apilimod salts do not commensurate with the scope of claim 1.
Applicant argues against each reference individually: “Lichenstein does not disclose or suggest an orally disintegrating tablet. Indeed, Lichenstein neither discloses nor suggest an ODT at all which Applicants found to be important to the disintegrating nature of the composition” (Remarks, page 7)… “The combination of Lichenstein in view of Sugimoto, Jones, and Green would not lead to the claimed invention with a reasonable expectation of success due to the unpredictable and counterintuitive dissolution behavior of the salts (IDRs) and their low solubility in non-acidic conditions as described herein. The addition of Sugimoto and Green cannot cure the deficiencies noted above in Lichenstein” (Remarks, page 13)
IN RESPONSE to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). A reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. The test for obviousness is not that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. As elaborated in previous office action and reiterated above, Lichenstein’ 884 collectively teaches solid oral dosage form (e.g. tablet, capsule) of apilimod, comprising apilimod salt (chloride, tartrate, etc.) and pharmaceutically acceptable excipients(e.g. gelatin, mannitol, etc.) at claimed range of unit dosage form. Sugimoto collectively teaches orally rapidly disintegrating tablets comprising acid salts of poorly water-soluble drug in combination with pharmaceutical excipients (e.g. gelatin, mannitol, etc.) have benefit of rapid dissolution, improved bioavailability and early onset of efficacy. Green teaches preparing oral rapidly dispersing dosage forms using no-gelling, non-hydrolyzed fish gelatin, which has better taste, simplified process step and lower preparation cost, etc.
Regarding the limitation and amount/concentration limitation of new claim 36 which was previously presented in claim 1, Green teaches the quantity of active ingredient vary according to the particular drug selected and the patient’s needs. The active ingredient can be generally present in an amount from about 0.2% to about 95%, typically from about 1% to about 20%, by weight of the composition of the dried dosage form(See Col. 9, lines 12-7). Green explicitly teaches embodiments comprising 1.5% of active ingredients(salt form), 4.0% of fish gelatin, 3.0% of mannitol, and 90.9% of water with disintegration time of 0.78 seconds (See Example 3)(which reads on instantly claimed range of fish gelatin, mannitol). The ratio of active ingredient to fish gelatin in Example 3 is calculated to be 15:40. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. MPEP 2144.05. For example, for embodiments comprising 20% of active ingredient and 4.0% of fish gelatin, the ratio of active ingredient to fish gelatin could be calculated as 5:1 (which would read on instantly claimed ratio of 3 to 12.5:1).
IN RESPONSE to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, Sugimoto explicitly teaches orally rapidly disintegrating tablets comprising acid salts of poorly water-soluble drug under neutral or alkaline conditions have benefit of rapid dissolution, improved bioavailability and early onset of efficacy. Green teaches the benefit of preparing oral rapidly dispersing dosage forms using no-gelling, non-hydrolyzed fish gelatin, which has better taste, simplified process step and lower preparation cost, etc. Orally disintegrating tablet (ODT) is a well-known oral dosage form in the pharmaceutical industry that has several advantages over conventional tablets, e.g. rapid disintegration, rapid onset of action, and improved patient compliance, especially for pediatric, geriatric, psychiatric patients, etc. as taught by Sugimoto and Green. The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to further explore dosage form of apilimod for better disintegrating profile, and bioavailability, based on combined teachings of Lichenstein’ 884, Sugimoto and Green.
IN RESPONSE to Applicant’s argument about reasonable expectation of success, As stated in MPEP 2144.08 II, obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g., In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988).
Sugimoto teaches intraorally rapidly disintegrating tablet comprising acid salt of a medicinal substance is preferably applicable to the free form in terms of taste, stability or operability. Sugimoto teaches dissolution test wherein samples were evaluated at 2, 5, 10, 15, 20, 25 and 30 minutes and the drug dissolution rate is preferably 80% and over for initial 30 minutes(See Col. 8, lines 53-54; Col. 22, Experiment 5). Sugimoto teaches property of oral disintegrating tablet which disintegration time in the oral cavity is within 60 seconds, preferably 45 seconds, and more preferably 30 seconds. A skilled artisan would have reasonable expectation that micronized salt form of basic active ingredients (e.g. apilimod) would have better dissolution file under acidic conditions of pH at about 1- 2.
Claims 1, 3-4, 11-14, 23, and 26-36 are rejected under 35 U.S.C. 103 as being unpatentable over Beeharry et al. (US 2017/0333439 A1, Beeharry’ 439), in view of Sugimoto et al. (US 7,927,623 B2), Jones et al. (Pharmaceutics 2011, 3, 440-457; doi:10.3390/pharmaceutics3030440, “The Influence of Formulation and Manufacturing Process Parameters on the Characteristics of Lyophilized Orally Disintegrating Tablets”) and Green et al.(US 9,192,580 B2)(maintained and reiterated as necessitated by amendment).
Regarding the active ingredient apilimod and salt thereof, Beeharry’ 439 teaches pharmaceutical composition comprising apilimod and pharmaceutical salt thereof, for treating melanoma (See abstract, [0006], [0014], claims 1-3). Beeharry’ 439 teaches exemplary pharmaceutically acceptable salt of apilimod, such as chloride, tartrate, maleate, methanesulfonate, etc. (See [0028]-[0030]).
Beeharry’ 439 teaches apilimod composition can be in the form of an orally acceptable dosage form including capsules, tablets, soft gelatin capsule, etc., wherein pharmaceutical excipients (e. g. gelatin, mannitol etc.) are used(See [0108]-[0112])(which reads on instant claims 3).
Beeharry’ 439 teaches unit dosage form comprises various amount of apilimod, e.g. from 50 milligrams to 500 milligrams, etc.(See [0106]) (which reads on instant claims 12-14).
Beeharry’ 439 collectively teaches solid oral dosage form (e.g. tablet, capsule) of apilimod, comprising apilimod salt (chloride, tartrate, etc.) and pharmaceutically acceptable excipients(e.g. gelatin, mannitol etc.) at the claimed range of unit dosage form.
Beeharry’ 439 is silent about orally rapidly disintegrating tablet and the stability profile and dissolution profile thereof. Orally disintegrating tablet (ODTs) is a well-known oral dosage form in the pharmaceutical industry and ODTs have several advantages over conventional tablets, e.g. rapid disintegration, rapid onset of action, and improved patient compliance, especially for patients having difficulty in swallowing, e.g. pediatric, geriatric, psychiatric, and bedridden patients, etc. Please note stability and dissolution profile are the property/direct result of composition once orally disintegrating tablet of apilimod is formulated and measured by a skilled artisan. The characterization and measurement of stability and dissolution profile do not necessarily contribute to the structural limitation of the apilimod composition.
The collective teachings of Sugimoto, Jones and Green are elaborated in preceding 103 rejection and applied as before.
It would have been obvious to one of the ordinary skilled in the art before the effective filing date of instantly claimed invention to explore dosage form of apilimod composition taught by Beeharry’ 439 with the teaching of oral disintegrating tablet taught by Sugimoto, Jones and Green, together with experimentation/ optimization based on general knowledge of apilimod and solid oral formulation(e.g. oral disintegrating tablet), and arrive at the instantly claimed invention with reasonable expectation of success. Beeharry’ 439 collectively teaches solid oral dosage form (e.g. tablet, capsule) of apilimod, comprising apilimod salt (chloride, tartrate, etc.) and pharmaceutically acceptable excipients(e.g. gelatin, mannitol, etc.) at claimed range of unit dosage form. Sugimoto collectively teaches orally rapidly disintegrating tablets comprising acid salts of poorly water-soluble drug in combination with pharmaceutical excipients (e.g. gelatin, mannitol, etc.) have benefit of rapid dissolution, improved bioavailability and early onset of efficacy. Jones teaches “gelatin and mannitol are both excipients which are used in the formulation of freeze-dried ODTs. Green teaches the benefit of preparing oral rapidly dispersing dosage forms using no-gelling, non-hydrolyzed fish gelatin, which has better taste, simplified process step and lower preparation cost, etc. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. MPEP 2144.05.
Orally disintegrating tablets (ODTs) are well-known formulation in the pharmaceutical industry that have several advantages over conventional tablets. The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to further explore dosage form for apilimod for better disintegrating profile, and bioavailability, etc. A skilled artisan would be motivated to combine the teachings of Beeharry’ 439 and Sugimoto because Sugimoto explicitly teaches orally rapidly disintegrating tablets comprising acid salts of poorly water-soluble drug under neutral or alkaline conditions have benefit of rapid dissolution, improved bioavailability and early onset of efficacy. Green teaches the benefit of preparing oral rapidly dispersing dosage forms using no-gelling, non-hydrolyzed fish gelatin, which has better taste, simplified process step and lower preparation cost, etc. The combined teachings of prior art and experimentation/ optimization based on general knowledge of apilimod and solid oral formulation would provide a new dosage form of apilimod as oral disintegrating tablet with rapid dissolution, improved taste and bioavailability and less cost for cancer treatment.
One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on the combined teachings of prior art and general knowledge of apilimod and solid oral formulation (e.g. oral disintegrating tablet) . Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant’s argument against individual references, Beeharry’ 439, Sugimoto, Jones and Green is similar as presented in rejection over Lichenstein’ 884 in view of Sugimoto and Green (Remarks, page 13-14).
The examiner' response is similar as presented in Lichenstein’ 884 in view of Sugimoto, Jones and Green. Beeharry’ 439 collectively teaches solid oral dosage form (e.g. tablet, capsule) of apilimod, comprising apilimod salt (chloride, tartrate, etc.) and pharmaceutically acceptable excipients(e.g. gelatin, mannitol etc.) at the claimed range of unit dosage form. Sugimoto collectively teaches orally rapidly disintegrating tablets comprising acid salts of poorly water-soluble drug in combination with pharmaceutical excipients (e.g. gelatin, mannitol, etc.) have benefit of rapid dissolution, improved bioavailability and early onset of efficacy. Green teaches the benefit of preparing oral rapidly dispersing dosage forms using no-gelling, non-hydrolyzed fish gelatin, which has better taste, simplified process step and lower preparation cost, etc. Orally disintegrating tablets (ODTs) are well-known formulation in the pharmaceutical industry that have several advantages over conventional tablets. The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to further explore orally disintegrating tablets ODTs of apilimod for better disintegrating profile, and bioavailability, based on combined beneficial teachings of prior art.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 3-4, 11-14, 23, and 26-36 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 of U.S. Patent No. 11,266,654 B2, in view of Sugimoto et al. (US 7,927,623 B2) and Green et al.(US 9,192,580 B2).
Reference claims refer to a method for treating lymphoma comprising administering a pharmaceutical composition comprising apilimod, or a pharmaceutically acceptable salt thereof. Reference claim 2 refers to an oral dosage form of apilimod composition. Reference claims 3 and 4 further recited apilimod salt of chloride, tartrate, etc. As such, reference claims teach the content of instant claimed oral apilimod composition except gelatin and dissolution profile thereof.
The collective teachings of Sugimoto and Green are elaborated in preceding 103 rejections and applied as before. Sugimoto collectively teaches orally rapidly disintegrating tablets comprising acid salts of poorly water-soluble drug under neutral or alkaline conditions have benefit of rapid dissolution, improved bioavailability and early onset of efficacy. Green teaches the benefit of preparing oral rapidly dispersing dosage forms using no-gelling, non-hydrolyzed fish gelatin, which has better taste, simplified process step and lower preparation cost, etc.
It would have been obvious to one of the ordinary skilled in the art before the effective filing date of instantly claimed invention to explore solid dosage form of apilimod composition taught by reference claims with the teaching of oral disintegrating tablet taught by Sugimoto and Green, and arrive at the instant claims with reasonable expectation of success. The limitation “dissolves up to at least 80% under acidic conditions of pH at about 1- 2 after 20 minutes of administration” recited in amended claim 1 and its dependent claims, is construed as intended result/property of the claimed apilimod composition which do not necessarily contribute to the structural limitation of composition product. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. MPEP 2144.05.
The instant application shares one common applicant/inventor/assignee with the reference patent. Based on the continuing data on the record, instant application is not related to the reference patent, thus no 35 USC 121 shield exists.
Claims 1, 3-4, 11-14, 23, and 26-36 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16, 23 and 29 of copending Application No. 18/528,630 , in view of Sugimoto et al. (US 7,927,623 B2) and Green et al.(US 9,192,580 B2). Although the claims at issue are not identical, they are not patentably distinct from each other. This is a provisional nonstatutory double patenting rejection.
Reference claims refer to a pharmaceutical composition comprising apilimod salt and pharmaceutically acceptable excipients. Reference claims 4-5 and 16 refer to specific apilimod salt (e.g. hydrochloride, tartrate, malonate etc.. Reference claims 8 and 23 refer the solid oral dosage form is an orally disintegrating tablet. Reference claim 9 recites the oral dosage form fast-dissolving under acidic conditions, optionally wherein the acidic condition has a pH of 1-2.
The collective teachings of Sugimoto and Green are elaborated in preceding 103 rejections and applied as before. Sugimoto collectively teaches orally rapidly disintegrating tablets comprising acid salts of poorly water-soluble drug under neutral or alkaline conditions have benefit of rapid dissolution, improved bioavailability and early onset of efficacy. Green teaches the benefit of preparing oral rapidly dispersing dosage forms using no-gelling, non-hydrolyzed fish gelatin, which has better taste, simplified process step and lower preparation cost, etc.
It would have been obvious to one of the ordinary skilled in the art before the effective filing date of instantly claimed invention to explore solid dosage form of apilimod composition taught by reference claims with the teaching of oral disintegrating tablet taught by Sugimoto and Green, and arrive at the instant claims with reasonable expectation of success. The limitation “dissolves up to at least 80% under acidic conditions of pH at about 1- 2 after 20 minutes of administration” recited in amended claim 1 and its dependent claims, is construed as intended result/property of the claimed apilimod composition which do not necessarily contribute to the structural limitation of composition product. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. MPEP 2144.05.
Instant application is the continuation of copending Application No. 18/528,630. There is no restriction requirement of 18/528,630 on the record, thus no 35 USC 121 shield exists.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/L.M./ Examiner, Art Unit 1628
/JARED BARSKY/Primary Examiner, Art Unit 1628