DETAILED ACTION
Pursuant to MPEP 1214.04, in light of the decision by the Patent Board issued July 22 2025, all previous rejections are withdrawn and the previously elected species of tizanidine and phthalic acid is allowable. Since the elected species is allowable, the species election has been expanded as set forth in MPEP 803.02. In light of discovered prior art, the species election has been expanded to include therapeutic agents: haloperidol, buprenorphine, ondansetron, granisetron, rivastigmine, letrozole and anastrozole; and acids: benzoic acid, salicylic acid and phthalic acid.
Claims 16-24, 28-29, 33-41, 43-52, 55-57 and 60-62 were/stand cancelled. Claims 1-15, 25-27, 30-32, 42, 53-54, 58-59 and 63-64 are pending. In light of the species expansion above, claims 7, 10, 25-27, 30-32, 42, 58-59 and 63 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on December 6 2021. Claim 1-6, 8-9, 11-15, 53-54 and 64 are directed to the elected invention.
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Objections
Claim 9 is objected to because of the following informalities: perampanel is incorrectly spelt as “peramanel” in line 2. Appropriate correction is required. The examiner notes that paragraph 0015 of the instant specification supports the correct spelling of perampanel.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 1-6, 8-9, 11-15, 53-54 and 64 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Martin et al. (US Patent No. 9561352) in view of Fikstad et al. (WO2005041929) and Ahmed et al. (WO2005020929) as evidenced by Loukas et al. (Journal of Pharmaceutical and Biomedical Analys, 1997).
Applicant Claims
The instant application claims a composition, comprising: a suspension comprising a therapeutic agent that (i) has a water solubility at room temperature of less than 1.0 g/L and (ii) is an organic base, and an organic acid that (i) has a water solubility at room temperature between 0.1 and 10 g/L and (ii) has a molar mass of less than 500 grams per mole, wherein the organic acid is present in the suspension in a stoichiometric (molar) excess relative to the therapeutic agent, and maintains a pH of the suspension in an environment of use of between 3.0-6.5, for delivery of the therapeutic agent from the suspension into the environment of use for a period of at least about 15 days, wherein the suspension remains in the environment of use for the period and the composition comprises an amount of the therapeutic agent sufficient for a therapeutic effect for the period, wherein the therapeutic agent is not risperidone, olanzapine, paliperidone, aripiprazole, brexpiprazole, or asenapine.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Martin et al. is directed to an implantable device for long-term delivery of drugs. The device comprises a non-erodible, non-porous housing member defining a reservoir. Contained within the reservoir is a drug formulation comprising a sparingly soluble drug and a solubility modifying excipient. The solubility modifying excipient is effective to provide a concentration of the drug, in an aqueous suspension when the drug formulation is hydrated, sufficient to provide release of a therapeutic dose of the drug from the device over a period of more than one month (i.e. 30 days) as soluble drug diffuses out of the device across the partition (column 2, lines 26-39). Specific drugs taught include haloperidol, risperidone (column 2, lines 55-57) and buprenorphine (claim 21). A partition affixed to the end of the housing comprises a plurality of pores which allow the therapeutic agent in soluble form, but not in an insoluble form, to diffuse out of the chamber into an external medium. Contained in the chamber is an aqueous suspension comprised of a mixture of a poorly water soluble therapeutic agent having a soluble agent form and an insoluble agent form and a solubility-modifying excipient to produce a concentration of the soluble agent form sufficient to provide a therapeutic dose of the drug over a selected period of time in the environment of use (column 3, lines 15-35). The pH of the suspension is adjusted to be in the range of 2.5 to 6.8 to control the equilibrium water solubility of the agent (column 3, lines 65-67). The porous portion can also permit passage of a solubility-modifying excipient that is part of the drug formulation in its soluble form (column 6, lines 43-46). As the soluble form of the agent moves from the device reservoir, through the porous partition and into the external medium under the influence of the concentration gradient, insoluble agent in the formulation contained in the device reservoir dissolves, replacing that which has been released. In this manner a constant concentration gradient is maintained and a constant outward flux of agent is maintained according to Fick’s law.
It is specifically taught when the aqueous suspension of the drug mixes with an excipient that generates acidic equivalents, the appearance of these acidic moieties lower the pH within the reservoir and in turn improves the solubility of the drug (columns 5-6, lines 65-67 and 1-3). Acidic groups which are released to control the solubility include lactic and glycolic acids (column 16, lines 33-38). As shown, for example in figure 8 and 9, increasing the concentration of the acid generating group increase the % cumulative release over 38 days.
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Martin et al. teaches a suspension comprising a poorly water soluble drug and a solubility modifier which is an acid and that the pH of the suspension is maintained at a pH of between 2.5 to 5.8 in the environment of use to provide for release over a period of at least one month, Martin et al. does not teach an organic that has a water solubility and molar mass as instantly claimed or that release of the acid can be controlled by use of something other than a polymer. However, these deficiencies are cured by Fikstad et al. and Ahmed.
Fikstad et al. is directed to a pharmaceutical composition comprising a therapeutically effective amount of a drug; a solubilizer and a release modulator wherein the release of the drug and solubilizer are synchronized (claim 1). It is taught that the solubility of many therapeutic agents is a significant problem. Without significant and sustained improvement in drug solubility, conventional controlled release of poorly soluble drug will not improve absorption thus leading to inadequate systemic drug concentration over the desired period of time (page 2, lines 11-12 and 27-31). The solubilizer significantly increases the aqueous solubility of the drug when synchronously released (page 3, lines 11-12). Taught is a drug that has an aqueous solubility of less than about 100 µg/ml (page 8, lines 4-5). Examples of drugs include ziprasidone, risperidone, anastrazole, letrozole, granisetron, ondansetron (incorrectly spelt as ondansetron), rivastigmine, etc. (page 9, lines 1-29).
Weakly basic drugs (pKa less than about 9.0) have high solubility at gastric pH and low solubility at intestinal pH may exhibit rapid absorption in the proximal gastrointestinal tract where the pH is low and the drug is predominantly in a water-soluble ionized form (page 10, lines 3-10).
A variety of suitable solubilizers may be used as long as the aqueous solubility of the drug is increased (page 12, lines 1-2). Examples include acids such as capric acid (page 12, lines 10-11). A release modulator synchronizes the release of the drug and the solubilizer over an extended period of time. Release modulators are known to those skilled in the art. (page 15, lines 5-24). It is taught that solvents are known to increase the solubility of the active ingredients. These solvents include acids such as lactic acid, maleic acid, tartaric acid, citric acid, salicylic acid, benzoic acid, succinic acid, acetic acid, etc. (page 17, lines 20-30). Forms include suspensions (page 22, line 32). Systemic formulations, for example subcutaneous, are suggested (page 22, lines 24-27).
Ahmed et al. is directed to sustained release dosage forms of ziprasidone. A solubility-improved form of ziprasidone is a combination of ziprasidone and a solubilizing agent. Solubilizing agents promote the aqueous solubility of ziprasidone. Examples of solubilizing agents include organic acid (pages 8-9, lines 32-36 and 1). Examples of organic acid solubilizing agents include acetic, benzoic, glutaric, lactic, maleic, phthalic, salicylic, tartaric, etc. (page 9, lines 14-21).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art at the time of the instant invention to combine the teachings of Martin et al, Fikstad et al. and Ahmed et al. and utilize a suspension of organic acid solubilizing agents such as benzoic acid, salicylic acid and/or phthalic acid with poorly water soluble drugs such as haloperidol, buprenorphine, anastrazole, letrozole, granisetron, ondansetron and/or rivastigmine and provide for their synchronized release. One skilled in the art would have been motivated to provide for their synchronized release as organic acids such as benzoic acid, salicylic acid and/or phthalic acid are taught by Fikstad et al. and Ahmed et al. as being solubilizers for poorly water soluble drugs. Since Martin et al. teaches a suspension comprised of a mixture of a poorly water soluble therapeutic agent having a soluble agent form and an insoluble agent form and a solubility-modifying excipient to produce a concentration of the soluble agent form sufficient to provide a therapeutic dose of the drug over a selected period of time in the environment of use and Fikstad et al. recognizes that the release of the therapeutic agent and solubilizer can be synchronized, one skilled in the art would have been motivated to synchronize the release to ensure the therapeutic agent is solubilized and released in a controlled manner. Since as taught by both Martin and Fikstad et al. poorly water soluble drugs are insoluble at neutral pH and soluble at acidic pH, one skilled in the art would have a reasonable expectation that the acids taught in Ahmed et al. (and also in Fikstad et al.) when released together in a synchronized controlled manner with the drug would provide an environment which would solubilize the drug as they would be expected to lower the pH of the environment of use or maintain the environment of use at a pH which would allow for drug solubilization. Furthermore, the organic solubilizer taught in Ahmed et al. are for a poorly water soluble drug also taught in Fikstad et al. Therefore, there is a reasonable expectation that the organic solubilizers would also solubilize other poorly water soluble drugs.
Regarding claim 1, buprenorphine, anastrazole, letrozole, granisetron, ondansetron and/or rivastigmine are specifically claimed and therefore would be expected to possess the claimed water solubility. As evidenced by Loukas et al., haloperidol has a water solubility at room temperature of 1.4 mg/100 ml or 0.014 g/L. The organic acids benzoic acid, salicylic acid and/or phthalic acid are specifically claimed and therefore would be expected to possess the claimed water solubility and molar mass and features of claim 5.
Martin et al. teaches pH of the suspension is adjusted to be in the range of 2.5 to 6.8 to control the equilibrium water solubility of the agent which overlaps with the claimed pH. Martin et al. teaches release of a therapeutic dose of the drug from the device over a period of more than one month which overlaps the claimed range. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Note MPEP 2144.05.
Regarding the concentration of the acid in claims 1 and 3-4, as taught by both Martin et al. and Fikstad et al., the acid/solubilizer is utilized to solubilize the drug. Therefore, at a minimum one skilled in the art would use equal molar concentrations of drug and organic acid. However, based on the teachings of Martin et al. and Fikstad et al. that the acid/solubilizer is responsible for converting the drug from the insoluble form to the soluble form, one skilled in the art would recognize that greater amounts of the acid would need to be present to ensure that all of the drug can be converted into the soluble form. Furthermore, Martin et al. teaches, for example in figure 8 and 9, increasing the concentration of the acid generating group increase the % cumulative release over 38 days. Therefore, one skilled in the art would recognize that the concentration of the acid can be manipulated in order to achieve the desired release rate. Since Applicants have not demonstrated an unexpected effect or criticality with regards to the molar excess, the amount is obvious for the reasons set forth above.
Regarding claim 2, Fikstad et al. teaches that weakly basic drugs (pKa less than about 9.0) have high solubility at gastric pH and low solubility at intestinal pH may exhibit rapid absorption in the proximal gastrointestinal tract where the pH is low and the drug is predominantly in a water-soluble ionized form. Based on this teaching, one skilled in the art would appreciate that the pH needs to be less than the pKa of the protonated therapeutic in order to form the water-soluble form. One skilled in the art would select the appropriate organic acid/solubilizer that would achieve the desired pH (i.e. less than the pKa) in order to solubilize the therapeutic agent.
Regarding claim 6, Martin et al. specifically claimed buprenorphine.
Regarding claim 8-9, Fikstad et al. teaches anastrazole, letrozole, granisetron, ondansetron and rivastigmine.
Regarding claims 11-15 and 53-54, organic acid solubilizers taught by Ahmed et al. include benzoic acid, salicylic acid and/or phthalic acid reading on the claims.
Regarding claim 64, Martin et al. teaches a constant concentration gradient is maintained and a constant outward flux of agent is maintained according to Fick’s law.
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 1-6, 8-9, 11-15, 53-54 and 64 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 9561352 in view of Martin et al. (US Patent No. 9561352), Fikstad et al. (WO2005041929) and Ahmed et al. (WO2005020929). Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
The instant application claims a composition, comprising: a suspension comprising a therapeutic agent that (i) has a water solubility at room temperature of less than 1.0 g/L and (ii) is an organic base, and an organic acid that (i) has a water solubility at room temperature between 0.1 and 10 g/L and (ii) has a molar mass of less than 500 grams per mole, wherein the organic acid is present in the suspension in a stoichiometric (molar) excess relative to the therapeutic agent, and maintains a pH of the suspension in an environment of use of between 3.0-6.5, for delivery of the therapeutic agent from the suspension into the environment of use for a period of at least about 15 days, wherein the suspension remains in the environment of use for the period and the composition comprises an amount of the therapeutic agent sufficient for a therapeutic effect for the period, wherein the therapeutic agent is not risperidone, olanzapine, paliperidone, aripiprazole, brexpiprazole, or asenapine.
Patent ‘352 claims a drug delivery device, comprising: a non-erodible, non-porous housing member defining a reservoir, said housing member having a water impermeable outer surface and first and second opposing ends; a porous partition positioned in the first end of the housing member; contained within said reservoir, a drug formulation comprised of a sparingly water soluble drug and a solubility-modifying excipient, said sparingly water soluble drug having a soluble form and an insoluble form, wherein the insoluble form of the drug is retained in the reservoir, and wherein said solubility-modifying excipient is capable of generating acid groups to provide a concentration of the drug, in an aqueous suspension when the drug formulation is hydrated, to provide release of a therapeutic dose of the drug from the device over a period of between about 2-12 months, as the soluble form of the drug freely diffuses out of the device across said partition; and wherein release of the therapeutic dose is dependent on pH of the drug formulation and independent of pore size of the porous partition. As claimed the drug is buprenorphine.
While Patent ‘352 claims an aqueous suspension of a sparingly water soluble drug and solubility modifying excipient and the drug can be buprenorphine, Patent ‘352 does not claim the solubility modifying excipient is one of the organic acids claimed nor does patent ‘352 claim all the instantly claimed drugs. However, these deficiencies are cured by Martin et al., Fikstad et al. and Ahmed et al.
Martin et al. is directed to an implantable device for long-term delivery of drugs. Contained within the reservoir is a drug formulation comprising a sparingly soluble drug and a solubility modifying excipient. The solubility modifying excipient is effective to provide a concentration of the drug, in an aqueous suspension when the drug formulation is hydrated, sufficient to provide release of a therapeutic dose of the drug from the device over a period of more than one month (i.e. 30 days) as soluble drug diffuses out of the device across the partition (column 2, lines 26-39). The pH of the suspension is adjusted to be in the range of 2.5 to 6.8 to control the equilibrium water solubility of the agent (column 3, lines 65-67). As the soluble form of the agent moves from the device reservoir, through the porous partition and into the external medium under the influence of the concentration gradient, insoluble agent in the formulation contained in the device reservoir dissolves, replacing that which has been released. In this manner a constant concentration gradient is maintained and a constant outward flux of agent is maintained according to Fick’s law.
It is specifically taught when the aqueous suspension of the drug mixes with an excipient that generates acidic equivalents, the appearance of these acidic moieties lower the pH within the reservoir and in turn improves the solubility of the drug (columns 5-6, lines 65-67 and 1-3). Acidic groups which are released to control the solubility include lactic and glycolic acids (column 16, lines 33-38). As shown, for example in figure 8 and 9, increasing the concentration of the acid generating group increase the % cumulative release over 38 days.
Fikstad et al. is directed to a pharmaceutical composition comprising a therapeutically effective amount of a drug; a solubilizer and a release modulator wherein the release of the drug and solubilizer are synchronized (claim 1). It is taught that the solubility of many therapeutic agents is a significant problem. Without significant and sustained improvement in drug solubility, conventional controlled release of poorly soluble drug will not improve absorption thus leading to inadequate systemic drug concentration over the desired period of time (page 2, lines 11-12 and 27-31). The solubilizer significantly increases the aqueous solubility of the drug when synchronously released (page 3, lines 11-12). Taught is a drug that has an aqueous solubility of less than about 100 µg/ml (page 8, lines 4-5). Examples of drugs include ziprasidone, risperidone, anastrazole, letrozole, granisetron, ondansetron (incorrectly spelt as ondansetron), rivastigmine, etc. (page 9, lines 1-29).
Weakly basic drugs (pKa less than about 9.0) have high solubility at gastric pH and low solubility at intestinal pH may exhibit rapid absorption in the proximal gastrointestinal tract where the pH is low and the drug is predominantly in a water-soluble ionized form (page 10, lines 3-10).
A variety of suitable solubilizers may be used as long as the aqueous solubility of the drug is increased (page 12, lines 1-2). Examples include acids such as capric acid (page 12, lines 10-11). A release modulator synchronizes the release of the drug and the solubilizer over an extended period of time. Release modulators are known to those skilled in the art. (page 15, lines 5-24). It is taught that solvents are known to increase the solubility of the active ingredients. These solvents include acids such as lactic acid, maleic acid, tartaric acid, citric acid, salicylic acid, benzoic acid, succinic acid, acetic acid, etc. (page 17, lines 20-30). Forms include suspensions (page 22, line 32). Systemic formulations, for example subcutaneous, are suggested (page 22, lines 24-27).
Ahmed et al. is directed to sustained release dosage forms of ziprasidone. A solubility-improved form of ziprasidone is a combination of ziprasidone and a solubilizing agent. Solubilizing agents promote the aqueous solubility of ziprasidone. Examples of solubilizing agents include organic acid (pages 8-9, lines 32-36 and 1). Examples of organic acid solubilizing agents include acetic, benzoic, glutaric, lactic, maleic, phthalic, salicylic, tartaric, etc. (page 9, lines 14-21).
It would have been obvious to one of ordinary skill in the art at the time of the instant invention to combine the teachings of Patent ‘352, Martin et al, Fikstad et al. and Ahmed et al. and utilize a suspension of organic acid solubilizing agents such as benzoic acid, salicylic acid and/or phthalic acid with poorly water soluble drugs such as haloperidol, buprenorphine, anastrazole, letrozole, granisetron, ondansetron and/or rivastigmine and provide for their synchronized release. One skilled in the art would have been motivated to provide for their synchronized release as organic acids such as benzoic acid, salicylic acid and/or phthalic acid are taught by Fikstad et al. and Ahmed et al. as being solubilizers for poorly water soluble drugs. Since Patent ‘352 teaches a suspension comprised of a mixture of a poorly water soluble therapeutic agent having a soluble agent form and an insoluble agent form and a solubility-modifying excipient to produce a concentration of the soluble agent form sufficient to provide a therapeutic dose of the drug over a selected period of time in the environment of use and Fikstad et al. recognizes that the release of the therapeutic agent and solubilizer can be synchronized, one skilled in the art would have been motivated to synchronize the release to ensure the therapeutic agent is solubilized and released in a controlled manner. Since as taught by both Martin and Fikstad et al. poorly water soluble drugs are insoluble at neutral pH and soluble at acidic pH, one skilled in the art would have a reasonable expectation that the acids taught in Ahmed et al. (and also in Fikstad et al.) when released together in a synchronized controlled manner with the drug would provide an environment which would solubilize the drug as they would be expected to lower the pH of the environment of use or maintain the environment of use at a pH which would allow for drug solubilization. Furthermore, the organic solubilizer taught in Ahmed et al. are for a poorly water soluble drug also taught in Fikstad et al. Therefore, there is a reasonable expectation that the organic solubilizers would also solubilize other poorly water soluble drugs.
Regarding claim 1, buprenorphine, anastrazole, letrozole, granisetron, ondansetron and/or rivastigmine are specifically claimed and therefore would be expected to possess the claimed water solubility.
Martin et al. teaches pH of the suspension is adjusted to be in the range of 2.5 to 6.8 to control the equilibrium water solubility of the agent which overlaps with the claimed pH. Martin et al. teaches release of a therapeutic dose of the drug from the device over a period of more than one month which overlaps the claimed range. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Note MPEP 2144.05.
Regarding the concentration of the acid in claims 1, 3-4, as taught by both Martin et al. and Fikstad et al., the acid/solubilizer is utilized solubilize the drug. Therefore, at a minimum one skilled in the art would use equal molar concentrations of drug and organic acid. However, based on the teachings of Martin et al. and Fikstad et al. that the acid/solubilizer is responsible for converting the drug from the insoluble form to the soluble form, one skilled in the art would recognize that greater amounts of the acid would need to be present to ensure that all of the drug can be converted into the soluble form. Furthermore, Martin et al. teaches, for example in figure 8 and 9, increasing the concentration of the acid generating group increase the % cumulative release over 38 days. Therefore, one skilled in the art would recognize that the concentration of the acid can be manipulated in order to achieve the desired release rate. Since Applicants have not demonstrated an unexpected effect or criticality with regards to the molar excess, the amount is obvious for the reasons set forth above.
Regarding claim 2, Fikstad et al. teaches that weakly basic drugs (pKa less than about 9.0) have high solubility at gastric pH and low solubility at intestinal pH may exhibit rapid absorption in the proximal gastrointestinal tract where the pH is low and the drug is predominantly in a water-soluble ionized form. Based on this teaching, one skilled in the art would appreciate that the pH needs to be less than the pKa of the protonated therapeutic in order to form the water-soluble form. One skilled in the art would select the appropriate organic acid/solubilizer that would achieve the desired pH (i.e. less than the pKa) in order to solubilize the therapeutic agent.
Regarding claim 6, Patent ‘352 specifically claims buprenorphine.
Regarding claim 8-9, Fikstad et al. teaches anastrazole, letrozole, granisetron, ondansetron and rivastigmine.
Regarding claims 11-15 and 53-54, organic acid solubilizers taught by Ahmed et al. include benzoic acid, salicylic acid and/or phthalic acid reading on the claims.
Regarding claim 64, Martin et al. teaches a constant concentration gradient is maintained and a constant outward flux of agent is maintained according to Fick’s law.
Claims 1-6, 8-9, 11-15, 53-54 and 64 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 10391288 in view of Martin et al., Fikstad et al. and Ahmed et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
The instant claims are set forth above.
Patent ‘288 claims a method for delivering a sparingly water soluble drug into an environment of use, comprising: providing a device comprising a porous partition with pores having a pore size and with a porosity, a reservoir and a formulation contained in the reservoir, the formulation comprising a sparingly water soluble drug having a soluble form and an insoluble form and a solubility-modifying excipient that generates acidic groups for a period of between about 2-12 months to provide, when the formulation is hydrated, a concentration of drug in the soluble form that is released across the porous partition and a concentration of drug in the insoluble form that is retained by the porous partition, and delivering a therapeutic dose of the drug for the period, wherein delivering the therapeutic dose is dependent on pH of the drug formulation and independent of pore size of the porous partition with said porosity. Buprenorphine is specifically claimed. An aqueous suspension is claimed.
While patent ‘288 claim an aqueous suspension and a sparingly water soluble drug that can be buprenorphine and a solubility modifying excipient, patent ‘288 does not expressly claim the organic acids instantly claimed or all the therapeutic agents instantly claimed. However, these deficiencies are cured by Martin et al., Fikstad et al. and Ahmed et al.
The teachings of Martin et al., Fikstad et al. and Ahmed et al. are set forth above.
It would have been obvious to one of ordinary skill in the art at the time of the instant invention to combine the teachings of Patent ‘288, Martin et al, Fikstad et al. and Ahmed et al. and utilize a suspension of organic acid solubilizing agents such as benzoic acid, salicylic acid and/or phthalic acid with poorly water soluble drugs such as haloperidol, buprenorphine, anastrazole, letrozole, granisetron, ondansetron and/or rivastigmine and provide for their synchronized release. One skilled in the art would have been motivated to provide for their synchronized release as organic acids such as benzoic acid, salicylic acid and/or phthalic acid are taught by Fikstad et al. and Ahmed et al. as being solubilizers for poorly water soluble drugs. Since Patent ‘288 teaches a suspension comprised of a mixture of a poorly water soluble therapeutic agent having a soluble agent form and an insoluble agent form and a solubility-modifying excipient to produce a concentration of the soluble agent form sufficient to provide a therapeutic dose of the drug over a selected period of time in the environment of use and Fikstad et al. recognizes that the release of the therapeutic agent and solubilizer can be synchronized, one skilled in the art would have been motivated to synchronize the release to ensure the therapeutic agent is solubilized and released in a controlled manner. Since as taught by both Martin and Fikstad et al. poorly water soluble drugs are insoluble at neutral pH and soluble at acidic pH, one skilled in the art would have a reasonable expectation that the acids taught in Ahmed et al. (and also in Fikstad et al.) when released together in a synchronized controlled manner with the drug would provide an environment which would solubilize the drug as they would be expected to lower the pH of the environment of use or maintain the environment of use at a pH which would allow for drug solubilization. Furthermore, the organic solubilizer taught in Ahmed et al. are for a poorly water soluble drug also taught in Fikstad et al. Therefore, there is a reasonable expectation that the organic solubilizers would also solubilize other poorly water soluble drugs.
Regarding claim 1, buprenorphine, anastrazole, letrozole, granisetron, ondansetron and/or rivastigmine are specifically claimed and therefore would be expected to possess the claimed water solubility.
Martin et al. teaches pH of the suspension is adjusted to be in the range of 2.5 to 6.8 to control the equilibrium water solubility of the agent which overlaps with the claimed pH. Martin et al. teaches release of a therapeutic dose of the drug from the device over a period of more than one month which overlaps the claimed range. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Note MPEP 2144.05.
Regarding the concentration of the acid in claims 1, 3-4, as taught by both Martin et al. and Fikstad et al., the acid/solubilizer is utilized solubilize the drug. Therefore, at a minimum one skilled in the art would use equal molar concentrations of drug and organic acid. However, based on the teachings of Martin et al. and Fikstad et al. that the acid/solubilizer is responsible for converting the drug from the insoluble form to the soluble form, one skilled in the art would recognize that greater amounts of the acid would need to be present to ensure that all of the drug can be converted into the soluble form. Furthermore, Martin et al. teaches, for example in figure 8 and 9, increasing the concentration of the acid generating group increase the % cumulative release over 38 days. Therefore, one skilled in the art would recognize that the concentration of the acid can be manipulated in order to achieve the desired release rate. Since Applicants have not demonstrated an unexpected effect or criticality with regards to the molar excess, the amount is obvious for the reasons set forth above.
Regarding claim 2, Fikstad et al. teaches that weakly basic drugs (pKa less than about 9.0) have high solubility at gastric pH and low solubility at intestinal pH may exhibit rapid absorption in the proximal gastrointestinal tract where the pH is low and the drug is predominantly in a water-soluble ionized form. Based on this teaching, one skilled in the art would appreciate that the pH needs to be less than the pKa of the protonated therapeutic in order to form the water-soluble form. One skilled in the art would select the appropriate organic acid/solubilizer that would achieve the desired pH (i.e. less than the pKa) in order to solubilize the therapeutic agent.
Regarding claim 6, Patent ‘288 specifically claims buprenorphine.
Regarding claim 8-9, Fikstad et al. teaches anastrazole, letrozole, granisetron, ondansetron and rivastigmine.
Regarding claims 11-15 and 53-54, organic acid solubilizers taught by Ahmed et al. include benzoic acid, salicylic acid and/or phthalic acid reading on the claims.
Regarding claim 64, Martin et al. teaches a constant concentration gradient is maintained and a constant outward flux of agent is maintained according to Fick’s law.
Claims 1-6, 8-9, 11-15, 53-54 and 64 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 10974036 in view of Martin et al., Fikstad et al. and Ahmed et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
The instant claims are set forth above.
Patent ‘036 claims a drug delivery device, comprising: a non-erodible, non-porous housing member defining a reservoir, said housing member having a water impermeable outer surface and first and second opposing ends; a microporous partition positioned in the first end of the housing member; contained within said reservoir, a drug formulation comprised of a sparingly water soluble drug and a solubility-modifying excipient, said sparingly water soluble drug having a soluble form and an insoluble form, wherein the insoluble form of the drug is retained in the reservoir, and wherein said solubility-modifying excipient is capable of generating acid groups to provide a concentration of the drug, when the drug formulation is hydrated, sufficient to provide release of a therapeutic dose of the drug from the device for a period of between about 2-12 months, as the soluble form of the drug freely diffuses out of the device across said microporous partition. A drug claimed is buprenorphine.
While Patent ‘036 claims a formulation comprising a sparingly water soluble drug which can be buprenorphine and a solubility modifying excipient, patent ‘036 does not expressly claim a suspension, the organic acids instantly claimed or all the therapeutic agents instantly claimed. However, these deficiencies are cured by Martin et al, Fikstad et al. and Ahmed et al.
The teachings of Martin et al, Fikstad et al. and Ahmed et al. are set forth above.
It would have been obvious to one of ordinary skill in the art at the time of the instant invention to combine the teachings of Patent ‘036, Martin et al, Fikstad et al. and Ahmed et al. and utilize a suspension of organic acid solubilizing agents such as benzoic acid, salicylic acid and/or phthalic acid with poorly water soluble drugs such as haloperidol, buprenorphine, anastrazole, letrozole, granisetron, ondansetron and/or rivastigmine and provide for their synchronized release. One skilled in the art would have been motivated to provide for their synchronized release as organic acids such as benzoic acid, salicylic acid and/or phthalic acid are taught by Fikstad et al. and Ahmed et al. as being solubilizers for poorly water soluble drugs. Since Martin et al. teaches a suspension comprised of a mixture of a poorly water soluble therapeutic agent, which is the combination as Patent ‘036, having a soluble agent form and an insoluble agent form and a solubility-modifying excipient to produce a concentration of the soluble agent form sufficient to provide a therapeutic dose of the drug over a selected period of time in the environment of use and Fikstad et al. recognizes that the release of the therapeutic agent and solubilizer can be synchronized, one skilled in the art would have been motivated to synchronize the release to ensure the therapeutic agent is solubilized and released in a controlled manner. Since as taught by both Martin and Fikstad et al. poorly water soluble drugs are insoluble at neutral pH and soluble at acidic pH, one skilled in the art would have a reasonable expectation that the acids taught in Ahmed et al. (and also in Fikstad et al.) when released together in a synchronized controlled manner with the drug would provide an environment which would solubilize the drug as they would be expected to lower the pH of the environment of use or maintain the environment of use at a pH which would allow for drug solubilization. Furthermore, the organic solubilizer taught in Ahmed et al. are for a poorly water soluble drug also taught in Fikstad et al. Therefore, there is a reasonable expectation that the organic solubilizers would also solubilize other poorly water soluble drugs.
Regarding claim 1, buprenorphine, anastrazole, letrozole, granisetron, ondansetron and/or rivastigmine are specifically claimed and therefore would be expected to possess the claimed water solubility.
Martin et al. teaches pH of the suspension is adjusted to be in the range of 2.5 to 6.8 to control the equilibrium water solubility of the agent which overlaps with the claimed pH. Martin et al. teaches release of a therapeutic dose of the drug from the device over a period of more than one month which overlaps the claimed range. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Note MPEP 2144.05.
Regarding the concentration of the acid in claims 1, 3-4, as taught by both Martin et al. and Fikstad et al., the acid/solubilizer is utilized solubilize the drug. Therefore, at a minimum one skilled in the art would use equal molar concentrations of drug and organic acid. However, based on the teachings of Martin et al. and Fikstad et al. that the acid/solubilizer is responsible for converting the drug from the insoluble form to the soluble form, one skilled in the art would recognize that greater amounts of the acid would need to be present to ensure that all of the drug can be converted into the soluble form. Furthermore, Martin et al. teaches, for example in figure 8 and 9, increasing the concentration of the acid generating group increase the % cumulative release over 38 days. Therefore, one skilled in the art would recognize that the concentration of the acid can be manipulated in order to achieve the desired release rate. Since Applicants have not demonstrated an unexpected effect or criticality with regards to the molar excess, the amount is obvious for the reasons set forth above.
Regarding claim 2, Fikstad et al. teaches that weakly basic drugs (pKa less than about 9.0) have high solubility at gastric pH and low solubility at intestinal pH may exhibit rapid absorption in the proximal gastrointestinal tract where the pH is low and the drug is predominantly in a water-soluble ionized form. Based on this teaching, one skilled in the art would appreciate that the pH needs to be less than the pKa of the protonated therapeutic in order to form the water-soluble form. One skilled in the art would select the appropriate organic acid/solubilizer that would achieve the desired pH (i.e. less than the pKa) in order to solubilize the therapeutic agent.
Regarding claim 6, Patent ‘036 specifically claims buprenorphine.
Regarding claim 8-9, Fikstad et al. teaches anastrazole, letrozole, granisetron, ondansetron and rivastigmine.
Regarding claims 11-15 and 53-54, organic acid solubilizers taught by Ahmed et al. include benzoic acid, salicylic acid and/or phthalic acid reading on the claims.
Regarding claim 64, Martin et al. teaches a constant concentration gradient is maintained and a constant outward flux of agent is maintained according to Fick’s law.
Claims 1-6, 8-9, 11-15, 53-54 and 64 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 79-102 of copending Application No. 17637755 (USPGPUB NO. 20220280494) in view of Martin et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
This is a provisional nonstatutory double patenting rejection.
The instant claims are set forth above.
Copending ‘755 claims a composition, comprising: a molar amount of a therapeutic agent that (i) has a water solubility at room temperature of less than 1.0 g/L and (ii) is an organic base, anda polyprotic acid in an amount that (i) is equal to or less than the molar amount of the therapeutic agent and (ii) provides a total number of acid hydrogens that exceeds the stoichiometric equivalent for the molar amount of therapeutic agent. Acids include phthalic acid, benzoic acid and salicylic acid. Therapeutic agents include buprenorphine, ondansetron, granisetron, rivastigmine, anastrozole, letrozole, etc. Controlled delivery is claimed.
The difference between the instant claims and copending ‘755 is that copending ‘755 is silent to the length of controlled release and pH and a suspension. However, this deficiency is cured by Martin et al.
The teachings of Martin et al. are set forth above.
It would have been obvious to one of ordinary skill in the art at the time of the instant invention to combine the teachings of copending ‘755 and Martin et al. and utilize a suspension of the organic acid such as benzoic acid, salicylic acid and/or phthalic acid with poorly water soluble drugs such as haloperidol, buprenorphine, anastrazole, letrozole, granisetron, ondansetron and/or rivastigmine. Since copending ‘755 already claims the combination of the acid and the therapeutic agent, one skilled in the art would have expected that a suspension would be useful based on the teachings of Martin et al. which also teaches the combination of an acid with a poorly water soluble therapeutic agent.
Regarding the claimed release and pH, Martin et al. teaches an overlapping range. Since copending ‘755 claims the same organic acids and therapeutic agents, one skilled in the art would expect, based on the teachings of Martin et al., that such release and pH can be achieved.
Regarding claim 64, Martin et al. teaches a constant concentration gradient is maintained and a constant outward flux of agent is maintained according to Fick’s law.
Claims 1-6, 8-9, 11-15, 53-54 and 64 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of copending Application No. 18807865 (USPGPUB No. 20250009886) in view of Martin et al. , Fikstad et al. and Ahmed et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
This is a provisional nonstatutory double patenting rejection.
The instant claims are set forth above.
Copending ‘865 claims a device, comprising: a housing member configured for subcutaneous implantation, the housing member defining a reservoir and comprising an opening for fluid communication between the reservoir and an environment of use; a composition within the reservoir, the composition comprising (i) a therapeutic agent that has a water solubility at 25 °C of less than 1.0 g/L and (ii) an organic acid that is an amino- derivative of benzoic acid and that has a molar mass of less than about 500 grams/mole, wherein the organic acid is present in a molar excess relative to the therapeutic agent; wherein the composition in its environment of use forms a heterogeneous aqueous mixture comprising a soluble form of the therapeutic agent and a soluble form of the organic acid, wherein the composition comprise an amount of the therapeutic agent sufficient for a therapeutic effect for a period of at least about 30 days upon release of the soluble form of the therapeutic agent from the device via the opening at a controlled release rate for the period. A substantially linear rate of release is claimed.
While Copending ‘865 claims a poorly water soluble therapeutic agent and an organic acid that provides a therapeutic effect for a period of at least 30 days which overlaps the instant claims, copending ‘865 does not expressly claim a suspension, the instantly claimed therapeutic agents or acids instantly claimed. However, these deficiencies are cured by Martin et al, Fikstad et al. and Ahmed et al.
The teachings of Martin et al, Fikstad et al. and Ahmed et al. are set forth above.
It would have been obvious to one of ordinary skill in the art at the time of the instant invention to combine the teachings of copending ‘865, Martin et al, Fikstad et al. and Ahmed et al. and utilize a suspension of organic acid solubilizing agents such as benzoic acid, salicylic acid and/or phthalic acid with poorly water soluble drugs such as haloperidol, buprenorphine, anastrazole, letrozole, granisetron, ondansetron and/or rivastigmine and provide for their synchronized release. One skilled in the art would have been motivated to provide for their synchronized release as organic acids such as benzoic acid, salicylic acid and/or phthalic acid are taught by Fikstad et al. and Ahmed et al. as being solubilizers for poorly water soluble drugs. Since Martin et al. teaches a suspension comprised of a mixture of a poorly water soluble therapeutic agent, which is the combination as copending ‘865, having a soluble agent form and an insoluble agent form and a solubility-modifying excipient to produce a concentration of the soluble agent form sufficient to provide a therapeutic dose of the drug over a selected period of time in the environment of use and Fikstad et al. recognizes that the release of the therapeutic agent and solubilizer can be synchronized, one skilled in the art would have been motivated to synchronize the release to ensure the therapeutic agent is solubilized and released in a controlled manner. Since as taught by both Martin and Fikstad et al. poorly water soluble drugs are insoluble at neutral pH and soluble at acidic pH, one skilled in the art would have a reasonable expectation that the acids taught in Ahmed et al. (and also in Fikstad et al.) when released together in a synchronized controlled manner with the drug would provide an environment which would solubilize the drug as they would be expected to lower the pH of the environment of use or maintain the environment of use at a pH which would allow for drug solubilization. Furthermore, the organic solubilizer taught in Ahmed et al. are for a poorly water soluble drug also taught in Fikstad et al. Therefore, there is a reasonable expectation that the organic solubilizers would also solubilize other poorly water soluble drugs.
Regarding claim 1, buprenorphine, anastrazole, letrozole, granisetron, ondansetron and/or rivastigmine are specifically claimed and therefore would be expected to possess the claimed water solubility.
Martin et al. teaches pH of the suspension is adjusted to be in the range of 2.5 to 6.8 to control the equilibrium water solubility of the agent which overlaps with the claimed pH. Martin et al. teaches release of a therapeutic dose of the drug from the device over a period of more than one month which overlaps the claimed range. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Note MPEP 2144.05.
Regarding the concentration of the acid in claims 1, 3-4, as taught by both Martin et al. and Fikstad et al., the acid/solubilizer is utilized solubilize the drug. Therefore, at a minimum one skilled in the art would use equal molar concentrations of drug and organic acid. However, based on the teachings of Martin et al. and Fikstad et al. that the acid/solubilizer is responsible for converting the drug from the insoluble form to the soluble form, one skilled in the art would recognize that greater amounts of the acid would need to be present to ensure that all of the drug can be converted into the soluble form. Furthermore, Martin et al. teaches, for example in figure 8 and 9, increasing the concentration of the acid generating group increase the % cumulative release over 38 days. Therefore, one skilled in the art would recognize that the concentration of the acid can be manipulated in order to achieve the desired release rate. Since Applicants have not demonstrated an unexpected effect or criticality with regards to the molar excess, the amount is obvious for the reasons set forth above.
Regarding claim 2, Fikstad et al. teaches that weakly basic drugs (pKa less than about 9.0) have high solubility at gastric pH and low solubility at intestinal pH may exhibit rapid absorption in the proximal gastrointestinal tract where the pH is low and the drug is predominantly in a water-soluble ionized form. Based on this teaching, one skilled in the art would appreciate that the pH needs to be less than the pKa of the protonated therapeutic in order to form the water-soluble form. One skilled in the art would select the appropriate organic acid/solubilizer that would achieve the desired pH (i.e. less than the pKa) in order to solubilize the therapeutic agent.
Regarding claim 6, Martin et al. specifically claims buprenorphine.
Regarding claim 8-9, Fikstad et al. teaches anastrazole, letrozole, granisetron, ondansetron and rivastigmine.
Regarding claims 11-15 and 53-54, organic acid solubilizers taught by Ahmed et al. include benzoic acid, salicylic acid and/or phthalic acid reading on the claims.
Regarding claim 64, Martin et al. teaches a constant concentration gradient is maintained and a constant outward flux of agent is maintained according to Fick’s law.
Claims 1-6, 8-9, 11-15, 53-54 and 64 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6-8, 10-22 and 25-30 of copending Application No. 17637756 (USPGPUB No. 20220280503) in view of Martin et al. , Fikstad et al. and Ahmed et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
This is a provisional nonstatutory double patenting rejection.
The instant claims are set forth above.
Copending ‘756 claims a composition, comprising: an aqueous mixture comprising an organic acid and an opioid antagonist at an organic acid:opioid antagonist mole ratio of less than or equal to 1:1, wherein the organic acid (i) has a water solubility at room temperature between 0.1 and 10 g/L, (ii) has a molar mass of less than 400 grams per mole, and/or (iii) maintains a pH of the mixture in its environment of use that is between about 3.0-11.5. Acids claimed include benzoic acid, salicylic acid.
While Copending ‘756 claims a therapeutic agent and an organic acid that provides a therapeutic effect for a period of at least 30 days which overlaps the instant claims, copending ‘765 does not expressly claim a suspension, the instantly claimed therapeutic agents or acids instantly claimed. However, these deficiencies are cured by Martin et al, Fikstad et al. and Ahmed et al.
The teachings of Martin et al, Fikstad et al. and Ahmed et al. are set forth above.
It would have been obvious to one of ordinary skill in the art at the time of the instant invention to combine the teachings of Copending ‘756, Martin et al, Fikstad et al. and Ahmed et al. and utilize a suspension of organic acid solubilizing agents such as benzoic acid, salicylic acid and/or phthalic acid with poorly water soluble drugs such as haloperidol, buprenorphine, anastrazole, letrozole, granisetron, ondansetron and/or rivastigmine and provide for their synchronized release. One skilled in the art would have been motivated to provide for their synchronized release as organic acids such as benzoic acid, salicylic acid and/or phthalic acid are taught by Fikstad et al. and Ahmed et al. as being solubilizers for poorly water soluble drugs. Since Martin et al. teaches a suspension comprised of a mixture of a poorly water soluble therapeutic agent, which is the combination as copending ‘865, having a soluble agent form and an insoluble agent form and a solubility-modifying excipient to produce a concentration of the soluble agent form sufficient to provide a therapeutic dose of the drug over a selected period of time in the environment of use and Fikstad et al. recognizes that the release of the therapeutic agent and solubilizer can be synchronized, one skilled in the art would have been motivated to synchronize the release to ensure the therapeutic agent is solubilized and released in a controlled manner. Since as taught by both Martin and Fikstad et al. poorly water soluble drugs are insoluble at neutral pH and soluble at acidic pH, one skilled in the art would have a reasonable expectation that the acids taught in Ahmed et al. (and also in Fikstad et al.) when released together in a synchronized controlled manner with the drug would provide an environment which would solubilize the drug as they would be expected to lower the pH of the environment of use or maintain the environment of use at a pH which would allow for drug solubilization. Furthermore, the organic solubilizer taught in Ahmed et al. are for a poorly water soluble drug also taught in Fikstad et al. Therefore, there is a reasonable expectation that the organic solubilizers would also solubilize other poorly water soluble drugs.
Regarding claim 1, buprenorphine, anastrazole, letrozole, granisetron, ondansetron and/or rivastigmine are specifically claimed and therefore would be expected to possess the claimed water solubility.
Martin et al. teaches pH of the suspension is adjusted to be in the range of 2.5 to 6.8 to control the equilibrium water solubility of the agent which overlaps with the claimed pH. Martin et al. teaches release of a therapeutic dose of the drug from the device over a period of more than one month which overlaps the claimed range. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Note MPEP 2144.05.
Regarding the concentration of the acid in claims 1, 3-4, as taught by both Martin et al. and Fikstad et al., the acid/solubilizer is utilized solubilize the drug. Therefore, at a minimum one skilled in the art would use equal molar concentrations of drug and organic acid. However, based on the teachings of Martin et al. and Fikstad et al. that the acid/solubilizer is responsible for converting the drug from the insoluble form to the soluble form, one skilled in the art would recognize that greater amounts of the acid would need to be present to ensure that all of the drug can be converted into the soluble form. Furthermore, Martin et al. teaches, for example in figure 8 and 9, increasing the concentration of the acid generating group increase the % cumulative release over 38 days. Therefore, one skilled in the art would recognize that the concentration of the acid can be manipulated in order to achieve the desired release rate. Since Applicants have not demonstrated an unexpected effect or criticality with regards to the molar excess, the amount is obvious for the reasons set forth above.
Regarding claim 2, Fikstad et al. teaches that weakly basic drugs (pKa less than about 9.0) have high solubility at gastric pH and low solubility at intestinal pH may exhibit rapid absorption in the proximal gastrointestinal tract where the pH is low and the drug is predominantly in a water-soluble ionized form. Based on this teaching, one skilled in the art would appreciate that the pH needs to be less than the pKa of the protonated therapeutic in order to form the water-soluble form. One skilled in the art would select the appropriate organic acid/solubilizer that would achieve the desired pH (i.e. less than the pKa) in order to solubilize the therapeutic agent.
Regarding claim 6, Martin et al. specifically claims buprenorphine.
Regarding claim 8-9, Fikstad et al. teaches anastrazole, letrozole, granisetron, ondansetron and rivastigmine.
Regarding claims 11-15 and 53-54, organic acid solubilizers taught by Ahmed et al. include benzoic acid, salicylic acid and/or phthalic acid reading on the claims.
Regarding claim 64, Martin et al. teaches a constant concentration gradient is maintained and a constant outward flux of agent is maintained according to Fick’s law.
Conclusion
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/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
/DANIEL M SULLIVAN/Director, Art Unit 1600