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
This office action is in reply to the Applicant’s Arguments/Remarks filed 31 August 2026 for application 18/703,099 filed 19 April 2024. Claims 14-15 are canceled. Currently, claims 1-13 and 16-22 are pending.
REJECTIONS WITHDRAWN
The status for each rejection and/or objection in the previous office action is set out below.
35 U.S.C. 102, 103 and Double Patenting
REJECTIONS – MAINTAINED & NEW
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(New) Claims 1-2, 4, 8-10, and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Badr-Eldin et al. (1) (Inclusion complexes of talalafil with natural and chemically modified β-cyclodextrins. I: preparation and in-vitro evaluation, Eur. J. Pharmaceutics and Biopharmaceutics 2008, 70, 819-827) in view of L. V. Allen (Tadalafil 5 mg/mL oral suspension, US Pharm. 2012, 37, 5, 43-44; entered into the IDS on 18 July 2024).
Badr-Eldin (1) teaches the inclusion complexation between tadalafil and hydroxypropyl-β-cyclodextrin (HP-β-CD) and heptakis-[2,6-di-O-methyl]-β-cyclodextrin (DM-β-CD) in comparison with natural β-cyclodextrin (β-CD) in order to improve solubility and dissolution rate of the drug in an attempt to enhance its bioavailability. Using UV spectral shifts, the solubilizing power of the cyclodextrins were found to be DM-β-CD > HP-β-CD > β-CD. Badr-Eldrin notes, that despite using several preparative means, both modified cyclodextrins yielded better performance than the corresponding ones using β-CD (abstract).
Badr-Eldin (1) does not, however, teach the use of co-processed microcrystalline cellulose and sodium carboxylmethyl cellulose (MCC-NaCMC), xanthan gum.
Allen rectifies this deficiency by teaching a Tadalafil oral suspension which is comprised of three components including Tadalafil and a solution termed Ora-Plus. Ora-Plus is described as an oral suspending vehicle that accepts dilutions of up to 50% or more with water, flavoring agents, and syrups while still retaining its suspending properties. It has a pH of approximately 4.2 and an osmolality of about 230 mOsm/kg, a viscosity of approximately 1,000 cps at 25°C, and contains purified water, microcrystalline cellulose (MCC), sodium carboxymethyl cellulose (NaCMC), xanthan gum, carrageenan, sodium phosphate, and citric acid as buffering agents, simethicone as an antifoaming agent, and potassium sorbate and methyl paraben as preservatives (pg. 3).
As such, it would have been prima facie obvious, to a person of ordinary skill in the art, before the effective filing date, to consider the use of cyclodextrins in combination with Tadalafil as a means to solubilize an otherwise aqueous insoluble compound as taught by Badr-Eldin (1), and to formulate with excipients including MCC-NaCMC and xanthan gum as taught by Allen in a formulation that is used in a commercial product.
(New) With regards to the limitation of claim 2, wherein the amount of tadalafil is comprised between 0.02-2.0% w/v, the Examiner contends that the optimization of the dosing regimen is refined as part of the research process as a person of ordinary skill in the art would necessarily be motivated to do as to obtain the desired clinical outcome or improved clinical outcome, whether it encompasses tumor inhibition or treating the signs and symptoms of erectile dysfunction. Moreover, it is well-known that dosages may vary between patients due to parameters such as patient mass, co-morbidities, physical condition, age, etc. The limitation of claim 2 can be construed as a conclusion from the optimization process.
(New) Concerning the limitations of claim 4, wherein the cyclodextrin is selected from an α-cyclodextrin, ß-cyclodextrin, y-cyclodextrin, highly-branched cyclodextrin, and mixture thereof, as Badr-Eldin (1) teaches the use of hydroxyl propyl beta cyclodextrin (abstract).
(New) With concern to the limitation of claim 8, wherein the composition further comprising a preservative, is met as Allen teaches that Ora-Plus includes the preservative methyl paraben (pg. 3).
(New) Regarding the limitation of claim 9, wherein the composition further comprises a pH adjusting agent to adjust the pH of the pharmaceutical composition to a value comprised between 2.5 and 7, is met as Allen teaches that Ora-Plus maintains a pH approximately 4.2 through the inclusion of sodium phosphate and citric acid as buffering agents (pg. 3).
(New) With regards to the limitations of claim 10, wherein the pH adjust agent is a buffering agent selected from a citrate buffer, acetate buffer, citrate-phosphate buffer, Tris buffer, and phosphate buffer, are met as Ora-Plus teaches the use of sodium phosphate and citric acid as buffering agents (pg. 3).
(New) With respect to the limitations of claim 13, a process for preparing the composition according to claim 1 wherein the process comprises the following steps: (i) mixing cyclodextrin, co- processed MCC-NaCMC, and xanthan gum with one part of total water to obtain a homogeneous mixture; (ii) separately mixing tadalafil with another part of total water, to obtain a homogenous mixture; (iii) adding the mixture of step (ii) to the mixture of step (i); (iv) adding the rest of water, are met as this type of generic formulation preparation is outlined by Allen who describes the preparation of Tadalafil oral suspension, which involves pulverizing Tadalafil, combining with Ora-Plus which includes water, and then adding a second mixture of Ora-Sweet which also contains water (pg. 1). This type of formula preparation is ubiquitously practiced in the pharmaceutical field and the motivation to determine the amounts, steps, and conditions to be taken to optimize this formula would have been appreciated by a person of ordinary skill in the art. Therefore, the limitations of claim 13 can be construed as a conclusion of the optimization process.
(New) Claims 5-6 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Badr-Eldin (1) and Allen as applied to claims 1-2, 4, 8-10 and 13 above, and further in view of P. L. Johnson (Ora-plus material safety data sheet, Paddock Laboratories, 1992).
Allen teaches a Tadalafil oral suspension in which the solution is made from Ora-Plus, which is described as including agents such as MCC-NaCMC and xanthan gum. Badr-Eldin (1) teaches the use of HPBCD in combination with Tadalafil solutions.
They do not, however, specify the concentrations in which the ingredients of Ora-Plus are used.
Johnson addresses this remiss, by teaching that Ora-Plus ingredients, including MCC and NaCMC are <1% each of the overall Ora-Plus solution (pg. 1 - ingredient table).
As such, it would be prima facie obvious, to a person of ordinary skill in the art, to utilize amounts of MCC-NaCMC comprised between 0.5-2.0% w/v., as the Ora-Plus mixture contains MCC-NaCMC of <2.0%.
(Maintained) With respect to the limitation of claim 6, wherein the amount of xanthan gum is comprised between 0.1-1.5% w/v., is met as Johnson teaches that xanthan gum in Ora-Plus is used <1% in the mixture.
(New) With concern to the limitation of claim 18, wherein an amount of preservative is between 0.001-5% w/v, is met as Johnson teaches that all non-listed ingredients, necessarily including methyl paraben as taught by Allen, to be present at less than 0.1%. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP § 2144.05.
(New) Claims 7 and 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over Badr-Eldin (1) and Allen as applied to claims 1-2, 4, 8-10 and 13 above, and further in view of Badr-Eldin et al. (2) (Improving tadalafil dissolution via surfactant-enriched tablets approach: statistical optimization, characterization, and pharmacokinetic assessment, J. Drug Delivery Sci. Tech. 2017, 41, 197-205).
Allen teaches a Tadalafil oral suspension in which the solution is made from Ora-Plus, which is described as including agents such as MCC-NaCMC and xanthan gum. Badr-Eldin (1) teaches the use of HPBCD in combination with Tadalafil solutions.
They do not, however, teach the composition further comprising a surfactant.
Badr-Eldin (2) fixes this omission by teaching the use of surfactants with Tadalafil to improve dissolution with the approach of surfactant-enriched tablets because the drug suffers from poor aqueous solubility that can lead to fluctuating blood levels and unreproducible effects.
As such, it would have been prima facie obvious, to a person of ordinary skill in the art, to consider the use of surfactants as another approach to Tadalafil solubilization as taught by Badr-Eldin (2).
(New) Regarding the limitation of claim 16, wherein the surfactant comprises sodium lauryl sulfate, is met as Badr-Eldin (2) teaches among the tested surfactants included sodium lauryl sulfate (pg. 198 - 2.1, materials).
(New) Concerning the limitation of claim 17, wherein an amount of sodium lauryl sulfate is between 0.01-0.1% w/v, is met as Badr-Eldin (2) teaches that the range of sodium lauryl sulfate tested was 0.1-20 mM in a 10 mL solution, which converts to 0.29 mg at the lowest end, giving a weight- volume ratio of 0.029% (pg. 198 - para. 2.2). In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP § 2144.05.
(New) Claims 11-12 and 19-21 are rejected under 35 U.S.C. 103 as being unpatentable over Badr-Eldin (1) and Allen as applied to claim 1-2, 4, 8-10 and 13 above, and further in view of Tak et al. (Composite capsule preparation containing tadalafil and tamsulosin and having improved stability and elution rate, US 2019/0125685 A1, 2019).
Allen teaches a Tadalafil oral suspension in which the solution is made from Ora-Plus, which is described as including agents such as MCC-NaCMC and xanthan gum. Badr-Eldin (1) teaches the use of HPBCD in combination with Tadalafil solutions.
They do not, however, teach in the form of a fixed-dose combination dosage form, wherein said combination dosage form further comprises a second drug selected from Tamsulosin, or a pharmaceutically acceptable salt form thereof, and Dutasteride, or a pharmaceutically acceptable salt thereof.
Tak overcomes this obstacle by teaching the use of Tadalafil, a PDE 5 inhibitor, and Tamsulosin, an α1a blocker that is effective in treating the symptoms of benign prostatic hyperplasia, chronic prostatitis, and chronic abdominal pain, as a combination as erectile dysfunction and benign prostatic hyperplasia are likely to occur in the same patient in 8.5 out of 10 patients in Korea. Tak notes that though the mechanism of actions differ, they are both effective in treating erectile dysfunction and benign prostatic hyperplasia (para. 0002-0004). Additionally, Tak teaches that the formulation can be taken once a day and daily (para. 0060).
As such, it would have been prima facie obvious, to a person of ordinary skill in the art, before the effective filing date, to consider the use of Tadalafil and Tamsulosin as taught by Tak as the combination is taught to be efficacious in the treatment of conditions such as erectile dysfunction.
(New) Regarding the limitation of claim 12, wherein the second drug is Tamsulosin hydrochloride, is met as Tak teaches that Tamsulosin hydrochloride is used in table 1 (para. 0078 - table 1).
(New) Concerning the limitation of claim 19, wherein the Tamsulosin, or a pharmaceutically acceptable salt thereof, is in the form of modified-release pellets, is met as Tak teaches a composite formulation which is prepared by including two kinds of Tadalafil and Tamsulosin drugs in one unit formulation, where both Tadalafil and Tamsulosin are stored in independent composite capsule formulations using a polyvinyl alcohol copolymer, the copolymer being used for film coating of a solid formulation such as a granule, a pellet, or tablet (para. 0029, 0030, 0031).
(New) With respect to the limitation of claim 20, a method of treating masculine erectile dysfunction, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a composition according to claim 1, is met as Tak teaches that both Tadalafil and Tamsulosin are effective in treating erectile dysfunction and benign prostatic hyperplasia (para. 0004).
(New) With regards to the limitation of claim 21, a method of treating benign prostatic hyperplasia, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a composition according to claim 1, is met as Tak teaches that both Tadalafil and Tamsulosin are effective in treating erectile dysfunction and benign prostatic hyperplasia (para. 0004).
(New) Pertaining to the limitations of claim 22 are met as Tak that both Tadalafil and Tamsulosin are effective in treating erectile dysfunction and benign prostatic hyperplasia (para. 0004).
Allowable Subject Matter
Claim 3 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Reasons for Indicating Allowable Subject Matter
The following is a statement of reasons for the indication of allowable subject matter: the limitation where cyclodextrin is utilized in a pharmaceutical composition for oral administration in the form of aqueous suspension containing tadalafil and other limitations listed in claim 1 where the cyclodextrin comprises between 0.01-0.25% w/v of the composition was not found in the prior art in a 100% embodiment.
Response to Arguments
The office kindly thanks the Applicant for their consideration and arguments to the previous office action. Responses are detailed below.
Applicant’s arguments, see pg. 5 – Rejection under 35 U.S.C. § 112, filed 31 August 2026, with respect to claim 22 have been fully considered and are persuasive. The rejection of claim 22 has been withdrawn.
Applicant’s arguments, see pgs. 6-9 – Rejections under 35 U.S.C. § 103, filed 31 August 2026, with respect to the rejection(s) of claim(s) 1-13 and 16-21 under 35 U.S.C. § 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Badr-Eldin et al. (Inclusion complexes of tadalafil with natural and chemically modified β-cyclodextrins. I: preparation and in-vitro evaluation, Eur. J. Pharmaceutics and Biopharmaceutics 2008, 70, 819-827).
Conclusion
Claims 1-2, 4-13 and 16-22 are rejected under 35 U.S.C. 103. Claim 3 is objected to being dependent on a rejected base claim.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Allen Chao whose telephone number is (571)272-7001. The examiner can normally be reached Monday - Friday 0700-1300.
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/ALLEN CHAO/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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