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 response to the application filed 27 June 2024, 371 of PCT/EP2022/088099 filed 30 December 2022, claiming priority from EP21386083.6 filed 31 December 2021. Claims 3-15 are amended. Currently, claims 1-15 are pending.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
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 (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 non-obviousness.
Claims 1-2, 4-6, and 13-15 are rejected under 35 U.S.C. 103 as being unpatentable over Rimkus et al. (Intermediate and oral administrative formats containing lenalidomide, US 2012/0046315 A1, 2012) in view of Revlimid (Revlimid (lenalidomide) capsules product information, AusPar, 2014).
Rimkus discloses formulations of Lenalidomide where embodiments include the use of hydrophilic polymers such as polyvinyl alcohol (para. 0051) and polyalkylene glycols (para. 0051), the use of solvents or mixture of solvents such as water (para. 0072).
They do not, however, disclose the use of mediums where the pH is 1-3.
This deficiency is rectified by Revlimid who teach that the solubility of Lenalidomide increases by several fold when comparing at pH 7.00 and 1.21 of <1.5 mg/mL and 18 mg/mL, respectively (pg. 1 – description).
As such, it would have been prima facie obvious, to a person of ordinary skill in the art, before the effective filing date, to preferentially utilize a low-pH solution in the preparation of a Lenalidomide aqueous solution because of the significant increase of solubility conferred by an acidic environment, as taught by Revlimid.
Regarding the limitations of claim 2, wherein the glycol is selected from propylene glycol, polyethylene glycol having an average molecular weight from 150 to 1500, or mixtures thereof, are met as Rimkus discloses the use of co-block polymers of polyethylene glycol and polypropylene glycol can be used with preferential weight-average molecular weights of 1,000-20,000 g/mol (para. 0053). 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.
Concerning the limitations of claim 4, wherein the polyol is selected from glycerol, sorbitol, mannitol, maltitol, xylitol, erythritol, isomalt, lactitol, polyvinyl alcohol, or mixtures thereof, are met as Rimkus teaches the use of polyvinyl alcohol (para. 0051), mannitol, sorbitol, xylitol, isomalt (para. 0054), or glycerol (para. 0055).
With respect to the limitations of claim 5, wherein the polyol is selected from glycerol, sorbitol, mannitol, maltitol, xylitol, or mixtures thereof, are met as Rimkus teaches the use of sorbitol, mannitol, xylitol (para. 0054) and glycerol (para. 0055).
With regards to the limitations of claim 6, wherein the concentration of Lenalidomide or the pharmaceutically acceptable Lenalidomide salt in the solution is from 2 mg/mL to 10 mg/mL, are met as Rimkus teaches that Lenalidomide is commonly marketed in the form of hard gelatine capsules with 5, 10, 15 and 25 mg Lenalidomide (para. 0006). 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 so as to obtain the desired clinical outcome or improved clinical outcome, whether it encompasses tumor inhibition or other therapy. Moreover, it is well-known that dosages may vary between patients due to parameters such as patient mass, gender, co-morbidities, age, etc. The limitations of claim 6 can be construed as a conclusion from the optimization process. In this case, if the volume of the solution is 1 mL, the range of Lenalidomide is 2-10 mg. 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.
With concern to the limitation of claim 13, wherein the pH of the solution is from 1.5-2.5, is met as Revlimid teaches that the solubility of Lenalidomide in an aqueous solution increase by several fold as the pH decreases (pg. 1 – description).
Regards the limitation of claim 14, wherein the active ingredient is Lenalidomide, is met as Rimkus teaches a formulation where the active ingredient is Lenalidomide (abstract).
Concerning the limitation of claim 15, wherein the solution does not comprise a surfactant, is met as Rimkus does not teach a solution comprising a surfactant.
Claim 3 and 7-9 are rejected under 35 U.S.C. 103 as being unpatentable over Rimkus and Revlimid as applied to claims 1-2, 4-6, and 13-15 above, and further in view of Gullapalli et al. (Polyethylene glycols in oral and parenteral formulations – a critical review, International J. Pharmaceutics 2015, 496, 219-239).
Rimkus disclosed a Lenalidomide formulation where certain embodiments teach the use of glycols, polyols and solvents including water, whereas Revlimid taught that Lenalidomide solubility increases with decreasing pH in aqueous solutions, thus motivating the solution to be highly acidic.
They do not, however, teach the use of glycol selected from propylene glycol, polyethylene glycol 200, 300, 400, 600, 800, or 1450.
Gullapalli addresses this paucity by teaching that polyethylene glycols are commercially available in a wide range of molecular weight grades, from 200 to 10,000,000 g/mol (pg. 220 – introduction), that lower molecular weight glycols are more hygroscopic, more miscible with aqueous fluids and can dissolve many poorly water-soluble compounds (pg. 200 – polyethylene glycols as solubility and oral bioavailability enhancers). In Table 1, several examples of oral products utilizing PEG 400 and 600 as a component of the excipient are exemplified (pg. 223 – Table 1).
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 glycols such as polyethylene glycols as well-known excipients for the use of solubilizing an otherwise poorly-soluble Lenalidomide in pH neutral water as taught by Revlimid.
Regarding the limitations of claims 7-9, wherein the glycol concentration in the solution is from 200-600 mg/mL, 250-550 mg/mL, and 300-500 mg/mL, are met as Gullapalli teaches how polyethylene glycol concentration, %w/v, increases the solubility of several otherwise aqueous insoluble drugs such as Progesterone (pg. 221 – Figure 2) and Celecoxib (pg. 226 – Figure 5), in a non-linear fashion. The range of 200-600 mg/mL, conversion to grams gives 0.2-0.6 g of glycol per 1 mL of volume, a more equivalent unit-to-unit comparison; giving a %w/v of 20-60 %w/v. This range appears to encompass a significant solubility range for Progesterone while not fully encompassing the soluble range of Celecoxib. This reinforces the concept of optimization of the dosing regimen as part of the research process as a person of ordinary skill in the art would necessarily be motivated to do so as to obtain the desired clinical outcome or improved clinical outcome. The limitations of claims 7-9 can be construed as a conclusion from the optimization process. 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.
Claims 10-12 are rejected under 35 U.S.C. 103 as being unpatentable over Rimkus and Revlimid as applied to claims 1-2, 4-6 and 13-15 above, and further in view of Badejo et al. (Aqueous-based compositions, US 2021/0162051 A1, 2021).
Rimkus disclosed a Lenalidomide formulation where certain embodiments teach the use of glycols, polyols and solvents including water, whereas Revlimid taught that Lenalidomide solubility increases with decreasing pH in aqueous solutions, thus motivating the solution to be highly acidic.
They do not, however teach where the polyol concentration in the solution is from 50-400 mg/mL, 100-350 mg/mL, or 100-300 mg/mL.
Badejo overcomes this dearth by teaching the use of natural polyols in aqueous-based compositions in combination with an active pharmaceutical ingredient for the administration of pharmaceutical doses, including several examples such as glycerin, sorbitol mannitol maltitol, xylitol, erythritol, and isomalt (para. 0029), used in ranges from 10-70% w/v (para. 0030). The range of 50-400 mg/mL, taking the conversion in paragraph 21 above, is 5-40% w/v. This falls within the taught range by Badejo of polyol excipient use, where the concept of optimization of the dosing regimen as part of the research process as a person of ordinary skill in the art would necessarily be motivated to do so as to obtain the desired clinical outcome or improved clinical outcome is again applied. The limitations of claims 10-12 can also be construed as a conclusion from the optimization process. 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.
Summary
Claims 1-15 are rejected under 35 U.S.C. 103.
Conclusion
No claims are allowed.
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/ALLEN CHAO/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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