Detailed Action
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 1 objected to because of the following informalities:
Claim 1 states “An oral pharmaceutical solution comprising lenalidomide or a pharmaceutically acceptable salt thereof as active ingredient”, should state “An oral pharmaceutical solution comprising lenalidomide or a pharmaceutically acceptable salt thereof as an active ingredient”
Appropriate correction is required.
Claim Interpretation
Claim 1 recites “a cosolvent selected from a glycol, or a polyol, wherein the pH solution is from 1.0 to 3.0”. Claims 5-7 recite “wherein the polyol is selected from…” however, claims 5-7 do not require a polyol to be present in the solution. Claims 5-7 are simply defining which species of the polyol must be present in the solution, if their category of cosolvent is included in the solution. For purposes of compact prosecution, the examiner will interpret claims 5-7 as requiring the solution to include the category of cosolvent listed in the claim.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 2 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 2 states “The oral pharmaceutical solution according to claim 1, wherein the glycol is selected from glycerol, polyethylene glycol having an average molecular weight from 150 to 1500, or a mixture thereof.” It is unclear if the applicant includes glycerol as a type of glycol, because the specification lists propylene glycol, polyethylene glycol, and other polyalkylene glycol products, such as the “PEG” series as defined glycol products. A glycol is defined as an organic compound containing two hydroxyl (-OH) groups, but glycerol is a sugar alcohol containing three hydroxyl groups. It is unclear if the applicant is including glycerol as a glycol compound in the claim.
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 nonobviousness.
Claims 1, 4-8, and 12-13 are rejected under 35 U.S.C. 103 as being unpatentable over Eilertsen (Kenneth Eilertsen et al., “Small molecule inhibitors of histone deacteylases”, WO 2013059582 A2, Pub. Date: 2013-04-25), in view of Rimkus et al. (Intermediate and oral administrative formats containing lenalidomide, US 2012/0046315 A1, 2012) and Revlimid (Revlimid (lenalidomide) capsules product information, AusPar, 2014).
Regarding Claims 1, 4-7, and 13, Eilertsen discloses small molecule pharmaceutical compositions administered for treating cancer (Abstract). Eilertsen discloses Lenalidomide as an anticancer agent in the pharmaceutical composition (Claim 7). Eilertsen discloses liquid and semi-solid oral formulations may be prepared by dissolving or dispersing the active compound in propylene glycol and additional carriers [0246] and teaches the formulation of solutions [00199]. Eilertsen discloses water, glycerol, and glycols as optional pharmaceutical carriers in liquid pharmaceutical compositions to form solutions [0207]. Eilertsen also discloses “One of skill in the art will appreciate that an aqueous solution of the compound will provide the most rapid absorption of the compound into the body of a subject being treated” [00195].
Eilertsen does not disclose the solubility of Lenalidomide, or the pH of the solution as 1.0 to 3.0.
Rimkus discloses non-crystalline lenalidomide in the form of storage stable intermediate and oral administrative formats, wherein the Lenalidomide is present in the form of a solid solution (Abstract and Title). Rimkus discloses that Lenalidomide has different forms, for example forms A, B, and E, and each form has a different solubility profile (para. 0010). Rimkus also discloses that different solubility profiles lead to an uneven rise in the concentration of Lenalidomide, and there is a motivation to provide Lenalidomide in a form that has good solubility with good storage stability (para. 0011).
Rimkus does not disclose the pH of the solution as 1.0 to 3.0.
Regarding Claims 1 and 12, Revlimid discloses that the solubility of Lenalidomide increases by several fold when compared at pH 7.00 versus pH 1.21 of <1.5 mg/mL and 18 mg/mL, respectively (pg. 1 – description).
Because Eilertsen teaches water, glycerol, and glycols as optional pharmaceutical carriers in the composition, it would be obvious to combine them, to form a third composition to be used for the very same purpose. Eilertsen disclosed that aqueous solutions provide the most rapid absorption in the subject being treated, this would motivate one skilled in the art to specifically pick water in combination with the other cosolvents to increase the absorption of Lenalidomide in solution. The courts have found “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious); and In re Couvaras, 70 F.4th 1374, 1378-79, 2023 USPQ2d 697 (Fed. Cir. 2023) (That the two claimed types of active agents, GABA-a agonists and ARBs, were known to be useful for the same purpose—alleviating hypertension—alone can serve as a motivation to combine).
It would have been prima facie obvious, to a person of ordinary skill in the art, before the effective filing date, to modify the teaching of Eilertsen for an oral pharmaceutical composition comprising lenalidomide and cosolvents water, glycol, and glycerol with in the teachings of Rimkus and Revlimid because Rimkus discloses that different forms of Lenalidomide have different solubilities, and Revlimid discloses that the solubility of Lenalidomide increases with a lower pH. One of ordinary skill would be motivated to optimize the composition disclosed in Eilertsen with the teachings of Rimkus and Revlimid, to arrive at the claimed limitations, because it was known in the art that Lenalidomide has a low solubility at neutral pH conditions, and one of ordinary skill would be motivated to increase solubility by lowering the pH of the solution to increase storage stability.
Regarding Claim 8, Eilertsen does not teach a dosage of Lenalidomide.
Rimkus discloses that 5.0 mg, 10 mg, 15 mg, and 25 mg of Lenalidomide was used to produce oral tablets and capsules ([0373], [0382], [0385], [0386]).
The concentration range disclosed in instant claim 8, for the concentration of Lenalidomide is 2 mg per 1 mL to 10 mg per 1 mL. To convert 2 mg/mL to 10 mg/mL to grams, assume the solution volume is 1 mL, and the resulting range of lenalidomide is 2 mg to 10 mg. Therefore, the Lenalidomide concentrations disclosed in Rimkus overlap with the concentration range of Lenalidomide disclosed in instant Claim 8. The courts found that, 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) The prior art taught carbon monoxide concentrations of “about 1-5%” while the claim was limited to “more than 5%.” The court held that “about 1-5%” allowed for concentrations slightly above 5% thus the ranges overlapped. See MPEP § 2144.05.
Therefore, it would have been prima facie obvious for one of ordinary skill to modify the Lenalidomide pharmaceutical solution taught in Eilertsen by utilizing the oral dosage range disclosed in Rimkus for Lenalidomide, to arrive at the concentration range disclosed in instant Claim 8, because routine optimization is known in the art. One of ordinary skill would be motivated to optimize the concentration of the Lenalidomide solution in Eilertsen, with the teachings of Rimkus, to achieve an improved clinical outcome.
Claims 2, 3 and 9-11 are rejected under 35 U.S.C. 103 as being unpatentable over Eilertsen (Kenneth Eilertsen et al., “Small molecule inhibitors of histone deacteylases”, WO 2013059582 A2, Pub. Date: 2013-04-25), in view of Rimkus et al. (Intermediate and oral administrative formats containing lenalidomide, US 2012/0046315 A1, 2012) and Revlimid (Revlimid (lenalidomide) capsules product information, AusPar, 2014) as applied to claims 1, 4-8, and 12-13 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).
The teachings of Eilertsen, Rimkus, and Revlimid discussed above, with respect to claim 1 are incorporated into this rejection
Rimkus, Eilertsen and Revlimid do not teach polyethylene glycol in the pharmaceutical solution, with an average molecular weight of 400.
Gullapalli discloses polyethylene glycols (PEGs) are commercially available in a wide range of molecular weight grades, from 200 to 10,000,000 g/mol, have low toxicity, are miscible with aqueous fluids, and can dissolve many poorly soluble compounds (Pg. 220, Introduction, and polyethylene glycols as solubility and oral bioavailability enhancers). Gullapalli discloses compounds with poor aqueous solubility, were shown to have increased bioavailability when dosed in solutions or suspensions with PEGs (Abstract).
Gullapalli teaches in Table 1, several examples of oral products utilizing PEG 400 as a component of the excipient are exemplified (pg. 223 – Table 1).
Regarding Claims 2 and 3, it would have been prima facie obvious, to a person of ordinary skill in the art, before the effective filing date, to combine the teachings of Gullapalli that PEGs can increase the solubility of active agents, with the teachings of the above references that Lenalidomide has different solubility profiles, and needs good solubility in solution, because one of ordinary skill would be motivated to choose a lower molecular weight glycol in solution with lenalidomide to increase the solubility because Gullapalli discloses that increased solubility provides better bioavailability.
Regarding the limitations of Claims 9-11, wherein the total concentration of the cosolvent is 100 mg/ml to 800 mg/ml, 150 mg/ml to 700 mg/ml, and 200 mg/ml to 600 mg/ml, Gullapalli discloses PEG 400 concentration, %w/w in water, increases the solubility of aqueous insoluble drugs, such as Progesterone (pg. 221-Figure 2). The conversion of concentration of mg/ml to % w/w is calculated by the following equation, % w/w= (concentration in mg/ml *(10*density of solution in g/ml)). For the range of 100-800 mg/ml of glycol disclosed in the instant claims, the conversion to % w/w, with a density of 1.125 g/ml for PEG 400, is % 8.88- % 71.11 w/w. Gullapalli discloses that PEG 400 % w/w in water increases the solubility of aqueous insoluble drugs, the higher the concentration of PEG 400.
The % w/w of PEG 400 in water disclosed in the instant claims, falls within the range disclosed in Gullapalli, the courts found that, 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) The prior art taught carbon monoxide concentrations of “about 1-5%” while the claim was limited to “more than 5%.” The court held that “about 1-5%” allowed for concentrations slightly above 5% thus the ranges overlapped.
Regarding Claims 9-11, it would have been prima facie obvious, for one of ordinary skill, before the effective filing date, to modify the method disclosed in Eilertsen, with the teachings of Rimkus and Gullapalli, to arrive at the claimed limitations, because Gullapalli teaches that PEG 400 % w/w in water, increases the solubility of aqueous insoluble drugs, and Rimkus teaches different crystal forms of Lenalidomide have different solubility profiles. One of ordinary skill would be motivated to increase the solubility of Lenalidomide, a known insoluble aqueous drug, with PEG 400, by routine optimization known in the art, for improved bioavailability.
Claims 9-11 are rejected under 35 U.S.C. 103 as being unpatentable over Eilertsen (Kenneth Eilertsen et al., “Small molecule inhibitors of histone deacteylases”, WO 2013059582 A2, Pub. Date: 2013-04-25) in view of Rimkus et al. (Intermediate and oral administrative formats containing lenalidomide, US 2012/0046315 A1, 2012) , and Revlimid (Revlimid (lenalidomide) capsules product information, AusPar, 2014) as applied to claims 1-2, 4-8 and 12-14 above, and further in view of Badejo et al. (Aqueous-based compositions, US 2021/0162051 A1, 2021).
Rimkus, Eilertsen, and Revlimid do not teach a concentration for the polyol in solution.
Badejo disclosed 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). Badejo disclosed an aqueous based composition containing polyols, is formulated to inhibit microbial growth without utilizing artificial preservatives (Abstract).
The largest range disclosed in instant claim 1, for the total concentration of the cosolvent is 100 mg/ml to 800 mg/ml. The range of 100-800 mg/mL, conversion to grams gives 0.1-0.8 g of glycol per 1 mL of volume, a more equivalent unit-to-unit comparison: giving a %w/v of 10-80 %w/v. This range overlaps with the range of 10-70% w/v disclosed in Badejo for natural polyols.
The courts found that, 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) The prior art taught carbon monoxide concentrations of “about 1-5%” while the claim was limited to “more than 5%.” The court held that “about 1-5%” allowed for concentrations slightly above 5% thus the ranges overlapped.
Therefore, it would have been prima facie obvious for one of ordinary skill, before the effective filing date to combine the teachings of Eilertsen and Rimkus with the teachings of Badejo to arrive at the limitations of the instant claims, because Badejo teaches a concentration range for natural polyols in aqueous based compositions with active ingredients, to inhibit microbial growth without artificial preservatives. It would be obvious to combine the teachings of Eilertsen, Rimkus and Badejo, because all of the methods disclose an aqueous composition, with an active ingredient, further comprising polyols. One of ordinary skill would be motivated to use utilize the amount of polyols disclosed in Badejo, to optimize the polyols disclosed in Eilertsen and Rimkus to achieve the desired inhibition rate.
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 1-14 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of copending Application No. 18/725,011 (reference application), herein ‘011.
Regarding instant Claim 1, and Claim 1 in copending application ‘011, both are directed to an oral pharmaceutical solution comprising Lenalidomide as an active ingredient, and a pharmaceutical carrier comprising water, and a cosolvent, wherein the pH of the solution is 1.0 to 3.0. Instant Claim 1 discloses a cosolvent of glycol or a polyol and Claim 1 in copending application ‘011 discloses a glycol and a polyol are required for the oral pharmaceutical composition, therefore copending application ‘011, discloses all the limitations of instant Claim 1.
Regarding instant claim 2, and Claim 2 in copending application ‘011, both disclose glycol having an average molecular weight of 150 to 1500.
Regarding instant Claim 3 and 4, and Claim 3 in copending application ‘011, both disclose polyethylene glycol with an average molecular weight of 400.
Regarding instant Claims 5-7, and Claims 4 and 5 in copending application ‘011, both disclose that the polyol maltitol, glycerol, mannitol, sorbitol, xylitol, erythritol, isomalt, lactitol, polyvinyl alcohol, or a mixture thereof.
Regarding instant Claim 8, and Claim 6 in copending application ‘011, both applications disclose the Lenalidomide concentration in solution, as 2 mg/mL to 10 mg/mL.
Regarding instant Claim 12, and Claim 13 in copending application ‘011, both disclose the pH of the solution as 1.5 to 2.5.
Regarding instant Claim 13, and Claim 14 in copending application ‘011, both disclose lenalidomide as the active ingredient.
Regarding instant Claim 14, and Claim 15 in copending application ‘011, both disclose that the solution does not comprise a surfactant.
Regarding instant Claims 9-11, Claims 7-9 in copending application ‘011 disclose the glycol concentration in the solution is from 200 to 600 mg/ml, 250-500 mg/ml, and 300 to 500 mg/ml. The concentration range of the cosolvent disclosed in instant Claims 7-9 overlap with the ranges disclosed in copending claims 7-9.
Regarding instant Claims 9-11, Claims 10-12 in copending application ‘011 disclose the polyol concentration in the solution is from 50 to 400 mg/ml, 100-350 mg/ml, and 100 to 300 mg/ml. The concentration range of the cosolvent disclosed in instant Claims 7-9 overlap with the ranges disclosed in copending claims 10-12.
Regarding instant Claims 9-11, and claims 7-12 in copending application ‘011, The courts found that, 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) The prior art taught carbon monoxide concentrations of “about 1-5%” while the claim was limited to “more than 5%.” The court held that “about 1-5%” allowed for concentrations slightly above 5% thus the ranges overlapped. Therefore, it would have been prima facie obvious, to optimize the concentration ranges disclosed in copending application Claims 7-12, to arrive at the concentration ranges of instant Claims 9-11, because routine optimization is known in the art.
Since both claim sets teach an oral pharmaceutical solution comprising Lenalidomide as an active ingredient, and a pharmaceutical carrier comprising water, and a cosolvent, wherein the pH of the solution is 1.0 to 3.0, the examiner maintains that the aforementioned claims of the instant application are substantially overlapping in scope as discussed hereinabove and are prima facie obvious over the cited claims of copending application ‘011.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
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/C.M.R./Examiner, Art Unit 1627
/JENNIFER A BERRIOS/ Primary Examiner, Art Unit 1613
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