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 . Claims 1-7, 9-16, 22-22 and 26-27 filed November 03, 2025 are currently pending. Claims 1-3 and 27 are independent.
Election/Restrictions
Applicant's election with traverse of Group (I), claims 1-7, 9-13 and 26-27 in the reply filed on 11/03/2025 is acknowledged. The traversal is on the ground(s) that there is no serious search burden because all the method claims essentially rely on the subject of claims 1-3 for their patentability. This argument has been considered but are not found persuasive as such arguments do not apply when restriction is required under 35 USC 121 and 372, as in the instantly filed application. Thus, when the Office considers international applications as an International Searching Authority, as an International Preliminary Examining Authority, and during the national stage as a Designated or Elected Office under 35 U.S.C. 371, only PCT Rule 13.1 and 13.2 will be followed when considering unity of invention of claims of different categories without regard to the practice in national applications filed under 35 U.S.C. 111. Thus, it is maintained that the technical feature linking the inventions of Groups (I)-(II) does not constitute a special technical feature as defined by PCT Rule 13.2 and does not define a contribution over the prior art for the reasons of record. The requirement is still deemed proper and is therefore made FINAL.
Claims 14-16 and 20-22 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 11/03/2025.
Secondly, Applicant’s election with traverse of a compound of Formula (III) claims 3, 5-7, 9, 11-13 and 27 in the response filed 11/03/2025 is acknowledged. The traversal is that there is no serious search burden to search compounds of Formula (I), (II), or (III) as they are closely related. Again, such search burden traversal does not apply when a species election is required under 35 USC 121 and 372, as in the instantly filed application. Only PCT Rule 13.1 and 13.2 will be followed when considering unity of invention of claims of different categories without regard to the practice in national applications filed under 35 U.S.C. 111.
Claims 1-2, 4 and 26 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/03/2025.
Priority
Acknowledgement is made of the national stage entry of PCT/US2020/031238 filed 05/03/2020, which claims priority to U.S. Provisional Application 62842658 filed 05/03/2019.
Claim Objections
Claims 3, 5-7, 9, 11-13 and 27 are objected to because of the following informalities: The moiety oxygen in (C=O) for moieties R2, R5, and R7 are each typed with a “zero” for the oxygen instead of a capital O. Appropriate correction is required.
Claims 11-13 are objected to because of the following informalities: Claims 11-13 depend upon a later numbered claim (claim 27). Appropriate correction is required.
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.
Claim(s) 3, 6-7 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Li (CN103396397 published 11/20/2013; machine translation provided) and AlQahtani (Biomedicine and Pharmacotherapy Vol. 113 published May 01, 2019).
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Li (CN103396397 published 11/20/2013; machine translation provided) teaches lenalidomide derivatives of Formula (I), efficacious at treating cancer in a subject in need. Li teaches that lenalidomide is rapidly absorbed following oral administration and is rapidly excreted with a half-life of 3-4 hours. Li teaches poor plasma binding of lenalidomide in patients (~30%) and that the short half-life is one of the biggest obstacles of the drug (pages 5-6 of translation). Li teaches functionalizing the phthalimide nitrogen of lenalidomide with alkyl esters in order to prolong the half-life of the original drug lenalidomide and improve the bioavailability of the drug (pages 5-6 of the translation). Embraced within Formula (I) is Example 48 as shown above which reads on the following claimed limitations: R1 is -CH2-, R2 is H, R5 is C(O)R7, wherein R7 is a straight chain alkylene. Li teaches that the alkylene chain can be adjusted with longer chains in order to improve the half-life of the therapeutic agent (Examples 49-51; pages 61-67 of translation). As shown in Example 55, Li also teaches modifying the lenalidomide derivative by attaching a polyethylene glycol polymer to improve the pharmacokinetic profile of lenalidomide derivative, wherein the polyethylene glycol polymer is attached at the indoline-nitrogen (page 68 of translation). Li teaches that the polyethylene glycol derivative releases the original drug slowly and but the conversion rate to lenalidomide is low (page 79 of the machine translation). However, Li also teaches also that conversion rate of the alkylester Example 48 to lenalidomide is the highest and efficiently delivers the desired lenalidomide (page 79 of machine translation).
The difference from the presently claimed compounds and that of Li is that Li does not specifically teach wherein R7 and R6 are each a pharmaceutically acceptable polymeric moiety, such as a polyethylene glycol (PEG) linker.
AlQahtani (Biomedicine and Pharmacotherapy Vol. 113 published May 01, 2019) teaches the impact of incorporating a polyethylene glycol polymer “pegylation” to an antineoplastic agent in order to overcome disadvantages of the therapeutic agent as the polyethylene glycol polymer is water soluble, non-ionic and biocompatible (abstract, page 3 left col.). Pegylation plays an essential role in prolonging the residence time in the circulation of the relatively small therapeutic agents, which is achieved by increasing the molecular size to above that needed for half-life extension (page 3 left col.). As shown in Tables 1-2, AlQahtani teaches that pegylation is an art-recognized technique to extend the half-life of the therapeutic agent (abstract; pages 5-6). The widespread acceptance of PEG conjugates can be attributed to the exceptional favorable combination of physiochemical and biological properties of the polymer including solubility in both aqueous and organic solvents, biocompatibility, lack or toxicity and low immunogenicity (page 9 left col).
Therefore, one of ordinary skill in the art prior to the time of the invention, knowing that lenalidomide is a potent chemotherapeutic agent and that it comprises poor plasma binding of lenalidomide in patients (~30%) and a short half-life is one of its biggest obstacles of the drug as taught by Li, coupled with the knowledge that it is known in the art to modify the phthalimide nitrogen of lenalidomide with alkylesters, such as Example 48 above in order to prolong the half-life of the original drug lenalidomide and improve the bioavailability of the drug as taught by Li, said skilled artisan would have found it prima facie obvious to substitute the alkyl chain on Example 48 with a polyethylene glycol polymer in view of AlQahtani, arriving at the presently claimed compound of Formula (III) with a reasonable expectation of success.
MPEP 2143 provides rationale for a conclusion of obviousness including (B): Simple substitution of one known element for another to obtain predictable results;
In the present case, both the alkyl chain appending the lenalidomide derivative and the incorporation of polyethylene glycol polymer to chemotherapeutic agent are each art-recognized techniques to improve the half-life of the antineoplastic agent. Accordingly, said skilled artisan would have readily predicted that compound 48 of further substituted with a polyethylene glycol polymer appending the alkyl-ester moiety would have improved the biological half-life of the lenalidomide derivative.
Applicant is also reminded of MPEP 2143, wherein it should be noted that the lead compound cases do not stand for the proposition that identification of a single lead compound is necessary in every obviousness rejection of a chemical compound. For example, one might envision a suggestion in the prior art to formulate a compound having certain structurally defined moieties, or moieties with certain properties. If a person of ordinary skill would have known how to synthesize such a compound, and the structural and/or functional result could reasonably have been predicted, then a prima facie case of obviousness of the claimed chemical compound might exist even without identification of a particular lead compound. As a second example, it could be possible to view a claimed compound as consisting of two known compounds attached via a chemical linker. The claimed compound might properly be found to have been obvious if there would have been a reason to link the two, if one of ordinary skill would have known how to do so, and if the resulting compound would have been the predictable result of the linkage procedure. Thus, Office personnel should recognize that in certain situations, it may be proper to reject a claimed chemical compound as obvious even without identifying a single lead compound. In the present case, the lenalidomide derivative of Li and the polyethylene glycol chemical linker are each known in the art as useful tools to improve the half-life of either the parent compound lenalidomide or therapeutic agents in general. As discussed above, it would have been obvious to link the polyethylene glycol polymer to the lenalidomide derivative of compound 48 of Li to further improve the bioavailability of the parent chemotherapeutic agent lenalidomide. The resulting compound of Formula (III) would have been the predictable result of the linkage procedure following the synthetic strategies embodied within the prior art of Li.
Regarding claim 6, formulation of said lenalidomide derivative with a pharmaceutically acceptable carrier is taught (page 12 of translation). Regarding claim 7, administration of said lenalidomide derivative via intravenous or intraperitoneal injection is taught (page 12 of translation).
Claim(s) 9 is rejected under 35 U.S.C. 103 as being unpatentable over the combination of Li (CN103396397 published 11/20/2013; machine translation provided) and AlQahtani (Biomedicine and Pharmacotherapy Vol. 113 published May 01, 2019) as applied to claims 3, 6-7 above in view of Van Eupen (WO2011/018101 published 02/17/2011).
As disclosed above, the combination of Li and AlQahtani render obvious the preparation of a lenalidomide derivative of instant Formula (III) by substituting the alkyl chain of the alkylester of lenalidomide derivative Example 48 of Li with a polyethylene glycol chain in view of AlQahtani in order to prolong the half-life of the original drug lenalidomide and improve the bioavailability of the drug as taught by Li, as both the alkyl chain appending the lenalidomide derivative and the incorporation of polyethylene glycol polymer to chemotherapeutic agent are each art-recognized techniques to improve the half-life of the antineoplastic agent.
The difference between the presently claimed composition and that of Li and AlQahtani is that neither Li nor AlQahtani teach formulating said lenalidomide derivative with the pharmaceutically acceptable carrier of castor oil or a derivative thereof.
Van Eupen (WO2011/018101 published 02/17/2011) teaches lenalidomide pharmaceutical formulations (abstract). Van Eupen teaches that lenalidomide comprises poor aqueous solubility, with a solubility of 0.4-0.5 mg/mL at pH 4.6-7.4 (page 1). Van Eupen further teaches that micronization of lenalidomide is necessary to prepare capsules comprising the poorly aqueous soluble lenalidomide for oral administration (page lines 8-20). Van Eupen teaches preparation of a pharmaceutical composition comprising lenalidomide with a pharmaceutically acceptable carrier. Examples of common carriers include hydrogenated castor oil, which reads on the presently claimed “castor oil or derivative thereof” (page 11 line 15 to page 12 line 15).
Therefore, one of ordinary skill in the art prior to the time of the invention would have found it prima facie obvious to formulate the lenalidomide derivative of Li and AlQahtani with the pharmaceutically acceptable carrier of the castor oil derivative hydrogenated castor oil in view of Van Eupen, arriving at the presently claimed composition with a reasonable expectation of success.
MPEP 2143 provides rationale for a conclusion of obviousness including (A): Combining prior art elements according to known methods to obtain predictable results;
In the present case, Van Eupen teaches that hydrogenated castor oil is a suitable pharmaceutically acceptable carrier to formulate lenalidomide pharmaceutical compositions. Consistent with this reasoning, it would have been obvious to have selected hydrogenated castor oil from within the prior art of Van Eupen above and apply it to the lenalidomide derivative pharmaceutical composition of Li and AlQahtani, arriving at the claimed composition yielding no more than one would expect from such an arrangement.
Claim(s) 27, 11-13 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Li (CN103396397 published 11/20/2013; machine translation provided) and AlQahtani (Biomedicine and Pharmacotherapy Vol. 113 published May 01, 2019) as applied to claims 3, 6-7 above in view of Rimkus (US2012/0046315 published 02/23/2012).
As disclosed above, the combination of Li and AlQahtani render obvious the preparation of a lenalidomide derivative of instant Formula (III) by substituting the alkyl chain of the alkylester of lenalidomide derivative Example 48 of Li with a polyethylene glycol chain in view of AlQahtani in order to prolong the half-life of the original drug lenalidomide and improve the bioavailability of the drug as taught by Li, as both the alkyl chain appending the lenalidomide derivative and the incorporation of polyethylene glycol polymer to chemotherapeutic agent are each art-recognized techniques to improve the half-life of the antineoplastic agent. Regarding claim 12, formulation of said lenalidomide derivative with a pharmaceutically acceptable carrier is taught (page 12 of translation). Regarding claim 13, administration of said lenalidomide derivative via intravenous or intraperitoneal injection is taught (page 12 of translation).
The difference between the presently claimed composition and that of Li and AlQahtani is that Li and AlQahtani do not specifically teach wherein the lenalidomide derivative is micronized and further contains a second pharmaceutically acceptable polymer, wherein the lenalidomide derivative is encapsulated in the second pharmaceutically acceptable polymer
Rimkus (US2012/0046315 published 02/23/2012) teaches lenalidomide pharmaceutical compositions. Rimkus teaches that in the preparation of lenalidomide dosage forms, lenalidomide is micronized into microparticles to ensure content uniformity of the pharmaceutical formulation ([0006], [0015]). Rimkus teaches formulating said micronized lenalidomide with a matrix material polymer, wherein said micronized lenalidomide is formulated within the matrix material polymer ([0030]-[0031], [0051]-[0052]). Polyvinyl pyrrolidone is taught by Rimkus as a suitable matrix material polymer to formulate with micronized lenalidomide, which reads on the pharmaceutically acceptable polymer embodied within claims 27, 11 and 12 of the present claims ([0030]-[0031], [0051]-[0052]).
Therefore, one of ordinary skill in the art prior to the time of the invention would have found it prima facie obvious to formulate the lenalidomide derivative of Li and AlQahtani in micronized form, further containing the pharmaceutically acceptable polymer of polyvinyl pyrrolidone in view of Rikmus, arriving at the presently claimed composition with a reasonable expectation of success.
MPEP 2143 provides rationale for a conclusion of obviousness including (C): Use of a known technique to improve similar products in the same way;
In the present case, Rikmus teaches that lenalidomide is micronized into microparticles to ensure content uniformity of the pharmaceutical formulation coupled with the knowledge that it is formulated with the matrix material polymer of polyvinylpyrrolidone in order to stabilize the micronized lenalidomide particle. Accordingly, it would have been obvious to apply the micronized form and further formulated in a matrix stabilizing polymer of polyvinyl pyrrolidone for lenalidomide as taught within the prior art of Rikmus above and apply it to the lenalidomide derivative pharmaceutical composition of Li and AlQahtani, arriving at the claimed composition, arriving at the claimed composition with a reasonable expectation of success.
Conclusion
In view of the rejections set forth above, no claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GEORGE W KOSTURKO whose telephone number is (571)270-5903. The examiner can normally be reached M-F 9:00-5:30.
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/GEORGE W KOSTURKO/Primary Examiner, Art Unit 1621