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 .
Priority
The instant application, filed on 26 January, 2024, is a 371 of PCT/KR2022/011119 filed on 28 July, 2022.
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d) to KR 10-2021-0099362, filed on 28 July, 2021. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 26, January, 2024 has been considered by the examiner.
Status of Application, Amendments, and/or Claims
The response filed on 28 February, 2024 has been entered in full. These are the amended claims of the original claim set received on 26 January, 2024. In the amendment, claims 1-20 are amended and claims 21 and 22 are new. Therefore, claims 1-22 are pending and are the subject of this Office Action.
Specification
The use of the terms xMark and gentleMACS, which are trade names or marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore, the terms should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
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.
Claims 2, 19, and 21 are rejected under 35 U.S.C. 112(b), as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, regards as the invention.
The claims recite “wherein the ETA antagonist is selected from the group consisting of ambrisentan, sulfisoxazole, macitentan, BQ-123, BQ-788, zibotentan, sitaxentan, artasentan, bosentan, tezosentan, and A192621.” This list encompasses antagonists which are specific to the endothelin receptor type B and not the ETA, as evidenced by Aubert and Jeanneret (2016) Endothelin-Receptor Antagonist beyond Pulmonary Arterial Hypertension: Cancer and Fibrosis J. Med. Chem. 59, 8168-8188, which teaches BQ788 and A192621 are ETB selective antagonist (Table 3), therefore it is unclear if the invention needs to specifically antagonize ETA. For the purpose of further examination, the claim will be interpreted to exclude BQ788 and A192621.
Claim Rejections - 35 USC § 103
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.
Claims 1-3 are rejected under 35 U.S.C. 103 as being unpatentable over Jamal et al. (US 2020/0289495, of record, IDS 1/26/2024).
In regards to claim 1 Jamal teaches therapeutic compositions or formulations for the treatment of cancer (pg.1, col 2, lines 16-18) which comprise of Endothelin B Receptor (ETBR) antagonist, and a synergistically effective amount of one or more of an Endothelin A Receptor (ETAR) antagonist, an anti-PD1 antibody (immune checkpoint inhibitor), a bRAF inhibitor, niacinamide or a combination thereof, and a pharmaceutically acceptable carrier (pg.1, col 2, lines 28-35). Further, Jamal teaches administering the antagonist and immune checkpoint inhibitor at the same time, or sequentially (claims 11 and 12).
In regards to claim 2 Jamal teaches the ETAR antagonist is BQ123, and further teaches Macitentan is an ETAR antagonist used in combination with BQ788 (an ETBR antagonist) and niacinamide to supplement weight loss from the BQ788 (pg.5, col 1, lines 56-62).
In regards to claim 3 Jamal teaches the addition of an anti-PD1 antibody (pg.1, col 2, lines 28-35).
Thus, Jamal discloses all of the components and embodiments claims in the instant claims as options to construct the method of treating cancer comprising administering an ETA antagonist and a checkpoint inhibitor. Therefore, a person of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to try the suggested combination of Jamal with a reasonable expectation of success to yield a more synergistic pharmaceutical composition.
Claims 1, 4-9, 12-17, 19 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Jamal et al. as applied to claim 1 above, and further in view of Cabral and Kataoka (2014) Progress of drug loaded polymeric micelles into clinical studies Journal of Controlled Release 190 456-476.
In regards to independent claims 1 and 12 Jamal teaches a pharmaceutical composition to treat cancer comprising an ETA antagonist and an anti-PD1 antibody as outlined above.
In regards to claims 19 and 20 which depend on claim 12 Jamal teaches the ETA antagonist is BQ123 with an anti-PD1 antibody as outlined above.
Jamal fails to teach the conjugation of the ETA antagonist to a biocompatible copolymer of claims 4 and 12, and the nonionic hydrophilic polymer, ionic polymer, or the copolymer of claims 5 and 13. Further Jamal fails to teach the linkers of claims 8 and 17, the copolymer being a block or graft copolymer of claims 9 and 16, a polymer from the list of nonionic hydrophilic polymers of claims 6 and 14, and a polymer from the list of ionic polymers of claims 7 and 15.
Cabral and Kataoka, however, in regards to claims 4, 5, 6, 7, 9, 12, 13, 14, 15, and 16 teaches polymeric micelles as carriers for delivering various bioactive molecules (pg.465, col 1, lines 20-23). The polymeric micelles are comprised by self-assembly of nonionic hydrophilic poly(ethylene glycol) and an ionic poly(amino acid) forming a poly(ethylene glycol)-b-poly(amino acid) block copolymer as a core-shell nanostructure (pg.465, col 1, line 23 – pg.465, col 2, line 1/ Table 1). The poly(amino acid) efficiently incorporates and releases the payload efficiently while the poly(ethylene glycol) for a dense soft shell which protects the drug core to prolong circulation in the bloodstream (pg.465, col 2, lines 1-7). Further Cabral and Kataoka teach various compositions of the block copolymer comprising poly(aspartic acid) and poly(glutamic acid) to deliver small molecule drugs (Table 1) which have made it to clinical trial.
In regards to claim 8 and 17, Cabral and Kataoka teach the linkage between a drug and the polymer can be selected to dissociate at desired conditions, to specifically release the drug, such as a linker comprising an ester bond which can be cleaved in phosphate buffer saline (pg.467, col 2, lines 43-54). Cabral and Kataoka also teach a micelle in which the linkage between the drug and block copolymer can be designed to be cleaved by using a liable linker allowing for release after cellular uptake (pg.469, col 1, lines 7-10).
Thus, Jamal discloses a pharmaceutical compositions for treating cancer comprising the ETA antagonist BQ123 and a PD1 antibody, and Cabral and Kataoka teach block copolymers comprising a poly(ethylene glycol) and a poly(amino acid) which can form polymeric micelles in which a small molecule drug is conjugated and protected for administration with a cleavable linker for localized delivery. Therefore, a person of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to combine the teachings of Jamal with the teachings of Cabral and Kataoka with a reasonable expectation of success to attach the ETA antagonist BQ123 to a block copolymer to form polymeric micelles to protect the BQ123 during migration through the blood stream for a more improved, and efficient treatment.
Claims 1, 10, 11, 18, 21, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Jamal et al. as applied to claim 1 above, and further in view of Chau et al. (of record, IDS 1/26/2024).
In regards to independent claims 1 and 18 Jamal teaches a pharmaceutical composition to treat cancer comprising an ETA antagonist and an anti-PD1 antibody as outlined above.
In regards to claims 21 and 22 which depend on claim 18 Jamal teaches the ETA antagonist is BQ123 with an anti-PD1 antibody as outlined above.
Jamal fails to teach the conjugation of the ETA antagonist to the anti-PD1 antibody using a linker of claims 10, 11, and 18.
However, Chau , in regards to claims 10 and 18 teaches conjugating antibodies with a variety of antitumor effector molecules has been a concept for a significant amount of time (pg.793, col 1, lines 22-31), and further that the conjugates are made to deliver the payload to a tumor site for improved efficiency and reduced systemic exposure and toxicity (pg.793, col 1, lines 32-37). Further Chau demonstrates examples in which antibodies are conjugated to small molecule drugs (pg.796, col 1, lines 5-8/ Table 1), including a PD-L1 conjugated to doxorubicin (pg.801, col 2, lines 37-45) and suggests improvements in the field include determining new cytotoxic payloads (pg.801, col 1, line 54 – pg.801, col 2, line 2).
In regards to claim 11, Chau teaches stable cleavable or non-cleavable linkers are component of antibody drug conjugates (pg.794, col 1, lines 3-5), and the linker chemistry and site of conjugation have a crucial role in the antibody drug conjugate’s stability, pharmacokinetics, and pharmacodynamics (pg.795, col 1, lines 14-17). Further Chau teaches cleavable linkers can include linkers that depend on proteolysis (protease cleavable linker) (pg.795, col 1, lines 27-30) to allows for the antibody drug conjugate to circulate in the bloodstream and localize without premature payload release (pg.795, col 1, lines 17-22).
Thus, Jamal discloses a pharmaceutical compositions for treating cancer comprising the ETA antagonist BQ123 and a PD1 antibody, and Chau teaches conjugating drug payloads to antibodies for targeted delivery and further that linkers are key components to their success, including cleavable linkers to allows for localized drug release. Therefore, a person of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to combine the teachings of Jamal and Chau with a reasonable expectation of success to attach the ETA antagonist BQ123 to the PD1 antagonist to allow for the localized delivery of the antagonist to improve treatment efficacy by reducing systemic exposure and toxicity to the antagonist.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DASIA A ALDARONDO whose telephone number is (571)272-1977. The examiner can normally be reached on Monday – Friday from 8:30am to 4:30pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama, can be reached at telephone number (571)272-2911. The fax phone number for the organization where this application or proceeding is assigned is (571)273-8300.
Information regarding the status of an application may be obtained from Patent Center. Status information for published applications may be obtained from Patent Center. Status information for unpublished applications is available through Patent Center to authorized users only. Should you have questions about access to the USPTO patent electronic filing system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
Examiner interviews are available via a variety of formats. See MPEP § 713.01. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) Form at https://www.uspto.gov/InterviewPractice.
/D.A.A/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
Prosecution Insights