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 .
Application Status
This action is written in response to applicant’s correspondence received 05/11/2026. Claims 1, 12-13, 16-17, 19-21, 23-24, 27-33, 35, 41, 47 are currently pending. Claims 28-32 and 47 are withdrawn from prosecution as being drawn to non-elected subject matter. Accordingly, claims 1, 12-13, 16-17, 19-21, 23-24, 27, 33, 35 and 41 are examined herein.
Election/Restrictions
Applicant's election without traverse of Formula XIV for Species Group A, XIV-A for Subspecies A1, and the compound represented by BL70 for Subspecies A2 in the reply filed 05/11/2026 is acknowledge. Claims 28-32 and 47 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determining the scope and contents of the prior art.
Ascertaining the differences between the prior art and the claims at issue.
Resolving the level of ordinary skill in the pertinent art.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 12-13, 16-17, 21, 23-24, 35 and 41 are rejected under 35 U.S.C. 103 as being unpatentable over Chen (Chen et al. Sequential combination therapy of ovarian cancer with cisplatin and γ-secretase inhibitor MK-0752. Gynecologic Oncology Volume 140, Issue 3, March 2016, Pages 537-544.) in view of Irby (Irby et al. Lipid-Drug Conjugate for Enhancing Drug Delivery. Mol Pharm. 2017 May 01; 14(5): 1325–1338.) and Ponziani (Antibody-Drug Conjugates: The New Frontier of Chemotherapy. Int. J. Mol. Sci. 2020, 21, 5510.).
Regarding claim 1:
Chen teaches the y-secretase inhibitor MK-0752 (Figure 1A, reproduced below):
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For comparison, Formula XIV is reproduced below with the relevant portion highlighted:
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Chen teaches that MK-0752 was effect at inducing cell growth inhibition, G2/M phase cell cycle arrest and apoptosis in ovarian cancer cells in vitro and in a mouse xenograft growth of ovarian cancer (Abstract).
Chen does not teach the remainder of Formula XIV, which comprises an amide bond joining the drug conjugate to the alkyl/diamine structure, as well as two substituted or unsubstituted alkyl chains.
Irby teaches lipid-drug conjugates for enhancing drug delivery (Title and Abstract below):
Lipid–drug conjugates (LDCs) are drug molecules that have been covalently modified with lipids. The conjugation of lipids to drug molecules increases lipophilicity and also changes other properties of drugs. The conjugates demonstrate several advantages including improved oral bioavailability, improved targeting to the lymphatic system, enhanced tumor targeting, and reduced toxicity. Based on the chemical nature of drugs and lipids, various conjugation strategies and chemical linkers can be utilized to synthesize LDCs.
In Table 1 (p. 29-30), Irby teaches a finite number of possible fatty acids and other lipids for conjugation.
Irby further teaches that fatty acids may be conjugated to an amine group of the drug to form a stable amide linkage (i.e., Formula XIV in which R5 is H), and that two-tailed fatty acids may form various delivery vehicles such as liposomes (Figure 5).
Irby does not specifically teach a 6 carbon alkyl linker connecting the drug payload to the fatty acid tails. However, Irby does teach a five carbon alkyl/diamine linker conjugated to an siRNA payload via an amide bond (Figure 4a).
Ponziani teaches that alkyl linkers are among the most used non-cleavable linkers in drug conjugates (p .9/26 § 2.2.2).
Ponziani further teaches that the advantage of non-cleavable (alkyl) linkers is that they minimize drug release into the circulation thus limiting non-specific toxicity while maintaining good in vivo stability (Id.).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the y-secretase inhibitor, MK-0752, as taught by Chen, by conjugating it to fatty acids for improved delivery as taught by Irby, and further conjugating the drug and fatty acids via an alkyl linker for improved in vivo stability, as taught by Ponziani. The ordinary artisan would have been motivated to synthesize a drug conjugate comprising MK-0752 based on Chen’s teachings that MK-0752 was effective against ovarian cancer cells and xenografts. They would further have been motivated to improve the compound’s delivery and in vivo stability by conjugating it to lipids, including fatty acids, via an alkyl linker, based on the combined teachings of Irby and Ponziani. Based on common sense and sound scientific reasoning, the length of the alkyl linker may be optimized depending on the required distance between the payload and lipids and properties of the linker, such as flexibility and/or solubility. Thus in regard to the limitations of the claims, where the prior art teaches a finite number of design options for the formulation of drug-lipid conjugates, one of ordinary skill in the art would have had good reason to try pursuing the known options within his or her technical grasp, with an eye towards optimization of the resulting conjugate for pharmaceutical use. If this leads to the anticipated success, it is likely that the product was not of innovation but of ordinary skill and common sense.
Regarding claim 12, the claim limits the compound to one comprising MK-0752 wherein R5 is H, which is rendered obvious by Chen, Irby and Ponziani as described above.
Regarding claim 13, Irby teaches wherein R1 and R2 are independently at least unsubstituted C5 alkyls, and the combination of references renders obvious optimization the choice of fatty acid/chain length.
Regarding claim 16, Irby teaches conjugating the drug and lipid moieties via amide bonds, as described above.
Regarding claims 17 and 21, Irby teaches various lipids including saturated fatty acids with the recited chain lengths, particularly lauroyl.
Regarding claim 23, Irby teaches a finite number of possible lipid conjugates with two fatty acid tails suitable for optimization, as described above.
Regarding claim 24, the combined references render obvious compound BL65, BL67, and BL69 (i.e., drug conjugates comprising MK-0752 as described above, conjugated to saturated fatty acid chains via an alkyl linker and an amide bond).
Regarding claims 35 and 41, the combination of references renders obvious the compound of claim 1 comprised in a lipid particle as a pharmaceutical agent, as described above.
Claims 19, 20, 24, 27, 33 are rejected under 35 U.S.C. 103 as being unpatentable over Chen, Irby and Ponziani as applied to claims 1, 12-13, 16-17, 21, 23-24, 35 and 41, further in view of U.S. PGPUB 20240140960 A1 to Dong (hereinafter ‘Dong’; effective filing date 02/21/2021; of record, cited on an IDS).
The applied reference has a common applicant and two inventors with the instant application. The reference has an additional inventor not named in the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
Chen, Irby and Ponziani render obvious the compound of claim 1, from which the instantly rejected claims depend, as described above.
Chen, Irby and Ponziani do not teach the compound wherein
Regarding claims 19 and 20, Dong teaches various ionizable lipids, including R10, for conjugation to a drug payload for cancer treatment (i.e., an mRNA). R10 is a species of the more generic structure recited in those claims:
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Dong further teaches that R10 was one of the two preferred LNP formulations for inducing a robust response in the target cancer cells and tissues (para [0206]).
Regarding elected species BL70 as depicted in claims 24, 27 and 33, R10 of Dong differs only insofar as it has slightly shorter alkyl chains. However, optimization of the alkyl chain length of the lipid moieties (such as via selection of different fatty acids or phospholipids from among those disclosed by Irby) is rendered obvious by Chen, Irby and Ponziani, as described above.
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified the compound of claim 1, as taught by Chen, Irby and Ponziani, by substituting the fatty acids with the ionizable lipid R10 as taught by Dong. The ordinary artisan would have been motivated to do so, and would have had a reasonable expectation of successfully formulating said compound, based on Dong’s teachings regarding its synthesis and their teachings that R10 yielded superior results compared to the other lipids tested in the conjugate.
Claim Rejections - 35 USC § 112 – Improper Markush Grouping
Claims 1, 12, 24 and 27 are rejected on the basis that they contain an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of claims 1, 12, 24 and 27 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: the various compounds comprise different head groups with different structures and different therapeutic applications. For example, BL70 comprises the MK-0752 molecule, which as described above is a drug which has applications in cancer treatment, whereas e.g., BL1 comprises L-DOPA, which is used to treat Parkinson’s disease (see Cools. Dopaminergic modulation of cognitive function-implications for L-DOPA treatment in Parkinson’s disease. Neuroscience and Biobehavioral Reviews 30 (2006) 1–23.).
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Conclusion
No claim is allowed at this time.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMANDA M ZAHORIK whose telephone number is (703)756-1433. The examiner can normally be reached M-F 8:00-16:00 EST.
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/AMANDA M ZAHORIK/Examiner, Art Unit 1636
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