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 1-43 are pending and currently under consideration.
Claim Objections
Claims 4-43 are objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim cannot depend from any other multiple dependent claim. See MPEP § 608.01(n). See “…of any preceding claim…” or “…of any one of the preceding claims…” at claims 4-22, 24-29, and 36-38. Accordingly, the claims 4-43 not been further treated on the merits.
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(a) as being unpatentable over DeVay et al (Bioconjugate Chem, 2017, 28: 1102-1114) in view of Pawar et al (Drug Discovery Today, 2021, 26(5): 1212-1225), Pires et al (Braz J Med Biol Res, 2012, 45(6): 557-564), and David et al (PLOS ONE, 2018, 13(2):e0191052, 1-30).
DeVay et al teaches use of an intracellularly-targeted drug conjugate comprising a bispecific binding agent and a toxin wherein the bispecific binding agent comprises (i) a binding domain that binds to a target protein on tumor cells and (ii) a binding domain that specifically binds APLP2 (a cell surface protein know to have increased expression on cancer cells that is internalized in vesicles and delivered to lysosomes) on the tumor cells to target the drug conjugate inside the tumor cells to lysosomes where the toxin is intracellularly released (Abstract and paragraph spanning pages 1102-1103, in particular).
DeVay et al does not specifically teach a bispecific binding agent comprising a binding domain that specifically binds an LDL receptor. However, these deficiencies are made up in the teachings of Pawar et al, Pires et al, and David et al.
Pawar et al teaches several LDL receptors are overexpressed in brain tumors and have been successfully targeted for drug delivery (left column on page 1215, in particular). Pawar et al further teaches LDL receptors are cell surface proteins that enter cells upon complexing with LDL, where the LDL-LDL receptor complex reaches endosomes where LDL is released from the LDL receptor and then the LDL is delivered to lysosomes (Figure 6, in particular). See Figure 6B:
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Pires et al teaches LDL is removed from circulation by LDL receptors that bind and internalize LDL and the LDL-LDL receptor complex is delivered to intracellular vesicles (page 557, in particular). Pires et al further teaches LDL receptor are up-regulated in many neoplastic cell lines and expressed by cells of breast cancer tissue (page 557 and Table 4, in particular).
David et al teaches LDL receptor-binding peptides that comprise payloads, such as antibodies, that are internalized into cells upon the binding peptides binding LDL receptor (Abstract and page 18, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to generate intracellularly-targeted drug conjugates of Devay et al comprising a bispecific binding agent and a toxin wherein the bispecific binding agent comprises (i) a binding domain that binds to a target protein on tumor cells and (ii) a binding domain (such as a domain of LDL that binds an LDL receptor, such as an LDL receptor-biding peptide of David et al, or an anti-LDL receptor antibody whose binding to LDL receptor mimics LDL) that specifically binds a single LDL receptor on tumor cells in place of the binding domain that specifically binds APLP2 of Devay et al to target the drug via LDL receptor to intracellular vesicles/exosomes and/or lysosomes where the toxin is intracellularly released because the binding domain that binds APLP2 (a cell surface protein known to have increased expression on cancer cells) of the bispecific binding agent of Devay et al functions by binding a cell surface protein (APLP2) that is internalized in vesicles bound to the cell surface protein and delivered to lysosomes where the toxin is intracellularly released and LDL receptor is a cell surface protein know to have increased expression on cancer cells that is internalized in vesicles when bound to LDL (or LDL receptor-binding peptides of David et al) and delivers payload to lysosomes. This is an example of (i) a simple substitution of one known element for another to obtain predictable results and (ii) some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Conclusion
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/SEAN E AEDER/ Primary Examiner, Art Unit 1642
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