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 1-111 have been canceled. Claims 112-131 have been added and are examined on the merits.
Information Disclosure Statement
WO2016/014920 of the IDS submitted 2/22/2023 has been lined-through because it is unrelated to the subject matter of the instant invention.
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.
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 112-123 and 128-131 are rejected under 35 U.S.C. 103 as being unpatentable over West et al (WO2016/149201, reference of the IDS filed 2/22/2023) in view of Murtaugh et al (Protein Science, 2011, Vol. 20, pp. 1619-1631, reference of the IDS filed 2/22/2023), Chen and Han (Journal of Clinical Investigation, 2015, Vol. 125, pp. 3384-3391) and Barar and Omidi (BioImpacts, 2013, Vol. 3, pp. 149-162).
West et al teach an activatable antibody, wherein when in an activated state specifically binds to mammalian PDL1, the activatable antibody comprising an antibody or antigen binding fragment that specifically binds to mammalian PDL1; a masking moiety, MM, that inhibits the binding of the antibody or antigen-binding fragment thereof to the mammalian PDL1 when in an uncleaved state; and a cleavable moiety, CM, joining the antibody to the masking moiety, wherein the cleavable moiety is a substrate for a protease (paragraph [0056]). West et al teach that the activatable antibody in the uncleaved state has the structural arrangement from N-terminus to C-terminus of AB-CM- MM (paragraph [000094]) which meets the limitation of “A-L-P” in claim 112. West et al teach West et al teach that the masking moieties that reduce the binding of the anti-PDL1 antibody C5H9v2 to the PDL1 target were identified through library screening [000603]-[000604]). West et al teach that the screening comprised one round of MACS and three rounds of FACS sorting (paragraph [000604]). West et al teach that individual clones were identified by sequence analysis and subsequently verified for their ability to bind the anti-PDL1 antibody C5H9v2 (paragraph [000604]). West et al teach masking moieties identified by the screen (paragraph [0006065] Table 9):
SEQ ID NO: 59LCEVLMLLQHPWCMG
SEQ ID NO: 60IACRHFMEQLPFCHH
SEQ ID NO: 61FGPRCGEASTCVPYE
SEQ ID NO: 62ILYCDSWGAGCLTRP
SEQ ID NO: 63GIALCPSHFCQLPQT
SEQ ID NO: 64DGPRCFVSGECSPIG
SEQ ID NO: 65LCYKLDYDDRSYCHI
SEQ ID NO: 66PCHPHPYDARPYCNV
SEQ ID NO: 67PCYWHPFFAYRYCNT
SEQ ID NO: 68VCYYMDWLGRNWCSS
SEQ ID NO: 69LCDLFKLREFPYCMG
SEQ ID NO: 70YLPCHFVPIGACNNK
SEQ ID NO: 71IFCHMGVVVPQCANY
SEQ ID NO: 72ACHPHPYDARPYCNV
SEQ ID NO: 73PCHPAPYDARPYCNV
SEQ ID NO: 74PCHPHAYDARPYCNV
SEQ ID NO: 75PCHPHPADARPYCNV
SEQ ID NO: 76PCHPHPYAARPYCNV
SEQ ID NO: 77PCHPHPYDAAPYCNV
SEQ ID NO: 78PCHPHPYDARPACNV
SEQ ID NO: 79PCHPHPYDARPYCAV
SEQ ID NO: 80PCHAHPYDARPYCNV
SEQ ID NO: 81PCHPHPYDARAYCNV
SEQ ID NO: 208YCEVSELFVLPWCMG
SEQ ID NO: 426SCLMHPHYAHDYCYV
West et al do not specifically teach that the peptide library comprises one or more peptide sequences having an ionizable group, such as a histidine, so that the masking moiety has a higher affinity for the unmodified antibody at physiological pH relative to its binding affinity for the unmodified antibody at acidic pH.
Murtaugh et al teach pH-dependent antibody binding selected from a library encoding a single domain antibody, wherein every possible combination of histidine and wild-type residue is sampled in order to isolate antibodies that retained near wild-type affinity but exhibited drastic decrease in binding to the cognate antigen in response to small decreases in pH due to the incorporation of multiple histidine groups (abstract). Murtaugh et al teach that the development of protein molecular switches where binding may be modulated through an environmental trigger such as pH are desired in many applications (page 1620, first column, lines 8-13). Murtaugh et al teach that library members were first subjected to solution capture at physiological pH at pH 7.4 using magnetic beads, and that the second step involved phage elution wherein the pH-sensitive variants were released using moderately acidic conditions (pH 4-5) (bridging paragraph).
Chen and Han teach that the first and most important principle of anti-PD therapy is its localized effect based on the unique expression pattern of PD-L1 in the tumor microenvironment wherein it exerts control over PD-1+ Teff inhibition as well as being the site at which anti-PD therapy predominantly takes place (page 3388, second column, lines 1-5 in the paragraph headed “Tumor site immune modulation”).
Barar and Omidi teach that the dysregulation of pH by cancerous cell of solid tumors is able to create a pH of 6.6 in the extracellular fluid within the tumor microenvironment and a pH of 7.4 within the cancer cells (abstract, lines 1-13) which meets the that imitations in claim 130 . Barar and Omidi teach that normal extracellular fluid has a pH between 7.2-7.4 (page 156, Figure 4A) which meets the that imitations in claim 130.
It would have been prima facie obvious at the time prior to the effective filing date to screen for MM that bound to the anti-PD-L1 antibody and blocked its binding to PD-1 at physiological pH but did not bind and block the anti-PD-L1 antibody at acidic pH by using a peptide library wherein one or more peptide sequences comprised histidine. One of skill in the art would have been motivated to do so because West et al teach screening a peptide library for masking moieties that bound to the anti-PD-L1 antibody, Murtaugh et al teach that the ionizable amino acid, histidine, can act as a molecular switch at low pH when it becomes protonated and cause loss of binding to the cognate antigen; Chen and Han teach that PD-L1, the target of the anti-PDL1 antibody of West et al, is expressed in the tumor microenvironment wherein it exerts control over PD-1+ Teff inhibition as well as being the site at which anti-PD therapy predominantly takes place and Barar and Omidi teach that the extracellular fluid within the tumor microenvironment has a pH of about 6.6. One of skill in the art would understand that having MM that did not bind to the anti-PDL1 antibody at the low pH of the extracellular fluid of the tumor microenvironment would insure that the anti-PDL1 antibody would be unassociated with the MM and available for binding to the target PD-L1, thus fulfilling the limitations of claims 112-115 and 125-131.
Murtaugh et al teach further teach that multiple ionizable groups can contribute to the pH binding switch (page 1626, lines 9-26). Murtaugh et al teach that regarding to other ionizable groups, including aspartate and glutamate, are not likely to be as useful as histidine because the expected pKa value shifts for these ionizable groups into the physiological range would require a significant cost in free energy resulting in protein destabilization (page 1621, first column, lines 7-13). One of skill in the art would understand that because Murtaugh et al is inserting groups into an antibody which has a complex tertiary structure (page 1621, Figure 1C) concerns about stabilization of the protein structure are valid. However, one of skill in the art would understand that short peptides acting as masking groups, such as the peptides of SEQ ID NO:59-81, 208 and 426 of West et al do not have tertiary structure, so “protein destabilization” does not pertain to the peptides. One of skill in the art would note that the peptides of SEQ ID NO:59-81, 208 and 426 of West et al all comprise either histidine, aspartate or glutamate (underlined above). Thus, one of skill in the art would have been motivated to provide one or more peptide sequences with at least two or three charged amino acid residues based on Murtaugh et al teaching that multiple ionizable groups can contribute to the pH binding switch, and the observation that the peptides of West et al comprise two, three or four ionizable amino acids of aspartate, glutamate and histidine. It would have been obvious to include peptides having at least one histidine and at least one aspartate; at least one histidine and at least one glutamate, at least one histidine, at least one aspartate and at least one glutamate because these are represented by the peptides of SEQ ID NO: 59, 60, 65, 66, 72, 7, 75, 77-81 and 426 of West et al, thus fulfilling the requirements of clams 120-122. Claim 123 is obvious over the aforesaid SEQ ID NO:s because it represents a further combination of all the ionizable groups found in the peptides of West et al.
Allowable Subject Matter
Claims 124-127 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KAREN A CANELLA whose telephone number is (571)272-0828. The examiner can normally be reached M-F 10-6:30.
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KAREN A. CANELLA
Examiner
Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643