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 .
DETAILED ACTION
1. The Amendment filed October 21, 2025 in response to the Office Action of July 22, 2025 is acknowledged and has been entered. Claims 3-5, 8-9, 12, 15, and 17-36 have been cancelled. Claims 1, 6, 7, 10, 13, and 14 have been amended. New claims 37-38 have been added.
2. Claims 1, 2, 6, 7, 10, 11, 13, 14, 16, 37 and 38 are currently being examined.
New Grounds of Rejection
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:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
3. Claim(s) 1, 2, 6, 7, 10, 11, 13, 14, 37 and 38 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/071399 A1 (Foss et al. April 19, 2018), “Foss” in view of WO 2014/138186 A1 (Hapuarachchige et al. Sep. 12, 2014, of record), “Hapuarachchige”.
It is noted that the word agglutinate means to cause to adhere, to combine into a compound, or to unite or combine into a group or mass. See Merriam-Webster (AGGLUTINATE Definition & Meaning, https://www.merriam-webster.com/dictionary/agglutinate, downloaded 12/01/2025).
Foss teaches nanoparticles comprising (a) a hydrophobic drug, (b) an albumin, and (c) a bioactive polypeptide conjugated to the albumin. In some embodiments, the bioactive polypeptide is an antibody or a fragment thereof. In some embodiments, the bioactive polypeptide is conjugated (either covalently or non-covalently) to the albumin of the nanoparticle by a crosslinker. See abstract and ¶¶ 0007-0008, 0011 and 0103.
Foss teaches that the bioactive polypeptide is on the surface of the of the nanoparticle. See ¶¶ 0009, 0066, and 0103.
Foss teaches that the nanoparticles are albumin based nanoparticles. See ¶¶ 0004, 0007 00012, 00014, and Examples 1 and 2.
Foss teaches that that albumin in the nanoparticles is crosslinked. ¶¶ 0014 and 0102.
Foss teaches that the crosslinker can be a click chemistry (e.g., a copper-free click chemistry) crosslinker. For example, in some embodiments, the crosslinker comprises a triazole moiety, which can be formed by reacting a cyclooctene derivative moiety (such as dibenzocyclooctyne (DBCO) moiety) with an azide through a strain-promoted alkyne azide cycloaddition reaction. The albumin or the antibody can be covalently linked to the cyclooctene derivative moiety, for example by reacting with NHS bridged to the cycooctene derivative moiety (e.g., DBCO-PEGn-NHS, wherein n is 2 or larger), and the other crosslinked entity (i.e., the albumin or the antibody) can be functionalized with an azide. See ¶¶ 0124, Example 26 and Fig. 21.
Foss teaches the nanoparticles comprise the diagnostic or therapeutic antibodies bevacizumab, trastuzumab, BGB-A317, or tocilizumab. See ¶¶ 0011, 0026 and 0047 and Fig. 11.
Foss teaches the nanoparticles can comprise antimicrobial agents. See ¶¶ 0203.
Foss teaches a 29 mM diarylcyclooctyne (DBCO)-PEG5-NHS solution was made by dissolving 3 mg of the linker reagent in 150 μL DMSO. Either 15 μL (20:1; linker:HSA) or 30 μL (40:1; linker:HSA) of DBCO solution was added to each aliquot of isolated nanoparticles. See ¶ 0535.
Foss teaches that antibody may be an IgG isotype. See ¶¶ 0076
Foss teaches as set forth above, but does not teach the crosslinked (agglutinated) protein molecules comprise about 14 covalently attached DBCO molecules.
Hapuarachchige teaches two-step/two-component system for intracellular delivery of therapeutics is based on the induced internalization of cross-linked and clustered mAb to target receptors of interest, including, for example, HER2 receptors. The system provides target-specific, and optionally, image-guided drug delivery, and highly efficient internalization and accumulation of chemotherapeutics in the target cells of interest. The present invention provides in situ complexation of two or more delivery components by the bioorthogonal click reactions between multiple azido-functionalized or tetrazine functionalized mAb and multiple cyclooctyne-functionalized nanocarriers, or trans-cyclooctene functionalization, and bovine serum albumin (BSA) substituted with chemotherapeutics, such as paclitaxel. See abstract and Fig. 1.
Hapuarachchige teaches in claims 1, 2 and 9:
1. A composition comprising a molecule of formula I:
Ab(Pega-Az)b (I); wherein Ab is a monoclonal antibody to a target of interest; (Pega -Az) is a polyethylene glycol chain containing a terminal azide(Az) functional group linked to the Ab by the other end; wherein a is an integer corresponding to the number of ethylene glycol units in a polyethylene glycol chain in a range from 0-24; and b is an integer corresponding to the number of (Pega -Az) groups covalently and directly linked to the Ab in a range from 1-30.
2. A composition comprising a molecule of formula II:
Alb(CTX)x(Pegn-DBCO)y(II); wherein Alb denotes albumin (bovine serum albumin, human serum albumin or other similar and biocompatible proteins and polymers); CTX is a chemotherapeutic agent covalently and directly linked to Alb and x is an integer corresponding to the number of CTX molecules attached per Alb in a range from 1-6; (Pegn-DBCO) is a polyethylene glycol chain containing a terminal dibenzylcyclooctyne (DBCO) functional group linked to the Alb by the other end; wherein n is an integer corresponding to the number of ethylene glycol units in a polyethylene glycol chain in a range from 0-24; and y is an integer corresponding to the number of (Pegn-DBCO) groups covalently and directly linked to the Alb in a range from 5-20.
9. A composition for the diagnosis or treatment of a disease comprising: the composition of claim 1 and the composition of claim 2.
See also pp. 8 [0031] to p. 12-[0052] and Examples 1-2.
Hapuarachchige teaches that the chemotherapeutic agents include taxanes, like paclitaxel and docetaxel, and antitumor antibiotics like anthracyclines. See p. 12-[0049].
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of Foss and Hapuarachchige and covalently attach about 14 DBCO molecules to the albumin or the antibody of the nanoparticles because Foss teaches the albumin or the antibody can be covalently linked to the DBCO moiety and Hapuarachchige teaches linking 5-20 DBCO groups to albumin for cross-linking. One would have been motivated to modify the number of DBCO groups to optimize the structure of the crosslinked nanoparticles to provide optimal strength, flexibility and target binding.
Regarding claim 37, product by process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps. See MPEP 2113 (I).
4. Claim(s) 11 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/071399 A1 (Foss et al. April 19, 2018), “Foss” in view of WO 2014/138186 A1 (Hapuarachchige et al. Sep. 12, 2014, of record), “Hapuarachchige” as applied to claims 1, 2, 6, 7, 10, 11, 13, 14, 37 and 38 above, and further in view of Hood et al. (J. Controlled Release 2012 163: 161-169, of record), “Hood-2”.
Foss and Hapuarachchige teach as set forth above.
Foss and Hapuarachchige do not specifically teach using an anti-PECAM and or adding a drug for treatment of ARDS to the liposome nanoparticle.
Hood-2 teaches that elevated levels of reactive oxygen species (ROS) induced by NADPH oxidase in endothelium are implicated in grave acute conditions including ischemia–reperfusion and acute lung injury (ALI or ARDS). See p. 161-right col.
Hood-2 teaches that they encapsulated an indirect NADPH oxidase (NOX) inhibitor, MJ33, into immunoliposomes (Ab-MJ33/IL) targeted to endothelial marker platelet endothelial cell adhesion molecule (PECAM-1) with an anti-PECAM-1. Ab-MJ33/IL are specifically bound to endothelium and attenuated angiotensin-induced ROS production in vitro and in vivo. Ab-MJ33/IL alleviated pathological disruption of endothelial permeability barrier function in cells exposed to vascular endothelial growth factor (VEGF) and in the lungs of mice challenged with lipopolysaccharide (LPS). Of note, the latter beneficial effect has been achieved both by prophylactic and therapeutic injection of Ab-MJ33/IL in animals. Therefore, specific suppression of ROS production by NOX in endothelium, attainable by Ab-MJ33/IL targeting, may help deciphering mechanisms of vascular oxidative stress and inflammation, and potentially improve treatment of these conditions. See abstract, Materials and Methods, Fig. 1-6 and conclusion.
Hood-2 teaches that MJ33 in combination with anti-oxidant enzyme (AOE) based therapeutics may have a synergistic effect in preventing ALI or ARDS. See p. 167-right col.-1st full paragraph.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of Foss, Hapuarachchige and Hood-2 and use the anti-PECAM-1 antibody and MJ33 NOX inhibitor of Hood 2 in the nanoparticle of Foss and Hapuarachchige because Hood-2 teaches Ab-MJ33/IL suppression of ROS production by NOX in endothelium and that it may be useful and synergistic in the prevention and treatment of ALI or ARDS. Thus, given the anti-NOX prophylactic and therapeutic activity of MJ33 taught by Hood-2 one would have been motivated to use the anti-PECAM-1 antibody and the MJ33 NOX inhibitor of Hood 2 to n the nanoparticle of Foss and Hapuarachchige for treatment of ARDS or ALI.
Conclusion
5. All other objections and rejections recited in the Office Action of July 22, 2025 are withdrawn in view of Applicant’s amendments and arguments.
6. No claims allowed.
7. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
8. Any inquiry concerning this communication or earlier communications from the examiner should be directed to PETER J REDDIG whose telephone number is (571)272-9031. The examiner can normally be reached on M-F 8:30-5:30 Eastern Time
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Janet L Epps-Smith can be reached on 571-272-0757. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Peter J Reddig/
Primary Examiner, Art Unit 1642