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 Status
The amendments and remarks filed 02/02/2026 are acknowledged.
Claims 20-31 are pending.
Claims 1-19 are cancelled.
Claims 22-31 are new.
Note: Applicant references the published US application of the instant application for support of new claims 22-31. This is an inappropriate reference to the published US application because the application file is used for examination, not the published US application, since amendments can be made after the application is published. Applicant should only reference the paragraph or page and line number of the document that is in the application file and not the published application.
Claims 20-21 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Therefore, claims 22-31 are under examination.
Withdrawn
The rejections under 35 U.S.C. 112(b) of claims 1-2, 8, 10, and 16-18 are withdrawn. Applicant has canceled the claims to overcome the rejections. However, the issues presented in the previous 112(b) rejection remain and are applied in the new 112(b) rejection below.
The rejections under 35 U.S.C. 112(a) enablement of claims 1-2, 8, 10, and 16-18 are withdrawn. Applicant has canceled the claims to overcome the rejections.
The rejections under 35 U.S.C. 112(a) written description of claims 1-2, 8, 10, and 16-18 are withdrawn. Applicant has canceled the claims to overcome the rejections.
New Grounds of Rejection Necessitated by Amendment
Claim Rejections - 35 USC § 112(b)
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 26, 29, and 30 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 26 recites “wherein the monoclonal antibody is a 5H9 anti-CD9 monoclonal antibody.” A person of ordinary skill in the art could not determine if they were infringing on the claim because the structure of the 5H9 antibody is never defined, and therefore one cannot tell if they are making the Fab (of claim 22 from which claim 26 depends) derived from the 5H9 antibody as claimed. If one were to make an antibody against CD9 (also called the 5H9 antigen as evidenced by UniProt, see Names and Taxonomy section; 10/01/2025 PTO-892), one would not know whether they were making what is claimed. Yokoyama et al., 2018 (10/01/2025 PTO-892) teaches that producing monoclonal antibodies (MAb) using hybridomas (i.e. the method of instant claim 22 from which claim 26 depends) produces many different Mabs and it is only through a screening effort that a specific antibody of interest is selected [see page 2.5. 23]. Thus, without knowing the specific structure of the 5H9 antibody, it cannot be determined what would and would not infringe upon the claim. Therefore, the scope of this claim is indefinite.
Claim 29 recites the limitation “wherein testing the CD9-binding antibodies comprises”. There is insufficient antecedent basis in this claim. The lack of antecedent basis arises from claim 29’s dependence on claim 22 where “testing” is not mentioned. For examination purposes, the Examiner has interpreted the “testing” as referring to step (e) of claim 22, i.e. the screening and selecting the CD9-binding antibodies for the ability, upon binding to CD9 on a cell surface, to interfere with at least one of: (i) endocytosis of extracellular vesicles by recipient cells; (ii) fusion of extracellular vesicles with recipient cells; or (iii) intracellular transport of endocytosed extracellular vesicle contents.
Further, claim 29 recites “intracellular transport of extracellular vesicle-associated proteins in recipient cells”. It is unclear if this is the same as the limitation in claim 22 (i.e. (iii) intracellular transport of endocytosed extracellular vesicle contents) or if the “extracellular vesicle-associated proteins” is referring to something else because an “associated protein” is not necessarily a content of the EV and could be a protein externally attached to the EV or a protein completely separate from the EV that influences the EV. Therefore, the scope of this claim is indefinite.
Claim 30 recites the limitation “wherein the antigen-binding fragment (Fab) has a molecular weight of approximately 50 kDa has a molecular weight of approximately: 40-60 kDa, 45-55 kDa, 48-52 kDa or 50 kDa.” It is unclear if Applicant is claiming a range for the weight of the Fab or if the claim should be limited to 50 kDa due to the improper sentence structure of “has a molecular weight of” being repeated twice. Further, if 50 kDa is intended, this may not be further limiting of claim 22 because a Fab necessarily has a molecular weight of 50 kDa [see Jackson ImmunoResearch, 2015; 07/24/2024 PTO-892, page 1, first paragraph]. Therefore, the scope of this claim is indefinite.
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.
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.
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 22-25 and 27-31 are rejected under 35 U.S.C. 103 as being unpatentable over Azorsa (WO2014145940; 07/24/2024 PTO-892) in view of Nishida-Aoki et al., 2017 (07/24/2024 PTO-892) and ThermoFisher, 2017 (instant PTO-892).
Regarding claims 22-24, 27, and 31, Azorsa teaches a monoclonal antibody that recognizes human CD9 produced by murine hybridomas [0022, 0036], and that monoclonal antibodies may be prepared using hybridoma methods, where a mouse is immunized with an immunizing agent [0036]. Azorsa further teaches that the immunizing agent includes a CD9 polypeptide, a portion thereof, a fusion protein thereof, and/or a whole fixed cell or fragment of a cell that expresses CD9, such as human platelets know to express CD9, which can be used as the immunizing agent (i.e. (a) immunizing an animal with cells expressing CD9) [0037]. Azorsa also teaches that spleen cells are used (i.e. (b) obtaining antibody-producing cells from the immunized animal by isolating splenocytes) and fused with an immortalized cell line to form a hybridoma cell (i.e. (c) generating monoclonal antibody-producing cell lines from the antibody-producing cells) [0037]. Azorsa further teaches that the culture medium in which the hybridoma cells are cultured can be assayed for the presence of monoclonal antibodies directed against CD9 (i.e. (d) screening and selecting antibodies produced by the monoclonal antibody-producing cell lines for binding to CD9) and then isolating and purifying the selected antibody [0039-0041]. Azorsa also teaches that CD9 has two extracellular domains, EC1 and EC2, and the anti-CD9 antibody of the invention can be used to bind to one or both of EC1 or EC2, and therefore, the antibodies can be used to bind to CD9 anchored in the cell membrane for selection of cells such as exosomes (extracellular vesicles) [0095]. Thus, the antibodies of Azorsa when screened and selected for step (d) would necessarily bind to an extracellular domain of CD9. Azorsa further teaches that the antibody can be a Fab [0023].
However, Azorsa does not specifically teach (e) screening and selecting the CD9-binding antibodies for the ability, upon binding to CD9 on a cell surface, to interfere with (i) endocytosis of extracellular vesicles by recipient cells and (iii) intracellular transport of endocytosed extracellular vesicle contents and (f) digesting the selected monoclonal antibody with a protease to generate the Fab.
Nishida-Aoki teaches that CD9 localizes at the surface of most exosomes (extracellular vesicles) [page 181, right column, third paragraph] and further teaches a therapeutic antibody treatment with a human-specific anti-CD9 antibody to target cancer-derived extracellular vesicles (EVs) [see Abstract]. Nishida- Aoki also teaches that the treatment resulted in decreased metastasis to lungs, lymph nodes, and thoracic cavity, and that EVs incubated with the targeted antibody were preferentially internalized by macrophages, suggesting that the antibody effectively suppresses EV-triggered metastasis in cancer [see Abstract]. Nishida-Aoki further teaches that the anti-CD9 antibodies reduced the amount of EVs in the organs, such as human umbilical vein endothelial cells (HUVECs), by both stimulating the removal of EVs by macrophages and inhibiting the uptake of EVs (interferes with endocytosis of EVs by recipient cells) [page 187, left column, third paragraph – right column, first paragraph]. Since the anti-CD9 antibody inhibits the uptake of EVs, it would also therefore necessarily interfere with (ii) fusion of extracellular vesicles with recipient cells and (iii) the intracellular transport of endocytosed EV contents if the EVs are not being endocytosed (i.e. uptaken), absent evidence to the contrary.
ThermoFisher teaches that because of their smaller size as functional components of the whole molecule, antibody fragments, such as a Fab, offer several advantages over intact antibodies such as reduced nonspecific binding from Fc interactions, elimination of Fc-associated effector functions, and lower immunogenicity [page 3, first paragraph] and that papain (i.e. a protease) can be used to digest IgG molecules resulting in two Fab fragments and one Fc fragment [page 4, third paragraph].
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 method of Azorsa, and to have additionally screened and selected CD9-binding antibodies for the ability, upon binding to CD9 on a cell surface, to interfere with endocytosis of extracellular vesicles by recipient cells, fusion of extracellular vesicles with recipient cells, and intracellular transport of endocytosed extracellular vesicle contents, as taught by Nishida-Aoki. One would have been motivated to have screened and selected CD9-binding antibodies for the ability, upon binding to CD9 on a cell surface, to interfere with endocytosis of extracellular vesicles by recipient cells, fusion of extracellular vesicles with recipient cells, and intracellular transport of endocytosed extracellular vesicle contents because Nishida-Aoki teaches an anti-CD9 antibody that targets cancer-derived extracellular vesicles (EVs), that the antibody reduced the amount of EVs in the organs by both stimulating the removal of EVs by macrophages and inhibiting the uptake of EVs (interferes with endocytosis of EVs by recipient cells, fusion of extracellular vesicles with recipient cells, and intracellular transport of endocytosed EV contents), and that treatment with the antibody resulted in decreased metastasis to lungs, lymph nodes, and thoracic cavity, and that EVs incubated with the targeted antibody were preferentially internalized by macrophages, suggesting that the antibody effectively suppresses EV-triggered metastasis in cancer. Therefore, one would want to obtain these antibodies that could be used as a treatment to suppress EV-triggered metastasis in cancer.
It further 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 method of Azorsa and Nishida-Aoki, and to have additionally digested the selected monoclonal antibody with a protease, such as papain, to generate a Fab, as taught by ThermoFisher. One would have been motivated to have digested the selected monoclonal antibody with a protease, such as papain, to generate a Fab because ThermoFisher teaches that Fabs offer several advantages over intact antibodies such as reduced nonspecific binding from Fc interactions, elimination of Fc-associated effector functions, and lower immunogenicity and that papain (i.e. a protease) can be used to digest IgG molecules resulting in two Fab fragments and Azorsa teaches that the antibody can be a Fab. There would be a reasonable expectation of success in making this modification because this is a known parameter in the art.
Claim 25 is included in this rejection because Nishida-Aoki teaches that the anti-CD9 antibody is clone 12A12 purchased from Cosmo Bio [page 187, right column, fourth paragraph]. As evidenced by Cosmo Bio, 2026 (instant PTO-892)., clone 12A12 is an IgG2b antibody [page 1].
Claim 28 is included in this rejection because Azorsa teaches that the anti-CD9 antibody of the invention can be used to bind to one or both of EC1 or EC2 (extracellular domains). Thus, since the anti-CD9 antibody of Azorsa binds to extracellular domains (i.e. EC1 and EC2) of CD9, it would have been obvious to one of ordinary skill in the art before the effective filing date to have specifically screened for binding to a target epitope in an extracellular part of CD9 (i.e. EC1 and/or EC2).
Claims 29 is included in this rejection because, Nishida-Aoki teaches that the EVs are fluorescently labeled and that fluorescence microscopic observations of the EV uptake revealed that CD9 antibodies influenced EV uptake [page 187, left column, third paragraph]. Therefore, while Nishida-Aoki does not specifically teach measuring the uptake of extracellular vesicles by recipient cells and intracellular transport of extracellular vesicle-associated proteins in recipient cells, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have measured the uptake of extracellular vesicles by recipient cells and intracellular transport of extracellular vesicle-associated proteins in recipient cells since Nishida-Aoki teaches that the EVs were fluorescently labeled and that fluorescence microscopic observations of the EV uptake revealed that CD9 antibodies influenced EV uptake.
Claim 30 is included in this rejection because since it would have been obvious to have digested the monoclonal antibody with papain to generate the Fab, the resulting Fab would necessarily have a molecular weight of approximately 50 kDa. This is evidenced by ThermoFisher, 2017 (instant PTO-892) that teaches Fab fragments are 50,000 Daltons (equivalent to 50 kDa) [page 3, see Fab fragments section].
Conclusion
No claims are allowed.
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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Brittney E Donoghue whose telephone number is (571)272-9883. The examiner can normally be reached Mon - Fri 7:30 - 3:30.
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/B.E.D./Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
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