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
Applicant Arguments/Remarks filed November 20, 2025 in response to the Office Actions of May 20, 2025 is acknowledged.
Claims 18, 20, and 22-33 are currently pending and under consideration.
Since no new amendments are made for claims, the rejections set forth in the previous Office Action of May 20, 2025 are maintained.
Information Disclosure Statement
The Information Disclosure Statements (IDS) filed on 06/26/2025, 10/31/2025 and 11/20//2025 have been considered and entered by examiner.
MAINTAINED/MODIFIED REJECTIONS
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.
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.
Claim(s) 18, 20, and 22-33 is/are rejected under 35 U.S.C. 103 as being obvious by Dominguez (Dominguez et al., Vaccine, 28, 1383-1390, Publication Date: 2009-11-18, of record), and further in view of Smith (Smith et al, WO 2014/047231 A1, Publication Date: 2014-03-27, of record), and Chen (Chen et al., Cellular Immunology, 287 (2014), 91-99, Publication Date: 2014-01-13, of record).
Dominguez teaches anti-RNEU and anti-CD40 antibodies are connected by a biodegradable nanoparticles (PLA) for the treatment of tumor.
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Dominguez teaches the method of making nanoparticle-2 antibody conjugates (page1389, col. 2, para. 2).
Dominguez teaches that CD40 is expressed by CD8+ T cells and plays a key role in the activation of memory cytotoxic T lymphocyte. And CD40 is a key molecule in the instructive activity of T-helper cells (pages 1383-1384 bridging paragraph).
Dominguez teaches that anti-neu/anti-CD40-NP retained their ability to recognize tumor cells and activated DCs (page 1385, § 3.2. Generation of anti-CD40/anti-neu-nanoparticles).
Dominguez teaches that anti-neu/anti-CD40-NP induces the formation of conjugates between tumor cells and DC. As shown in Fig. 3, the combination of anti-neu-NPs + anti-CD40-NPs did not form conjugates between tumors and DCs (Fig. 3A). In contrast, the addition of anti-neu/anti-CD40-NPs brought to proximity TUBO cells (green) and DCs (red) inducing the formation of conjugates between these cells (Fig. 3B–D). These results support the hypothesis that with the use of anti-neu/anti-CD40-NPs, the anti-CD40 mAb could be anchored at the tumor site retaining for longer periods of time APCs within the tumor microenvironment resulting in the induction of an antitumor response (page 1385, § 3.3. Anti-neu/anti-CD40-NP induces the formation of conjugates between tumor cells and DC).
Dominguez teaches that the anti-neu/anti-CD40-NP conjugate has strong anti-tumor activity in mouse model (Balb/c mice implanted with TUBO cells, Figs. 4 and 5). No antitumor effect was observed in animals treated with anti-neu-NP, antiCD40-NP or the combination of anti0neu-NP plus anti-CD40-NP (page1386, col.1, para. 1).
Dominguez teaches that the antitumor response is depended on the activation of APCs and T-cell response (page 1386, col. 2, para. 1).
Dominguez teaches that compared to traditional bispecific antibodies, the advantage of using a nanoparticle is that other ligands or antibodies could be conjugated onto the nanoparticle (page 1389, col. 2, para. 2).
Dominguez teaches that the bispecific antibody-nanoparticle conjugate can be delivered specifically targeting the tumor and also induce immune responses (Discussion).
Dominguez teaches although we have only tested the biodegradable polylactic acid (PLA) nanoparticles there are other biodegradable nanoparticles such as poly(lactic-co-glycolic acid) (PLGA) nanoparticles that can be used in vivo (page 1389, col. 2).
Dominguez does not teach producing a CD3/CD20 biodegradable nanoparticles conjugate, or explicitly teaches using carboxyl groups of the nanoparticle surface and the amino groups of the antibody moieties.
Smith teaches that CD3 is a homodimeric or heterodimeric antigen expressed on T cells in association with the T cell receptor complex and is required for T cell activation. See [0002].
Smith teaches that bispecific antibodies that are capable of binding CD3 and a target antigen have been proposed for therapeutic uses involving targeting T cell immune responses to tissues and cells expressing the target antigen. See [0002].
Smith teaches that CD20 is a non-glycosylated phosphoprotein expressed on the cell membranes of mature B cells. CD20 is considered a B cell tumor-associated antigen because it is expressed by more than 95% of B-cell non-Hodgkin lymphomas (NHLs) and other B-cell malignancies, but it is absent on precursor B-cells, dendritic cells and plasma cells. Methods for treating cancer by targeting CD20 are known in the art. See [0003].
Smith teaches bispecific antigen-binding molecules that bind both CD3 and a target antigen (such as CD20) would be useful therapeutic settings, in which specific targeting and T cell-mediated in killing of cells that express the target antigen is desired. See [0004].
Smith teaches anti-CD3 antibody are useful for targeting T cells expressing CD3 and for stimulating T cell activation. The anti-CD3 antibody may be included as part of a bispecific antibody that direct CD3-mediated T cell activation to specific cell type such as tumor cells. See [0005].
Smith teaches specifically about bispecific antigen-binding molecules comprise a first antigen-binding domain that specifically binds human CD3, and a second antigen-binding domain that specifically binds CD20. The simultaneous binding of CD20 on a tumor cell and CD3 on a T-cell facilitates directed killing (cell lysis) of the targeted tumor cell by the activated T-cell. The anti-CD3/anti-CD20 bispecific molecules of the invention are therefore useful, inter alia, for treating diseases and disorders related to or caused by CD20-expressing tumors. See [0034-0058], [0099], claim 22.
Smith teaches that an antibody or fragment thereof can be functionally linked (e.g., by chemical coupling, genetic fusion, noncovalent association or otherwise) to one or more other molecular entities, such as another antibody or antibody fragment to produce a bi-specific or a multispecific antibody with a second binding specificity. See [0092].
Smith teaches that the antibodies of the invention can be monospecific as well as bispecific or multispecific that can be linked to other molecules by various methods, such as chemical coupling or non-covalent associations. See, e.g., paragraphs [0092]-[0093] and claims 1-17.
Smith teaches that the first antigen-binding domain and the second antigen-binding domain may be directly or indirectly connected to one another to form a bispecific antigen-binding molecule. See [0101].
Smith teaches that the mechanism of action by which the bispecific antigen-binding molecule include killing of the cells expressing CD20 in the presence of effector cells. See [0156].
Smith teaches the method of generating bispecific antibody that bind CD3 and CD20. See Example 7.
Smith teaches the CD20xCD3 bispecific antibodies induce T-cell mediated cytotoxicity on tumor cells. See Examples 11 and 15.
Smith teaches that CD20xCD3 bispecific antibody can be used to treat B cell cancer, e.g. follicular lymphoma, B cell chronic lymphocytic leukemia, B cell lymphoblastic lymphoma, Hodgkin lymphoma, Non-Hodgkin lymphoma, diffuse large B cell lymphoma, marginal zone lymphoma, Mantle cell lymphoma, hairy cell leukemia and Burkitt lymphoma. See claims 45-47.
Chen teaches that nanoparticles (NPs) are defined as particulate dispersions or solid particles with a size in the range of 10–1000 nm and have shown great potential in various biomedical applications. See page 92, col. 1, para. 2.
Chen teaches that among the nanoparticulate carriers, poly(lactic-co-glycolic acid) (PLGA) is one of the most successfully developed biodegradable polymers whose hydrolysis releases two metabolite monomers, lactic acid and glycolic acid, which are endogenous and readily metabolized by the body via the Krebs cycle. Thus, a minimal systemic toxicity is associated with the use of PLGA for drug delivery or biomaterial applications. PLGA based NP presents many advantages for delivery of drugs, proteins, peptides or nucleic acids by protecting them from degradation and enhancing their stability. Another major advantage of PLGA over other polymers is that PLGA is approved by the US FDA and European Medicine Agency (EMA) in various drug delivery systems in humans, leading PLGA-based NP in a good position for clinical trials. See page 92, col. 1, para. 2.
Chen teaches that nanoparticles were prepared from a PLGA polymer containing free carboxylic end groups (on the surface of the nanoparticle as shown in Fig. 1D). To generate anti-OX40-PLGA-NP, the EDC and NHS activation method was used to covalently link amine groups of antibodies to the carboxylic group of PLGA-NP. The encapsulation efficacy was 65.8 ± 5.6%. A high loading efficiency (~25%) was also achieved (248 ± 16.3 µg antibody in per mg polymers of nanoparticles. See Fig. 1D and page 94, § 3.1. Characterization of PLGA nanoparticles.
Chen teaches that NPs demonstrated a sustained release of the conjugated antibody, with approximately 55% cumulative antibody in 20 days. See Fig. 2B.
Chen teaches that PLGA-OX40 antibody conjugate shows good therapeutic activity. See § Results: 3.3-3.6.
Chen teaches that PLGA-based nanoparticle formulation can provide efficient delivery for possibly other potential antibodies or proteins for cancer immunotherapy. See page 98, § 5. Conclusions.
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to modify the teachings of Dominguez and to add teaching of Smith, Chen, to generate a CD3/CD20 – PLGA biodegradable nanoparticle conjugate using carboxyl groups of the nanoparticle surface and the amino groups of the antibody moieties. The skilled artisan would have expected success in substituting anti-CD3/CD20 antibodies taught by Smith, for cancer treatment because Dominguez teaches that multiple antibody-nanoparticle conjugates are useful for treating cancer and have advantages compared to traditional bispecific antibodies and Smith teaches the CD3/CD20 bispecific antigen-binding molecules are useful in treating various cancers. Chen teaches PLGA is one of the best biodegradable nanoparticles for protein/peptide conjugates and FDA-approved. Chen further teaches the method of making PLGA-nanoparticle antibody conjugate using carboxyl groups of the nanoparticle surface and the amino groups of the antibody moieties with EDC and advantage of using the PLGA-NP platform for antibody application. The person of ordinary skill in the art would have found it obvious to make the substitution because ordinarily skilled artisans would have concluded based on the aforementioned teachings that the CD3/CD20 - PLGA nanoparticle conjugate: a bispecific antigen-binding molecule the first antigen-binding domain specifically binds a first antigen (e.g., CD3), and the second antigen-binding domain specifically binds a second, distinct antigen (e.g., CD20), would still have therapeutic effectiveness, e.g. killing of the cells expressing CD20 in the presence of effector cells such as various lymphoma, as taught by Smith. The motivation would have been to expand the options of cancer treatment, and to develop a new CD3/CD20 conjugate platform with more flexibility, as recognized by Dominguez.
Regarding claims 24-26, 29, 30, 31, Dominguez teaches the method of making nanoparticle-2 antibody conjugates: Biodegradable polylactic acid (PLA) nanoparticles with surface carboxyl groups (PLA-COOH) were washed in 25mM MES (N-morpholino ethane sulfonic acid) buffer, pH 6. Washed nanoparticles (10 mg) were mixed with 1mg of antibody in 25mM MES buffer, pH 6. Nanoparticles and antibodies were incubated overnight at 4⁰C. After incubation, nanoparticles were washed three times with PBS by centrifugation to remove excess of antibody. Possible free carboxyl groups were blocked with 1% bovine serum albumin (BSA). After blocking, conjugated nanoparticles were washed with PBS and resuspended in 1mL of PBS-Triton-0.01% and stored at 4⁰C. (page 1384, 2.2). This is the first time that a nanoparticle conjugated with multiple antibodies to modulate the tumor microenvironment and activate antitumor responses has been generated (page1389, col. 2, para. 2).
Chen also teaches method of preparation of antibody-loaded PLGA-NP. Briefly, 50 mg of the PLGA was dissolved in 500 µl of acetone and 750 µl of DCM. The polymer solution was added to 10 ml of an aqueous solution containing 3% (w/v) PVA as a stabilizer. The mixture was emulsified for 20 s with a sonicator operated at 70 W. The formed o/w emulsion was poured into 50 ml of a PVA aqueous solution (0.25%, w/v) and magnetically stirred for 24 h at room temperature to completely extract/evaporate the organic solvent and harden the particles. The produced nanoparticles were collected by centrifugation at 11,000 rpm (Optima™ L-100 XP ultracentrifuge, Beckman coulter), washed three times with deionized water and freeze-dried. For the covalent attachment of anti-OX40 antibody onto the nanoparticle surface, 4.5 µg of EDC (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, sulfo-NHS (sulfosuccinimidyl ester), was added to a 360 µl mixture of 400 µg nanoparticles and 400 µg mAb. The reaction mixture was stirred gently for 2 h at room temperature. Excess linking reagent and soluble byproducts were separated by centrifugation at 13,200 rpm for 10 min, and the sediment was washed three times with 1 ml PBS (pH 7.4). Finally, the antibody-loaded nanoparticles were redispersed in 100 µl of PBS and protein content determined by Bradford assay. See page 92, § 2.2 Preparation and Characterization of anti-OX40 antibody-loaded PLGA-NP.
Response to Arguments
For the rejection of claims 18, 20, and 22-33 under 35 U.S.C. 103 over Dominguez and further in view of Smith and Chen, Applicant argues that:
Firstly, Dominguez does not teach that a nanoparticle conjugated with any two different antibodies can be used in a cancer therapy. In fact, not nanoparticle conjugated with any two different antibodies can be used in a cancer therapy. For example, Steenblock (as previously submitted with the IDS dated July 27, 2021 - Steenblock ER et al, A Comprehensive Platform for Ex Vivo T-cell Expansion Based on Biodegradable Polymeric Artificial Antigen presenting cells, Molecular Therapy, 2008, 16, 765-772) ("Steenblock") teaches a nanoparticle conjugated with anti-CD3 and anti-CD28 antibodies, as artificial Antigen-presenting Cells (aAPCs), useful for Ex Vivo T-cell Expansion (see, e.g., Abstract and Fig. l), not for inducing an anti-tumor response.
Applicant’s arguments have been considered, but have not been found persuasive.
First, in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Dominguez teaches: 1) a nanoparticle can conjugate two different antibodies (not limited to anti-neu + anti-CD40); 2) both antibodies are still functional with this platform. Steenblock’s results further showed that the nanoparticle platform can be used to bring two different antibodies (not limited to anti-neu + anti-CD40) to generate a functional molecule.
Applicant further argues that Dominguez teach different antitumor mechanism (anti-neu/anti-CD40) from that of the anti-CD3/anti-CD20 bispecific antibody instantly claimed, as shown below:
Instead, Dominguez teaches that a nanoparticle with dual function – recognizing tumors and activating dendritic cells (DCs, a kind of Antigen Presenting Cell), i.e., a nanoparticle conjugated with antibody binding tumor cell antigen and anti-CD40 antibody (which binds and activates DCs) can be used in a cancer therapy (see, e.g., Abstract and page 1388 of Dominguez "Our results indicate that the anti-neu/anti-CD40-NP retains its dual function recognizing RNEU+ tumors and activating DCs'').
As the Examiner indicated, the antibodies conjugated on the nanoparticle taught by Dominguez are not limited to anti-neu + anti-CD40. However, the antibodies conjugated taught by Dominguez are limited to anti-tumor antigen antibody + anti-CD40 ( + optional additional antibody, the advantage over traditional bispecific antibody, as the Examiner indicated), because Dominguez teaches the mechanism of action of anti-neu/anti-CD40-NP, i.e., the hypothesis demonstrated, that anchoring anti-CD40 at tumor site by the formation of conjugates between dendritic cells (DCs) and tumor cells could induce an immune response with antitumor effects by activating DCs and the conjugated nanopa1ticle could be used as cancer vaccine.
Specifically. after anti-neu/anti-CD40-NP has been administrated, anti-tumor antigen antibody (i.e., anti-neu) will bind tumor cells targeted, anchoring the nanoparticle and anti-CD40 thereon at the tumor site, while ananti-CD40 antibody will bind DCs (a kind of Antigen Presenting Cells (APCs)), fonning the conjugate between DCs and tumor cells, that is, anchoring anti-CD40 and retaining DCs bound by anti-CD40 at tumor site.
On the other hand, the conjugated nanoparticles are intended to be used as cancer vaccine. It is well-known to a skilled person that, a cancer vaccine is useful to simulate APC (Antigen Presenting Cells, e.g., DCs) to present tumor Ag to T cell. inducing CTL against targeted cells (i.e., tumor cells).
Applicant’s arguments have been considered, but have not been found persuasive.
As set forth in the previous Office Action, different antitumor mechanism between anti-neu/anti-CD40 and anti-CD3/anti-CD20 would not prevent one of ordinary skilled in the art to develop the claimed bispecific antibody. Moreover, Dominguez’s teaching is not limited to anti-neu/anti-CD40 combination or cancer vaccines. Dominguez teaches: 1) a nanoparticle can conjugate two different antibodies (not limited to anti-neu + anti-CD40); 2) both antibodies are still functional with this platform; 3) can be used in a cancer therapy with good therapeutic activity. Dominguez further teaches the advantage of using a nanoparticle is that in addition to the anti-neu and anti-CD-40 mAb other ligands or antibodies could be conjugated onto the nanoparticle (page 1380, right col., para. 2). Chen further teaches that antibody-NP conjugate not only maintain antibody functions, but also have better therapeutic effects/properties, as set forth above. One ordinary skilled in the art would have been motivated to apply the platform of Dominguez to other antibody combination (e.g. CD3/CD20 as taught by Smith) to solve various problems in immunotherapy. One ordinary skill in the art would have recognized that the platform can be used to target CD3 and CD20 simultaneously, although anti-CD3/anti-CD20 has different antitumor mechanism compared to anti-neu/anti-CD40.
Applicant further argues that Smith’s teachings are limited to traditional bispecific antibody format, and does not include molecules comprising a nanoparticle, as shown below:
However, Smith explicitly provides definitions of the terms used therein, from paragraph [0069], including the definition of the tem1 "antigen-binding molecules":
"The tem1 "antigen-binding molecule" includes antibodies and antigen-binding
fragments of antibodies, including, e.g., bispecific antibodies." (paragraph [0072]);
"The term "antibody" includes immunoglobulin molecules comprising four
polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by
disulfide bonds, as well as multimers thereof (e.g., IgM)" (paragraph [0073]);
"The terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of
an antibody, and the like, as used herein, include any naturally occurring,
enzymatically obtainable, synthetic. or genetically engineered polypeptide or
glycoprotein that ... " (paragraph [0074]);
"As with full antibody molecules, antigen-binding fragments may be monospecific or
multispecific (e.g., bispecific)" (paragraph [0078]).
Smith also explicitly teaches the method of making bispecific antigen-binding molecules -- "[A]ny bispecific antibody format or technology may be used to make the bispecific antigen-binding molecules of the present invention" (paragraph [0104]). It is well-known that the technologies for making bispecific antigen-binding molecules taught by Smith, chemical coupling (through chemical linkers), genetic fusion, noncovalent association (i.e., chain association by use of multimerizing domain), are conventional means for making traditional bispecific antibodies or antigen-binding fragments thereof in the field of antibodies (see, e.g., paragraph [0101] "The association of one rnultimerizing domain with another multimerizing domain facilitates the association between the two antigen-binding domains, thereby forming a bispecific antigen-binding molecule").
That is, the term "bispecific antigen-binding molecules" taught by Smith does not include molecules comprising a nanoparticle.
Applicant’s arguments have been considered, but have not been found persuasive. The paragraphs of Smith cited by Applicants does not limit the antibodies to traditional bispecific antibodies. The term “includes” does not exclude nanoparticle in the bispecific antibody. Contrary to Applicant’s argument, Smith is not limited to only CD3xCD20 traditional bispecific antibodies format. Smith teaches bispecific antigen-binding molecules comprise a first antigen-binding domain that specifically binds human CD3, and a second antigen-binding domain that specifically binds CD20 (See [0034-0058], [0099], claim 22). Smith teaches that an antibody or fragment thereof can be functionally linked (e.g., by chemical coupling, genetic fusion, noncovalent association or otherwise) to one or more other molecular entities, such as another antibody or antibody fragment to produce a bi-specific or a multispecific antibody with a second binding specificity (See [0092]). Thus, “functionally linked” taught by Smith would encompass the antigen-binding domains “functionally linked” with nanoparticles. Smith explicitly teaches that bispecific antigen-binding molecules binding both CD3 and a target antigen (such as CD20) would be useful in therapeutic settings, in which specific targeting and T cell-mediated in killing of cancer cells that express the target antigen is desired. Smith explicitly teaches the CD20xCD3 bispecific antibodies induce T-cell mediated cytotoxicity on tumor cells (See Examples 11 and 15). Given that various NP-antibody conjugates show good therapeutic activity and properties (e.g. improved stability), as taught by Dominguez and Chen, one of ordinary skilled in the art would have recognized that nanoparticles could be used to make an anti-CD3/anti-CD20 bispecific antigen binding molecule, which can bind CD3 and CD20, for cancer treatment. Combining teachings from the references, one of ordinary skilled in the art would have recognized that nanoparticles could be used to make an anti-CD3/anti-CD20 bispecific antigen binding molecule e.g. the claimed bispecific-NP, which can bind CD3 and CD20, for cancer treatment.
Applicant further argues with similar arguments addressed above, shown below:
Firstly, the bispecific antigen-binding molecules as taught by Smith do not include molecules comprising a nanoparticle, instead include traditional bispecific antibodies and antigen-binding fragments thereof, as indicated above. Thus, the anti-CD3/anti-CD20 conjugated nanoparticle is not the bispecific antigen-binding molecules as taught by Smith.
Applicant’s arguments have been considered, but have not been found persuasive. As set forth above, Smith does not limit the antibodies to traditional bispecific antibodies. The term “includes” does not exclude nanoparticle in the bispecific antibody.
Secondly, the platform of Dominguez is, as cancer vaccine, a nanoparticle conjugated
with two different antibodies, anti-TRA (i.e., tumor-relative antigen)+ anti-CD40 or an antibody
which can bind and activate APCs (e.g., DCs) to present tumor antigen to T cell inducing CTL to
kill targeted tumor cells, not the one conjugated with any two antibodies, as indicated above.
Applicant’s arguments have been considered, but have not been found persuasive. As set forth in the previous Office Action, different antitumor mechanism between anti-neu/anti-CD40 and anti-CD3/anti-CD20 would not prevent one of ordinary skilled in the art to develop the claimed bispecific antibody. Moreover, Dominguez’s teaching is not limited to anti-neu/anti-CD40 combination or cancer vaccines. Dominguez teaches: 1) a nanoparticle can conjugate two different antibodies (not limited to anti-neu + anti-CD40); 2) both antibodies are still functional with this platform; 3) can be used in a cancer therapy with good therapeutic activity.
Applicant further argues that Dominguez teaches that both antibodies conjugated remain those own functions, but anti-CD3/anti-CD20 produce new functions, shown below:
Thirdly, as the Examiner indicated, Dominguez teaches that both antibodies conjugated are still functional with this platfom1 (see page 18 of the Action), that is, both antibodies conjugated are still retain those own functions….
As the components of the anti-CD3/anti-CD20 bispecific antigen-binding molecules as taught by Smith, the anti-CD20 antibody fragment and the anti-CD3 anti body fragment linked together into one molecule are able to mediate killing of tumor cells expressing antigen CD20 by T cells, when linked together into bispecific antigen-binding molecules (e.g., bispecific antibodies, BsAbs). However, the two antibody fragments, when used alone, cannot induce killing of tumor cells. See Applicant's Declaration submitted with the Supplemental Response dated May 7. 2024, Table 1, the killing rate for Group anti-CD3-PLGA (CIK cells + cancer cells + anti-CD3-PLGA) and Group Anti-CD20-PLGA (CIK cells + cancer cells + Anti-CD20-PLGA) are 12.67% and -9.85%, while he killing rate for Group Control (CIK cells + cancer cells) is 15.25% (note: CIK cells were used as effector T cells).
That is, the two antibody components in the anti-CD3/anti-CD20 bispecific antigen binding molecules as taught by Smith, the anti-CD20 and anti-CD20 antibody fragments cooperate to produce a new effect, -- resulting in T cell-medicated killing of tumor cells expressing CD-20, unlike the platform of Dominguez.
Applicant’s arguments have been considered, but have not been found persuasive. Applicant argues that the bispecific anti-CD3 and anti-CD20 antibody produces “new function”. As acknowledged by applicant, Smith teaches the “new function” of the bispecific antigen-binding molecules which targets both CD3 and CD20 simultaneously. One of ordinary skilled in the art would have been motivated to use different platform or method to produce the “new function”. As set forth above, Dominguez and Chen teach that antibody-nanoparticle conjugates would provide a new and better alternative option to bring anti-CD3 and anti-CD20 antibodies together to produce the “new function”.
In addition, Smith explicitly teaches that bispecific antigen-binding molecules binding both CD3 and a target antigen (such as CD20) would be useful in therapeutic settings, in which specific targeting and T cell-mediated in killing of cells that express the target antigen is desired. Smith explicitly teaches the CD20xCD3 bispecific antibodies induce T-cell mediated cytotoxicity on tumor cells (See Examples 11 and 15). Thus, a skilled person in the art would have been motivated to develop a treating method by targeting both CD3 and CD20, no matter whether the combination produces new function or just improve therapeutic activities.
Lastly, Applicant further argues that one of ordinary skill in the art would not have been motivated to make substitution of anti-CD3 and anti-CD20 for anti-neu and anti-CD40 in the platform of Dominguez, as shown below:
Smith does not teach whether anti-CD3/anti-CD20 conjugated nanoparticle. which is not a bispecific antigen-binding molecule as taught by Smith as discussed above, could also mediate killing of tumor cells expressing antigen CD20 by T cell.
Dominguez does not teach whether a nanoparticle conjugated with anti-TRA + antibody binding and activating T cells, which cannot activate APCs (i.e .. DCs) and cannot be used as cancer vaccine, could induce antitumor activity.
Therefore, one of ordinarily skilled in the art would not have been motivated to make substitution of anti-CD3 and anti-CD20 for anti-neu and anti-CD40 in the platform of Dominguez, because one of ordinarily skilled in the art would not have been reasonably concluded that anti-CD3/anti-CD20-PLGA nanoparticle conjugate, which is not a bispecific antigen-binding molecule as taught by Smith, and cannot activate APCs (e.g., DCs) and cannot be used as cancer vaccine like the platform of Dominguez. would still have therapeutic effect, e.g., killing the tumor cells expressing CD20 in the presence of effector T cells.
Applicant’s arguments have been considered, but have not been found persuasive. Dominguez and Chen teach that antibody-nanoparticle conjugates would provide a new and better alternative option to bring anti-CD3 and anti-CD20 antibodies together. In the field of biological technology, no invention has absolute certainty of success before experimental tests. Thus, only a reasonable expectation of success (not absolute) would have motivated an artisan to make the claimed bispecific antibody. Given the teachings from references, one of ordinary skill in the art would have would have had a reasonable expectation of success in producing the claimed invention.
Thus, Applicant’s arguments are not found persuasive for the reasons set forth above and the rejection is maintained for the reasons of record.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 18, 20, and 22-33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. 10758625 B2, hereinafter Pat.625, of record), in view of Dominguez (Dominguez et al., Vaccine, 28, 1383-1390, Publication Date: 2009-11-18, of record), and Smith (Smith et al, WO 2014/047231 A1, Publication Date: 2014-03-27), Chen (Chen et al., Cellular Immunology, 287 (2014), 91-99, Publication Date: 2014-01-13).
The Pat. ‘625 claims teach a bispecific antibody capable of being combined with an immune cell to enhance a targeting tumor killing capability, wherein the antibody comprises a first antibody moiety that binds to an antigen expressed on an effector T cell and a second antibody moiety that binds to an antigen expressed on a target cell, wherein the first antibody moiety and the second antibody moiety are connected by a nanomaterial which is a biodegradable nanomaterial, wherein the nanomaterial is polylactic acid-glycolic acid, the target cell is a cancer cell, the antigen expressed on the target cell is Muc1, and the antigen expressed on the effector T cell is CD3 (claim 1).
The Pat. ‘625 claims teach a method for producing a bispecific antibody which comprises connecting the nanomaterial to the first antibody moiety and the second antibody moiety (claim 2).
The Pat. ‘625 claims teach the method, which comprises the steps of: (1) preparation, collection and activation of the nanomaterial; (2) connecting the nanomaterial obtained in step (1) with a mixture of the first antibody moiety and the second antibody moiety (claim 3).
The Pat. ‘625 claims teach the method, wherein the nano-material is polylactic acid-glycolic acid and the solvent is any one of acetone, butanone, methanol, ethanol or isopro-panol or a mixture thereof (claim 4).
The Pat. ‘625 claims teach that the bispecific antibody can be used to treat a tumor, including liver cancer, non-small cell lung cancer, small cell lung cancer, adrenocortical carcinoma, acute (chronic B) lymphocytoma, myeloma, prostate cancer, breast cancer, esophageal cancer, gastric cancer, colorectal cancer, cervical cancer, kidney cancer, bladder cancer and lymphoma (claims 5-6).
The Pat. ‘625 claims a CD3/MUC1-NP bispecific antibody, however, the Pat.625 claims do not teach a specific CD3/CD20 antibody conjugate, or explicitly teach using carboxyl groups of the nanoparticle surface and the amino groups of the antibody moieties.
Dominguez, Smith, Chen’s teachings are set forth above. In particular, Dominguez teaches the advantages of the platform for a bispecific antibody; Smith teaches the combination of anti-CD3/CD20 in cancer treatments, e.g. for treating various lymphoma, both Chen and Dominguez teach the method of making bispecific antibody-NP.
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to modify the teachings of ‘625 claims in view of the teachings of Dominguez, Smith and Chen, to generate a CD3/CD20 bispecific antibody with biodegradable nanoparticle by substituting the MUC1 antibody with an CD20 antibody, doing so would produce a multifunctional therapeutic agent that can target CD20 specific cancer cells (e.g. various lymphomas) and possess T-cell-mediated cytotoxicity with good therapeutic properties, as recognized by Smith and Dominguez, and to use a preparation method for antibody-PLGA using carboxyl groups of the nanoparticle surface and the amino groups of the antibody moieties, taught by Chen, because the method is commonly used, does not need prior modification of antibody, and has high efficiency, as taught by Chen. The motivation would have been to generate a new therapeutic bispecific antibody-NP for cancer treatment.
Response to Arguments
For the Double Patenting rejection, Applicant argues:
It is noted that the present rejection can be overcome by timely filing a terminal disclaimer. Applicant respectfully requests that the rejections be held in abeyance until the claims are held otherwise allowable.
Applicant’s arguments have been fully considered but they are not persuasive because the claims of the instant application are still obvious in view of the patented claims and a terminal disclaimer has not been filed. Therefore, the rejections above are maintained for the reasons of record.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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 CHENG LU whose telephone number is (571)272-0334. The examiner can normally be reached Monday-Friday 8-5.
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/CHENG LU/ Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642