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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on July 27, 2026 has been entered.
DETAILED ACTION
Applicant Arguments/Remarks filed July 27, 2026 in response to the Office Actions of January 26, 2026 are 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 January 26, 2026 are maintained.
Information Disclosure Statement
The Information Disclosure Statements (IDS) filed on 06/04/2026, 07/27/2026 and 08/28/2026 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.
Claims 18, 20, and 22-33 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 tumors (the whole document, e.g. Title).
Dominguez teaches that nanoparticles have been proven to be an effective delivery system. The anti-neu/anti-CD40-NP were functional in vitro recognizing RNEU+ tumors and activating dendritic cells. The delivery of anti-neu/anti-CD40-NP but not anti-neu-NP or anti-CD40-NP induced an antitumor response resulting in complete tumor elimination and generation of protective memory responses. The anti-neu/anti-CD40-NP specifically activated an antitumor response against RNEU+ tumors but not against RNEU− tumors. The antitumor immune responses correlate with the induction of a Th1-proinflammatory response, reduction in the number of Tregs within the tumor and activation of a specific cytotoxic response. These results indicate that anti-neu/anti-CD40-NP with immunomodulatory properties are safe and can be used effectively as cancer vaccines strategy for the specific induction of antitumor immune responses (Abstract).
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. 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 anti-neu-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 directs 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 includes killing of the cells expressing CD20 in the presence of effector cells. See [0156].
Smith teaches the method of generating bispecific antibody that binds 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 before 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 first argues there is no motivation to combine Dominguez, Smith and Chen to arrive at the instant claims with a reasonable expectation of success, as shown below:
Firstly, Applicant submits that one of skill in the art would not consider two antibodies conjugated with a nanoparticle (e.g., the bispecific antibody claimed in claim 18 or the anti-neu/anti-CD40-NP of Dominguez) to be a bispecific antibody as defined in the art. Further, the claimed CD3/CD20-PLGA nanoparticle (NP) conjugate is not a bispecific antigen-binding molecule (including a bispecific antibody) of Smith….
In fact, Applicant submits that Dominguez does not consider the anti-neu/anti-CD40- NP as a bispecific antibody. Dominguez explicitly states, "[e]ven though bispecific-antibodies could be generated with the anti-neu and anti-CD40 mAb and might have the same antitumor
effect as the anti-neu/anti-CD40-NP in inducing an antitumor immune response" (page 1385, col.2, para. 2).
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). It does not matter whether the anti-neu/anti-CD40-NP of Dominguez is called as a bispecific antibody or a bispecific molecule. However, it is noted that Applicant called the molecule as “bispecific antibody” as evidenced by claim 18. Importantly, Dominguez teaches: 1) nanoparticles can conjugate two different antibodies (not limited to anti-neu + anti-CD40); 2) both antibodies are still functional with this platform; 3) the platform produces bispecific molecules with better therapeutic activity.
Applicant then argues that Smith does not teach nanoparticles and the Smith’s teachings are limited to traditional bispecific antibodies, or bispecific structures disclosed in Brinkerman, or chemical coupling (or association) disclosed in Tutt and Kufer, as shown below:
It is well-known in the field of antibodies that bispecific antibodies can be produced by chemical conjugation/coupling, fusing two antibody-producing cells (e.g., hybridomas), recombinant DNA technology (i.e., molecular or genetic means, including gene fusion), and linking two antibodies or antibody fragments with different specificities. Further, bispecific antibodies have a structure resembling that of an IgG antibody or antigen-binding fragments thereof and bispecific antibodies do not comprise a nanoparticle. See Brinkmann, Fig. 2: Box 1 (chemical conjugation), Box 2 (fusing two antibody-producing cells), Boxes 3-19 (recombinant DNA technology) (Brinkman, "The Making of Bispecific Antibodies", submitted to the Office and listed in line 1 of PTO/SB/08a filed April 18, 2024, of record)….
The Office alleges that Smith includes 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 (Action, p. 15, citing Smith para. [0092]) and that the "functionally linked" taught by Smith would encompass the antigen-binding domains "functionally linked" with nanoparticles. Action,p. 15.
However, Smith teaches that the bispecific antigen-binding molecules may be made by any bispecific antibody format or technology, e.g., by chemical coupling, genetic fusion, noncovalent association or otherwise) ([0104]).
This paragraph of Smith makes no mention of nanoparticles. Instead, this paragraph refers to chemical coupling and association as known in the art. It is well-known in the art that "chemical coupling" refers to using a bifunctional cross-linker (e.g., o-phenylenedimaleimide (oPDM), 5,5' -dithiobis(2 nitrobenzoic acid (DTNB)) to conjugate two antibodies or antibody fragments) and that bifunctional cross-linker is a small molecule, not a nanoparticle. See Tutt et al., ("Trispecific F(ab')3 derivatives that use cooperative signaling via the TCR/CD3 complex and CD2 to activate and redirect resting cytotoxic T cells" submitted to the Office and listed in line 7 of PTO/SB/08a filed March 17, 2023, of record) and Kufer et al., "A revival of bispecific antibodies" submitted to the Office and listed in line 2 of PTO/SB/08a filed March 17, 2023, of record) each cited in Smith [0092], and Tohoku et al., J. Exp. Med., 1999, 188, 275-288, page 276, para. 2; Fig. 1 (a copy of which is submitted here along with an SB/08a).
Further, it is well-known in the art that the term "association" in the field of antibodies refers to the association or dimerization between certain protein domains by means of the natural ability of such protein domains as described in Kufer or as a homodimer as described in Klein. See, e.g., Kufer, page 239, col. 2, para. 3, "One strategy made use of the natural ability of certain protein domains to associate as heterodimers"; Fig. 1 (b)-(f)); See also Klein, FIG. 1A ("Progress in overcoming the chain association issue in bispecific heterodimeric IgG antibodies" submitted to the Office and listed in line 2 of PTO/SB/08a filed April 18, 2024, of record).
Such association or dimerization does not form a covalent bond between the protein domains, instead, the bond formed is non-covalent.
As such, Smith teaches that the CD3 bispecific antibodies or CD3 bispecific antigen-binding molecules can be produced by chemical coupling (using a small molecular bifunctional
cross-linker) or non-covalent association (as dimers between certain protein domains). Smith
fails to name, include, or suggest nanoparticles in creating these CD3 bispecific antibodies or
bispecific antigen-binding molecules.
In this way, the ordinary skilled artisan would not have concluded that the CD3/CD20-PLGA nanoparticle (NP) conjugate is a bispecific antigen-binding molecule taught by Smith and that the CD3/CD20-PLGA NP conjugate would still have therapeutic effectiveness, killing of the cells expressing CD20 in the presence of effector cells taught by Smith, contrary to the Office's assertion.
Contrary to Applicant’s argument, Smith is not limited to only traditional antigen-binding domains or traditional bispecific antibodies, nor limited by antibody structures disclosed in Brinkermann or Tutt or Kufer. As Applicant acknowledged, Smith’s “functionally linked” (coupling and association) encompasses methods known in the art, thus, would encompass the method of linking antibodies to nanoparticles as taught by Dominguez and Chen (not only method taught by Tutt, or Kufer, or Tohoku as argued by Applicant).
Furthermore, 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, thus, would encompass nanoparticles linking anti-CD3 and anti-CD20 antibodies. 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. 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, as set forth above (that would encompass the method of linking antibody to nanoparticles taught by Dominguez and Chen). 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). A skilled person in the art would have been motivated to develop a treating method by targeting both CD3 and CD20. 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.
Applicant further argues that Dominguez only teaches anti-CD40 anti-neu/anti-CD40-NP and the field of antibody treatment is unpredictable:
Further, Dominguez does not teach that an NP conjugate with any two different antibodies would have the same antitumor effect as the bispecific antibody generated by the two corresponding antibodies. Dominguez speculates that bispecific antibodies generated with the anti-neu and anti-CD40 mAb and might have the same antitumor effect as the anti neu/antiCD40-NP based on the mechanism of action by which the anti-neu/anti-CD40-NP successfully induced an antitumor immune response. Dominguez, p. 1385, col. 2, para. 2. This is not confirmed nor is data presented to demonstrate it. Instead, Dominguez forms the hypothesis that an antitumor response would be induced if anti-CD40 mAb could be anchored at the tumor site. Dominguez, p. 1385, col. 2, para.3 ("These results support our 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").
In other words, Dominguez only demonstrates that an antitumor response would be induced, if anti-CD40 mAb could be anchored at the tumor site. Dominquez only speculates that bispecific-antibodies generated with the anti-neu and anti-CD40 mAb might have the same antitumor effect as the anti-neu/anti-CD40-NP, because such bispecific antibodies may also anchor anti-CD40 mAb at the tumor site. Dominguez does not say or suggest that the platform of binding any two antibodies via nanoparticle will result in the same effect as the corresponding bispecific antibody. Rather, it is specific to anti neu /antiCD40 bispecific antibodies generated with the anti-neu and anti-CD40 mAb might have the same antitumor effect as the anti-neu/antiCD40-NP, as speculated based on the hypothesis supported by the test results. This hypothesis which relies on the specific mechanism of anti-CD40 mAb cannot be generalized to all antibody-NP conjugates and corresponding bispecific antibodies generated with any two different antibodies. Different bispecific antibodies have different mechanisms of action, and thus, it is not reasonable to conclude that all antibody-NP conjugates could have the same effect as the corresponding bispecific antibody.
In this way, Dominguez does not teach that an NP conjugate with any two different antibodies would have the same antitumor effect as the corresponding bispecific antibody generated by the same two antibodies.
Therefore, one of ordinary skill in the art would not consider it to be obvious to make substitution because ordinarily skilled artisans would not have concluded based on the teachings of Dominguez, Smith and Chen that the CD3/CD20-PLGA nanoparticle (NP) conjugate, which is not a bispecific antigen-binding molecule taught by Smith, would have still have therapeutic effectiveness, i.e., killing of the cells expressing CD20 in the present of effector cells, as taught by Smith.
Applicant’s arguments have been considered but have not been found persuasive. Again, 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 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 had a reasonable expectation of success in producing the claimed invention.
In addition, the combination of CD3 and CD20 is not “any two different antibodies” connected by 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 cells that express the target antigen is desired.
Applicant further argues that anti-neu/anti-CD40-NP and anti-CD3/anti-CD20-NP have different anti-tumor mechanisms, as shown below:
Further, in an unpredictable art such as antibody sciences, it cannot be assumed that bispecific-antibodies and antibody-NP conjugates generated with the anti-neu and anti-CD40 mAb might have the same antitumor effect as the anti-neu/anti-CD40-NP. This is evident in that Dominguez hypothesized, but did not know that the antibody-NP conjugate of Dominguez will indeed have an antitumor effect. Further, the generalization that all antibodies can be combined through NP conjugation and effectively support treatment of tumors is unsupported and conclusory. Applicant submits that not all antibody-NP conjugates and corresponding bispecific antibodies generated with any two antibodies will show therapeutic effects, as the Office alleges.
Additionally, Dominguez teaches an NP conjugated with two different antibodies (not limited to anti-neu + anti-CD40) and the use of the antibody-NP conjugates are not limited to cancer vaccine (page 1389, col. 2, para. 2).
However, all antibody-NP conjugates taught by Dominguez comprise anti-CD40 and are used as a vaccine, at least in the treatment of cancer/tumor, aimed at anchoring anti-CD40 at the tumor or target site, retaining for longer periods of time APCs within the microenvironment resulting in the induction of an antitumor response (page 1385, col. 2, para.3).
Moreover, each of the antibody-NP conjugates taught by Dominguez comprise anti-40. Dominguez, p. 1385, col. 2, para.3. Instead, one of skill in the art would see Dominguez's platform as an NP conjugated with two different antibodies, where one of them is anti-CD40. Therefore, one of skill in the art would not read Dominguez as stating generically that all antibody-NP conjugates would have the same effect as their corresponding bispecific antibodies.
Dominguez teaches that anti-neu/anti-CD40-NP retains its dual function recognizing RNEU+ tumors and activating DCs, that is, each of the antibodies retain its own function, recognizing/binding tumors or binding and activating DCs. This result is different than the antiCD3/anti-CD20 bispecific antibody or antigen-binding molecule taught by Smith, which antiCD3 had no effect on tumor cells unless it was paired with anti-CD20 antibody.
It was known to one of skill in the art that anti-CD40 mAb can stimulate DC cocultured with tumor cells, and the stimulated/activated DCs showed priming T cells which could mediate potent anti-tumor therapeutic efficacy (3hDCs) and good antigen presentation ability to induce cell killing (24h-DCs). See Watanabe, Abstract and page 5828, col. 2, para. 4 (Reference 22 cited in Dominguez, page 13, col. 1, para. 1 ("The Duration of Signaling through CD40 Directs Biological Ability of Dendritic Cells to Induce Antitumor Immunity", submitted to the Office and listed in line 3 of PTO/SB/08a filed April 18, 2024, of record).
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 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:
In the anti-neu/anti-CD40-NP, anti-neu retains its function, recognizing/binding tumor cell, anchoring the NP at the tumor site, while anti-CD40 retains its function, binding DCs, activating DCs at the tumor site (corresponding to activate DCs co-cultured with tumor cells), in tum presenting tumor antigen to T cell, resulting in inducing CTL which specifically killed the tumor cells, stating "[o]ur results also indicate that following injections with anti-neulanti-CD40-NP there is an activation of a cytotoxic response in which the CTLs effectively recognize and kill TUBO but no cytotoxic effect was observed against REN CA cells indicating that a RNEU tumor specific immune response was generated". Dominguez p. 1387, cols 1-2, bridging paragraph.
Contrary to Dominguez and anti-CD40, it is known in the art that anti-CD20 antibody can recognize and bind tumor cells expressing CD20, while anti-CD3 antibody can bind and activate T cells, and that T cells, when co-cultured tumor cells and activated with anti-CD3, cannot specifically recognize and kill the tumor cells, but when co-cultured with and activated with an anti-CD3/anti-CD20 bispecific antibody, specifically recognize and killing the tumor cells. That is, in an anti-CD3/anti-CD20 bispecific antibody, anti-CD3 and anti-CD20 have a synergistic effect, producing a new effect -- specifically recognize and killing the tumor cells, i.e., specifically redirect cytotoxicity to Raji cells. See, e.g., Smith.
Smith teaches that CD20 x CD3 bispecific antibodies (BS3/20-001 to BS3/20-005) were able to redirect T-cell mediated killing to CD20-expressing Raji cells in an in vitro cytotoxicity assay, i.e., to specifically redirect cytotoxicity to Raji cells in the presence of human or monkey T cells (when Raji cells were incubated with T cells and the bispecific antibodies), while anti-CD3 had no activity to the tumor cells (Example 13 and Table 27).
Therefore, in Dominguez's platform, each of the two antibodies retains its own function, while in the anti-CD3/anti-CD20 bispecific antibodies taught by Smith, the two different antibody fragments have a synergistic effect, producing a new effect.
In this way, one of ordinary skill in the art would have no motivation to apply the platform of Dominguez wherein each of the two antibodies retains its own function to antiCD3/anti-CD20 bispecific antibodies taught by Smith, in the latter the two different antibody fragments have a synergistic effect, producing a new effect, -- specifically redirecting cytotoxicity of effector T cells to the tumor cells, because each of anti-CD3 and anti-CD20 antibody fragments, if retaining its own function in this platform, would have no therapeutic effectiveness, because anti-CD3 cannot induce cytotoxicity to the tumor cells in the presence of effector T cells, although anti-CD20 can bind tumor cells (Smith, Example 13 and Table 27,
"Control (anti-CD3)" to Raji cells).
Applicant’s arguments have been considered but have not been found persuasive. Dominguez teaches that the delivery of anti-neu/anti-CD40-NP but not anti-neu-NP or anti-CD40-NP induced an antitumor response resulting in complete tumor elimination and generation of protective memory responses (Abstract). Thus, contrary to Applicant’s argument, the platform of Dominguez also results in “new effect” of the antibodies.
In addition, Applicant argues that the bispecific anti-CD3 and anti-CD20 antibody produces “new effect”. One of ordinary skilled in the art would have been motivated to use different platform or method to produce the “new effect”. 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 effect”.
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 functions or just improve therapeutic activities.
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.
Patent No. 10758625
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, of record), Chen (Chen et al., Cellular Immunology, 287 (2014), 91-99, Publication Date: 2014-01-13, of record).
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 before 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:
Applicant recognizes that the rejection can be overcome by filing a Terminal Disclaimer over the '625 patent. Applicant requests that the rejection be held in abeyance until the claims are found 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.
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/CHENG LU/Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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