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
Continued Examination Under 37 CFR 1.114
1. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 9/23/2026 has been entered.
Status of the Claims
2. Claims 1-20 are the original claims filed 5/19/2023. In the Preliminary Amendment of 10/30/2023, claims 1-20 are canceled and new claims 21-37 are added. In the Response of 4/29/2026, claims 21 and 26 are amended and new claims 38-39 are added. In the Response of 9/23/2026, Claims 21, 27 and 30 are amended, claims 25-26 and 38-39 are canceled, and new claims 40-41 are amended.
Claims 21-24, 27-37 and 40-41 are pending.
Priority
3. USAN 18/320,599, filed 05/19/2023, and having 1 RCE-type filing therein, is a Continuation of 16/805,105, filed 02/28/2020, now U.S. Patent # 11697684, 16/805,105 is a Divisional of 15/313,765, filed 11/23/2016, now U.S. Patent # 10633440, 15/313,765 is a National Stage entry of PCT/US2015/033081, International Filing Date: 05/29/2015,
PCT/US2015/033081 Claims Priority from Provisional Application 62/107,824, filed 01/26/2015, PCT/US2015/033081 Claims Priority from Provisional Application 62/008,229, filed 06/05/2014, PCT/US2015/033081 Claims Priority from Provisional Application 62/004,571, filed 05/29/2014.
Information Disclosure Statement
4. As of 10/14/2026, a total of one (1) IDS is filed: 10/30/2023. The corresponding initialed and dated 1449 form is considered and of record.
Withdrawal of Rejections
Double Patenting
5. The rejection of Claims 21-37 and 38-39 on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 10647768 in view of claims 1-13 of U.S. Patent 11697684 is moot for the canceled claims and withdrawn for the pending claims. Claims 21-24, 27-37 and 40-41 are amended to recite the target antigens DR5, EphA2 and/or gpA33 expressed on the cancer cells intended for treatment in the method invention and that are not specific antigens alone or in combination as claimed in ‘684. Even assuming any one or all the antigens are claimed in ‘684, the claims do not identify the same VH/VL domain sequences for the antibodies corresponding to the respective antigens as in amended instant claim 21.
6. The rejection of Claims 21-37 and 38-39 on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 11820818 in view of claims 1-13 of U.S. Patent 11697684 and 1-21 of U.S. Patent No. 10633440 is moot for the canceled claims and withdrawn for the pending claims. Claims 21-24, 27-37 and 40-41 are amended to recite the target antigens DR5, EphA2 and/or gpA33 expressed on the cancer cells intended for treatment in the method invention and that are not specific antigens alone or in combination as claimed in ‘818. Even assuming any one or all the antigens are claimed in ‘818, the claims do not identify the same VH/VL domain sequences for the antibodies corresponding binding to the respective antigens as in amended instant claim 21.
Rejections Withdrawn-in-Part/ Maintained-in-Part
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Written Description
7. The rejection of Claims 21-24, 27-37 and 40-41 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is:
Withdrawn-in-Part: Claims 21-24, 27-37 and 40-41 are amended to recite the target antigens DR5, EphA2 and/or gpA33 expressed on the cancer cells intended for treatment in the method invention including the VH/VL domain sequences for the antibodies corresponding binding to the respective antigens as in amended instant claim 2; Claims 21-24, 27-37 and 40-41 are amended to clarify the method is for treatment in a patient having any cancer that expresses DR5, EphA2 and/or gpA33 and not for the prevention of the cancer.
Maintained-in-Part: Claims 21-24, 27-37 and 40-41 are not limited by the specific DR5, EphA2 and/or gpA33- expressing cancer that is responsive to the claimed antibodies where the method readout is cancer cell killing; while cancer antigens are specified and with corresponding to VH/VL domain sequences for each of the antigens, no VH/VL sequences for the CD3 are claimed. None of the claims define the cancer environment nor the properties for any combination of anti-cancer antibodies specific to 2 cancer antigens plus the anti-CD3 antibodies in a trispecific format that are effective in killing any cancer, in vivo.
Applicant alleges that actual reduction to practice and functionality of a representative subset of the claimed trispecific binding molecules is shown in the specification. Each of these trispecific binding molecules will have the structure shown in FIG. 4A. Applicant demonstrates that trispecific binding molecules assembled with particular cancer antigen binding domains bind to the corresponding cancer-associated cell-surface antigen (see, e.g., FIGS. 9A-9C). As shown in FIGS. 10A-10C, the trispecific binding molecules of the instantly claimed methods can be used to target CHO cells expressing various cell-surface antigens linked to cancer. FIG. 10A is a cytotoxicity study on EphA2-expressing CHO cells. As shown in FIG. 10A, the trispecific binding molecules that include an EphA2 cancer antigen-binding domain (e.g., an EphA2 x CD3 x DR5 trispecific binding molecule or a EphA2 x CD3 x gpA33 trispecific binding molecule) mediate cytotoxicity. Similarly, FIG. 10B shows that trispecific binding molecules that include a DR5 cancer antigen-binding domain (e.g., the EphA2 x CD3 x DR5 tri-specific binding molecule and the gpA33 x CD3 x DR5 trispecific binding molecule) mediate increased cytotoxicity when incubated with DR5-expressing CHO cells. FIG. 10C is a cytotoxicity study using a Du145 prostate cancer cell line that expresses EphA2 and DR5, but not gpA33. As shown in FIG. 10C, trispecific binding molecules that include both of these antigen-binding domains mediate increased cytotoxicity compared to trispecific binding molecules that include only one of the antigen-binding domains and greatly increased cytotoxicity compared to trispecific binding molecules that do not include either of these antigen-binding molecules.
Applicant has not introduced extrinsic evidence showing the use of the claimed trispecific antibodies in an actual cancer cell-killing model.
Prior Art Status: Immunotherapeutics especially cancer therapy is unpredictable
The use of antibody immunotherapy for the treatment of tumors has been shown to have limitations. Five (5) art references spanning over 25 years in the field of immunotherapeutics and recognizing the complexity of antibody delivery to tumors in vivo are Fujimori et al. (J. Nuc. Med. 31:1191-1198 (1990)); Beckman et al. (Can. 109:170-179 (2007)); Thurber et al. (Adv. Drug Deliv. Rev. 60:1421-1434 (2008)); Rudnick et al. (Can. Biotherp. & Radiopharm. 24: 155-162 (2009)); and Huang et al. (Appl Microbiol Biotechnol (2010) 87:401–410).
Fujimori teaches for further understanding of Mab distribution in the tumor, one must consider as well the microscopic pharmacology: transport across the capillary wall, transport in tumor interstitium, cellular binding and metabolism. Fujimori discusses predictive models for accessing tumor antigen availability by Mab to examine the relationship between affinity and distribution. Fujimori teaches on p. 1196, Col. 2, ¶1:
“One strategy to overcome the binding-site barrier would be to increase the initial Mab dose. Even though Mab concentration in tumor does not always increase linearly as initial Mab concentration increases, a high initial plasma concentration leads to better percolation and results in more uniform distribution in tumor. Increasing Mab dose, however, decreases the specificity ratio and may cause toxicity or other side effects. For each Mab species and set of circumstances, there is an inherent balance of factors. Other causes of heterogeneous distribution include the functional and anatomical heterogeneity of tumors and their vessels..., and the elevated interstitial tissues…”
Beckman teaches on p. 175, Col. 2, ¶2-4:
“Optimizing biodistribution properties of Ab constructs depends on a large number of host and tumor variables. These include: the density and distribution of target Ag in tumors and normal tissues: the degree of target occupancy and residence tiemr equired for tumor cell kill; possible toxicities from normal tissue distribution; tumor size and vascularity; tumor interstitial pressure, convection and diffusion; and metabolism and internilzation rates for Ab-Ag constructs.
An equally large number of Ab construct and therapy variables are available for optimization, including size, charge, and valence; constant region type and glycosylation pattern; presence or absence of a radioisotope or a toxic moiety; dose, route, and schedule of administration; and use of a traditional or a pretargeting strategy. Given the complexity of the problem, systematic preclinical programs may enhance the likelihood of success in subsequent clinical studies. Such preclinical investigations should integrate both experimental and theoretical approaches.
Preclinical studies of a putative Ab-based therapeutic agent can encompass a variety of constructs, differing in molecular weight, affinity, valence, and/or other features of interest, which bind to the same epitope as demonstrated by competition experiments. The Ag density and target affinities should be known for both tumor cells and cross-reacting normal tissues, and the percent target occupancy and required residence time for tumor cell kill should ideally be investigated in vitro. Similarly, rate constants for Ab-Ag internalization should be determined, if applicable. Dose and schedule should be varied and antitumor efficacy, pharmacokinetics, overall biodistribution, homogeneity of intratumoral distribution, and tumor microvessel density and distribution ideally should be measured in tumor-bearing animals with a variety of tumor sizes.”
Studies in tumor-bearing rodents are often confounded by lack of normal tissue reactivity with Ab constructs directed toward human Ags, but studies in transgenic animal can be performed in some instances to alleviate this issue.”
Thurber teaches on p. 1431, Col 2, ¶3:
“Analyzing the fundamental rates that determine antibody uptake and distribution provides a theoretical framework for understanding and interpreting targeting experiments and improving on the limitations of uptake. It also provides a background for a more rational design of in vitro experiments, animal studies, and clinical trials. The insight gained from this type of modeling has multiple implications for imaging and therapy. For example, not all cells are exposed to the “average” concentration obtained in a tumor. A significant portion of cells can survive even if the tumor-averaged concentration is well above the LD50 in vitro. Also, the concentration that cells in a solid tumor are exposed to ([Ab]surf) is well below the plasma concentration. This means that the bulk antibody concentration in an in vitro spheroid experiment is not analogous to the plasma concentration but is actually well below it; large doses are required to overcome this poor extravasation. Knowing the rate of uptake in a tumor and clearance from the plasma and normal tissues also provides estimates of ratios between tumor and normal tissue concentrations, and these ratios are important in both imaging and therapy. These examples illustrate the utility of combining theoretical analysis also suggest ways to rationally improve uptake, and determining the limiting rates is the first step in overcoming these problems.”
Rudnick teaches on p. 155, Col. 2:
“Not strictly limited to tumor cells, target antigen is commonly expressed on normal tissue, found in circulation, and shed into the tumor interstitial space. These nontarget pools of antigens can reduce treatment effectiveness, increase systemic clearance, and increase side-effects (especially for radioimmunoconjugates) by impairing mAb specificity for the tumor.”
and on p. 158, Col. 2, last ¶ - p. 159, Col. 1:
“…antigen selection will be a critical factor for internalization and catabolism of mAbs. The relative rates of antigen recycling and dissociation are important in mAb penetration into tumors. Therefore, in applications dependent on targeting every cell of a tumor, the mAb needs to dissociate before it is internalized and degraded. In the case of ADCC, a slow internalizing antigen would be the best target. However, if one is trying to deliver a cytotoxic agent to the cytoplasm of cells in a limited region of a tumor, such as the vasculature, a mAb with slow dissociation targeting a rapidly recycling antigen would be appropriate. These are just simple examples of the interplay of affinity, avidity, and efficacy in tumor targeting.”
Huang supports and substantiates the challenges for recombinant antibodies as immunotherapeutic agents (p. 403 and 408):
“Genetic engineering has long been employed to increase the affinity of mAb to its target by altering the amino acid sequence in complementary determining region (CDR; Maynard and Georgiou 2000; Reff et al. 2002). However, high specificity must be maintained while increasing antibody affinity as it might augment cross reactivity with other nonspecific antigens, causing unwanted side effects (Hu et al. 2009). High-affinity CDR also can be suboptimal for targeting solid tumors; thus, a suitable affinity may need to be determined (Chames et al. 2009).”
“Many hurdles remain, however,due to the complexity of human immunology as demonstrated by our limited success in chronic infectious diseases and cancer. The approach to combine both active and passive immunotherapies to have synergic effects to maximize desired immune responses may lead a way for treatments of these diseases in the near future.”
Therefore, due to the unpredictability of immunotherapeutics in general and in view of the insufficient guidance and/or working examples concerning the use of the claimed trispecific antibodies as immunotherapeutic agents in vivo, one skilled in the art could reasonably conclude that the broadly claimed invention was not fully supported in the specification, and thereby removing applicants from full possession of the invention.
The rejection is maintained.
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 §§ 706.02(l)(1) - 706.02(l)(3) 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.
8. The rejection of Claims 21-24, 27-37 and 40-41 on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 10633440 is maintained. Applicants request to hold the rejection in abeyance is granted. The response is incomplete.
Conclusion
9. No claims are allowed.
10. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LYNN A. BRISTOL whose telephone number is (571)272-6883. The examiner can normally be reached Mon-Fri 9 AM-5 PM.
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/LYNN A BRISTOL/Primary Examiner, Art Unit 1643
