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
Status of the Claims
1. Claims 1-28 are the original claims filed on 3/24/2022. In the Preliminary Amendment of 3/24/2022, Claims 3-9, 11, 13-15, 24-25, and 27 are amended, claims 2, 16-23, and 26 are cancelled, and new claim 29 is added. In the Response of 10/21/2025, Claims 1, 3-6, 14-15, and 24 are amended. In the Response After Final Action of 1/30/2026, Claims 1, 3-6, and 14-15 are amended.
Claims 1, 3-15, 24-25, and 27-29 are pending.
The finality of the rejection of the last Office action is withdrawn in view of new grounds for rejection.
Priority
2. USAN 17/763,582, filed 03/24/2022, is a National Stage entry of PCT/US2020/ 053064, International Filing Date: 09/28/2020, PCT/US2020/ 053064 Claims Priority from Provisional Application 62/907,275, filed 09/27/2019, PCT/US2020/053064 Claims Priority from Provisional Application 62/989,327, filed 03/13/2020.
Information Disclosure Statement
3. As of 2/9/2026, a total of two (2) IDS are filed: 7/13/2022; and 2/20/2024. The corresponding initialed and dated 1449 form is considered and of record.
Withdrawal of Rejection(s)
Claim Rejections - 35 USC § 112(a)
4. The rejection of Claims 1, 3-15, 24-25, and 27-29 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112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is withdrawn. The amended claims delete the variants associated with the proteins to which the VHH of elements (a)-(f) are shown to bind. The claims are clarified to identify the proteins to which the VHH bind as being human: human CD47, human PD-L1, human CD33, human LAG3 or human CD16.
New Grounds for Rejection
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.
Enablement
5. Claims 25 and 27-29 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Factors to be considered in determining whether undue experimentation is required, are summarized in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). They include the nature of the invention, the state of the prior art, the relative skill of those in the art, the amount of direction or guidance disclosed in the specification, the presence or absence of working examples, the predictability of the art, the breadth of the claims, the quantity of experimentation which would be required in order to practice the invention as claimed.
Claim interpretation
The method claims encompass preventing any disease in any patient in need thereof by administering the pharmaceutical composition of claim 24 that corresponds to a multispecific antibody of claim 3 comprising a first and a second antibody binding domain. The first binding domain is any one of elements (a)-(f) for the corresponding VHH domain, whilst the second antibody binding domain is unlimited in scope and with the proviso that its binding specificity is different from the first binding domain.
“treatment”/ “treating”: the specification is unequivocal in teaching the term encompasses both therapy and prophylaxis (prevention) as outcomes for a method
[0151] The disclosed antibodies are useful in medicine. The terms “treatment” “treating”, etc., refer to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder. Various embodiments may specifically include or exclude one or more of these modes of treatment.
[0153] Further, the term “treating” or “treatment” broadly includes any kind of treatment activity, including the diagnosis, mitigation, or prevention of disease, or aspect thereof, in man or other animals, or any activity that otherwise affects the structure or any function of the body of man or other animals.
Disclosure in the Specification
[0018] FIGS. 8 depicts inhibition of MC38-hPD-L1 tumor growth in B-hPD-L1 mice by the PD-L1-binding multi-specific molecule 1518 (SEQ ID NO:135).
[0022] FIG. 12 depicts a cell-based functional assay of the multi-specific molecules 1511 and 3321 in Jurkat NFAT CD16 reporter assay (ADCC assay) using IgG1 B6H12 and IgG4 B6H12 as controls.
Applicants specification does not nearly support or enable the use of the claimed multispecific antibody for use in the prevention of just any disease in any subject, in vivo.
Applicants seek over potentially millions of multispecific antibodies for not only any one VHH sequence selected from any one of elements (a)-(f) of claim 3 (reach through for claim 24) much less inclusive of the second antigen binding domain having unlimited specificity and structure than what the specification teaches how to make and use. Accordingly, the method to which those potentially millions of multispecific antibodies is drawn is not enabled for preventing just any disease.
The nature of the invention is such that the method of the instant claims must be able to prevent a tumor from forming in a patient, much like a vaccine. The art teaches that a vaccine must be prophylactic (Stedman's Medical dictionary, 2000, lines 1-3). The specification does not provide any teachings of the prophylaxis of any disease much less a cancer, how to determine the individuals who will develop a particular cancer, nor how to effectively prevent said particular cancer type before occurrence. Thus, one of skill in the art would not be able to use the method of the invention as a preventing vaccine without undertaking to determine how to select for individuals who will develop a particular cancer type before the said cancer occurs in the individual. An effective therapeutic protocol for the treatment or prevention of the formation of a tumor is subject to a number of factors, which enter the picture beyond simply the administration of the genus of multispecific antibodies of claim 3.
The Patent Act requires that patent applicant describes the invention in explicit terms to enable any person skilled in the art to make and use the invention. 35 U.S.C. 112. The enablement requirement is a crucial aspect of the patent “bargain”: an inventor is granted limited protection from competition in exchange for publicly disclosing their new technology. See the decision in Morse, Incandescent Lamp, and Holland Furniture, establishing the requirement that if a patent claims an entire class or genus of processes, machines, or compositions of matter, the specification must enable a person skilled in the field to make and use the entire class. If a patent claims an entire class of processes, machines, manufactures, or compositions of matter, the patent’s specification must enable a person skilled in the art to make and use the entire class. In other words, the specification must enable the full scope of the invention as defined by its claims. The more one claims, the more one must enable. See §112(a); see also Continental Paper Bag Co. v. Eastern Paper Bag Co., 210 U. S. 405 (1908) (“[T]he claims measure the invention.”)
Scope of Enablement
6. Claims 25 and 27-29 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for tumor cell inhibition using the multispecific antibody clones 3321, 1518 and 1511, does not reasonably provide enablement for treating any disease using any multispecific antibody to obtain a therapeutic endpoint. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required, are summarized in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). They include the nature of the invention, the state of the prior art, the relative skill of those in the art, the amount of direction or guidance disclosed in the specification, the presence or absence of working examples, the predictability of the art, the breadth of the claims, the quantity of experimentation which would be required in order to practice the invention as claimed.
Claim interpretation
The method claims encompass treating (therapeutic) any disease in any patient in need thereof by administering the pharmaceutical composition of claim 24 that corresponds to a multispecific antibody of claim 3 comprising a first and a second antibody binding domain. The first binding domain is any one of elements (a)-(f) for the corresponding VHH domain, whilst the second antibody binding domain is unlimited in scope and with the proviso that its binding specificity is different from the first binding domain.
Disclosure in the Specification
[0015] FIG. 5 depicts anti-tumor activity of the CD47-binding multi-specific molecule 3321 in Raja-Luc xenografted mice.
[0018] FIGS. 8 depicts inhibition of MC38-hPD-L1 tumor growth in B-hPD-L1 mice by the PD-L1-binding multi-specific molecule 1518 (SEQ ID NO:135).
[0022] FIG. 12 depicts a cell-based functional assay of the multi-specific molecules 1511 and 3321 in Jurkat NFAT CD16 reporter assay (ADCC assay) using IgG1 B6H12 and IgG4 B6H12 as controls. The multispecificity for the antibodies 1511 (SEQ ID NO:156) and 3321 (SEQ ID NO:157) have binding specificity for CD47.
While being enabling for tumor cell inhibition using the multispecific antibody clones 3321, 1518 and 1511, the specification does not reasonably provide enablement for treating any disease using any multispecific antibody to obtain a therapeutic endpoint.
The scope of the claims must bear a reasonable correlation with the scope of enablement. See In re Fisher, 166 USPQ 19 24 (CCPA 1970). Without such guidance, the amount of in vitro and in vivo animal model testing for any given mutlispecific antibody much less the breadth and scope of multispecific antibodies, is unpredictable and the experimentation left to those skilled in the art is unnecessarily and improperly extensive and undue. See Amgen, Inc. v. Chugai Pharmaceutical Co. Ltd., 927 F,2d 1200, 18 USPQ 1016 (Fed. Cir. 1991) at 18 USPQ 1026 1027 and Ex parte Forman, 230 USPQ 546 (BPAI 1986).
A tumor is a 3-dimensional complex consisting of interacting malignant and non-malignant cells. Vascularisation, perfusion and drug access to the tumor cells are not evenly distributed and this is an important source of heterogeneity in tumor response to drugs. Therefore, prediction of drug effects in an animal subject based solely on in vitro cell based assays or limited in vivo assays is not reliable and further evaluation in animal tumor systems is essential.
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 multispecific antibodies as immunotherapeutic agents, in vivo, for the treatment of any disease, one skilled in the art would reasonably conclude that the broadly claimed invention was not fully supported in the specification, and thereby removing applicants from full possession of the invention.
Conclusion
7. Claims 1, 3-15 and 24 are allowed.
8. 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