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 1-48 are the original claims filed 5/6/2024. In the preliminary response of 5/6/2024, claims 36-44 are amended, claims 1-35 and 45-48 are canceled, and new claims 49-55 are added. Claims 36-44 and 49-55 are the pending claims.
Priority
2. USAN 18/656,201, filed 05/06/2024, is a Divisional of 17/239,010, filed 04/23/2021, now U.S. Patent # 12049499, 17/239,010 Claims Priority from Provisional Application 63/015,385, filed 04/24/2020.
Information Disclosure Statement
3. As of 10/2/2026, a total of two (2) IDS are filed: 5/6/2024; and 3/7/2025. The corresponding initialed and dated 1449 form is considered and of record.
Objections
Specification
4. The disclosure is objected to because of the following informalities:
a) The use of the terms BIACore, Octet, FACSAria, EtraAvidin, Dynabeads, Dynamag-2, EZ-LINK, BiTE, KALBITOR, nanobody, DARPIN, Affibody, KALBITOR, NCBI, FACS, microbeads, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
b) The specification on p. 71 at [0249] states (from Kymriah's "Tisagenlecleucel" and Yescarta's "Axicabtagene ciloleucel") which is unclear and/or requires translated text. The references Kymriah and Yescarta are not cited in the IDS.
c) The specification teaches an antigen binding structure in [0086] and [0152] named “Feb.” There is no known antigen-binding fragment by that nomenclature.
d) Amend the specification to replace “binning” with “binding.”
Appropriate correction is required.
Claim Objections
5. Claims 36-44 and 49-55 are objected to because of the following informalities:
a) Claims 36-44 and 49-55 are objected for inconsistency in reciting “antigen-binding fragment thereof” or “fragment thereof”. The preferred limitation is “antigen-binding fragment thereof”.
b) Amend claim 54 to reduce verbosity to recite “wherein the comprises a linker sequence comprising any one of SEQ ID NOs: 36- 39.”
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
6. Claims 50-51 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
a) Claim 50 is indefinite and confusing for the species Fd’ fragment, Fd fragment and polypeptide-Fc fusion. In depending from claim 36, the CD19 antibody is required to comprise HCCDR1-3 and LCCDR1-3, whereas the species Fd’ fragment and Fd fragment do not comprise a LC variable region aspect. The Fd’ fragment comprises (VH)-(CH1)-(part of a hinge) while the Fd fragment comprises (VH)-(CH1). It is unclear how the antibody or fragment thereof relates to the polypeptide in the polypeptide-Fc fusion.
b) Claim 51 recites the limitation "a monoclonal antibody". There is insufficient antecedent basis for this limitation in the claim. None of the preceding claims 36 or 50 recite a monoclonal antibody.
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 (Prevention)
7. Claims 36-44 and 49-55 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.
Claims 36-44 and 49-55 are drawn to a method of preventing any cancer comprising administering an anti-CD19 antibody, or antigen-binding fragment thereof to a subject in need of treatment. The specification defines treatment as inhibiting a cancer and a therapeutic amount as preventing the cancer:
[0071] Therapeutically effective amount: As used herein, the term “therapeutically effective amount” refers to an amount of a therapeutic molecule (e.g., an anti-CD19 antibody described herein) which confers a therapeutic effect on a treated subject, at a reasonable benefit/risk ratio applicable to any medical treatment. Therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect). In particular, the “therapeutically effective amount” refers to an amount of a therapeutic molecule or composition effective to treat, ameliorate, or prevent a particular disease or condition, or to exhibit a detectable therapeutic or preventative effect, such as by ameliorating symptoms associated with the disease, preventing or delaying the onset of the disease, and/or also lessening the severity or frequency of symptoms of the disease. A therapeutically effective amount can be administered in a dosing regimen that may comprise multiple unit doses. For any particular therapeutic molecule, a therapeutically effective amount (and/or an appropriate unit dose within an effective dosing regimen) may vary, for example, depending on route of administration, on combination with other pharmaceutical agents. Also, the specific therapeutically effective amount (and/or unit dose) for any particular subject may depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific pharmaceutical agent employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and/or rate of excretion or metabolism of the specific therapeutic molecule employed; the duration of the treatment; and like factors as is well known in the medical arts.
[0072] Treatment: As used herein, the term “treatment” (also “treat” or “treating”) refers to any administration of a therapeutic molecule (e.g., an anti-CD19 antibody described herein) that partially or completely alleviates, ameliorates, relieves, inhibits, delays onset of, reduces severity of and/or reduces incidence of one or more symptoms or features of a particular disease, disorder, and/or condition. Such treatment may be of a subject who does not exhibit signs of the relevant disease, disorder and/or condition and/or of a subject who exhibits only early signs of the disease, disorder, and/or condition. Alternatively or additionally, such treatment may be of a subject who exhibits one or more established signs of the relevant disease, disorder and/or condition.
The Patent Act requires that patent applicants describe the invention in explicit terms to enable any person skilled in the art to make and use the invention. 35 U.S.C. 112. Applicants seek prophylactic endpoints for an anti-CD19 antibody therapy, in vivo, against any cancer irrespective of CD19 expression in the absence of intrinsic or extrinsic evidence that substantiates the enablement for the breadth and scope of the claimed invention at the time of filing. 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 (Therapeutic)
8. Claims 36-44 and 49-55 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 on-cell binding to Raji and NALM-6 cells using the anti-CD19 clones AB1, Ab2, Ab4-Ab8, and Ab15, does not reasonably provide enablement for therapeutic outcomes, in vivo, for any CD19+/- cancer in a subject using any one of the instant claimed anti-CD19 clones. 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.
Claims 36-44 and 49-55 are drawn to a method of treating any cancer comprising administering an anti-CD19 antibody, or antigen-binding fragment thereof to a subject in need of treatment. The cancer biomarkers are not identified nor is the CD19 correlated with the cancer. The antibodies in claim 36 comprise the VH/VL CDR1-3 for each of anto-CD19 clones, Ab1-Ab2, Ab4-Ab8, and Ab15.
Disclosure in the Specification
Example 2 with data shown in Figure 1 and Table 4 is the extent of experimentation performed and is limited to binding characteristics (flow cytometry) on Raji and NALM-6 cells lines.
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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 anti-CD19 antibody, 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).
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 the microscopic pharmacology as well: 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 time required for tumor cell kill; possible toxicities from normal tissue distribution; tumor size and vascularity; tumor interstitial pressure, convection and diffusion; and metabolism and internalization 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 antibodies as immunotherapeutic agents in vivo, 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
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 ANNE BRISTOL
Primary Examiner
Art Unit 1643
/LYNN A BRISTOL/Primary Examiner, Art Unit 1643
