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 1-30 are the original claims filed 4/30/2024. In the preliminary amendment of 11/26/2024, Claims 1, 5-8, 12-13, 17-18, 21-23, 25-28, and 30 are amended and Claims 2-4, 9-11, 14-16, and 19-20 are canceled.
Claims 1, 5-8, 12-13, 17-18, and 21-30 are pending and under examination.
Priority
2. USAN 18706263, filed 04/30/2024, is a National Stage entry of PCT/CN2022/ 127036, International Filing Date: 10/24/2022, claims foreign priority to PCT/CN2021/ 128208, filed 11/02/2021. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
3. As of 9/28/2026, a total of two (2) IDS are filed: 4/30/2024 and 9/16/2025. The corresponding initialed and dated 1449 form is considered and of record.
Objections
Specification
4. The abstract of the disclosure is objected to because the use of the term duobody, which is a trade name or a mark used in commerce, has been noted in this abstract. 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.
A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
5. The disclosure is objected to because of the following informalities:
a) The use of the term ATCC, Swiss Prot, Biacore, Matrigel, duobody, WAVEchip, CellTrace, Phosflow, and Expi293, 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 disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. See pp. 50 and 52. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Appropriate correction is required.
Claim Objections
6. Claims 1, 5-8, 12-13, 17-18 and 21-30 are objected to because of the following informalities:
a) Amend Claims 1, 5-8, 12-13, 17-18 and 21-30 for proper consistency to recite “antigen binding fragment thereof” to comport with Claim 1.
b) Amend claim 22(v) to recite “[[;]];”.
c) Amend claim 25 to recite “[[A]] An isolated host cell.”
d) Amend claims 28-30 to recite in claim 28 “[the] a function[s] of effector T cells and/or NK cells" and “[the] an immune response[s]".
e) Amend claim 28 to recite “downregulated.”
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.
7. Claims 1, 5-8, 12-13, 17-18, and 21-30 are 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) Claims 1, 5-8, 12-13, 17-18, and 21-30 are indefinite for reciting “optional” language under MPEP 2173.05(h)(II). The instance where the list of potential alternatives varies and ambiguity arises occurs in:
Claim 1 for the list of alternatives starting with the “wherein” clause “the antibody is a chimeric” to the final “optionally wherein” clause and dependent claim 18 that incorporates the subject matter of claim 1; and
Claim 8 for the list of alternatives starting with “optionally, the VH domain” to the final “optionally, wherein” clause.
b) A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
In the present instance, claim 5 recites the broad recitation ”an Fc region”, and the claim also recites “an Fc region having an amino acid sequence of SEQ ID NO: 70” which is the narrower statement of the range/limitation.
In the present instance, claim 8 recites the broad recitation ”an Fc region”, and the claim also recites “an Fc region having an amino acid sequence of SEQ ID NO: 70” which is the narrower statement of the range/limitation.
The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
c) Claim 21 recites the limitation "the first polypeptide chain", “the second polypeptide chain” and “the third polypeptide chain”. There is insufficient antecedent basis for this limitation in the claim. None of the preceding claims from which claim 21 depends recite an antecedent basis for a polypeptide chain much less a first, second or third.
d) Claim 22(iv) contains the trademark/trade names “WAVEsystem” and “Biacore.” Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name.
e) Regarding claim 22(vii), the phrase "for example" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
f) Clam 22(i), (ii) and (iv) is indefinite for the term “about”. The specification does not provide a definition for the term. The term "about" is treated as a term of degree or approximation, and it is indefinite because it does not provide reasonable certainty regarding the scope of the invention. See MPEP § 2173.05(b).
g) Claim 26 is indefinite for the phrase under “conditions that allow the production of the bispecific binding protein.” The term “allow” implies that some undefined structure or condition is what predicates whether production does or does not occur. Allowability or allowing the activity suggests that production may sometimes occur but not always, and what determines the degree or amount of production is not definite using the term.
h) A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
In the present instance, claim 30 recites the broad recitation “cancer”, and the claim also recites “melanoma, metastatic melanoma, renal cell carcinoma, ovarian cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, brain cancer, head and neck cancer, breast cancer, colon cancer, colorectal cancer, cervical carcinoma, hepatocellular carcinoma, prostate cancer, or bladder cancer”, which is the narrower statement of the range/limitation.
The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
i) Claim 26 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential elements, such omission amounting to a gap between the elements. See MPEP § 2172.01. The omitted elements are: the host cell comprising a nucleic acid molecule encoding the bispecific antibody of claim 18.
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)
8. Claims 28-31 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 28-30 are drawn to the prevention of any disease where a function of a T or NK cell is impaired and an immune response is downregulated in a subject in need thereof by administering a therapeutic effective amount of the bispecific antibody of claim 18.
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 a method encompassing the prevention of myriad diseases conditioned on their being associated with impaired T-/NK-cell function and downregulation of an immune response in a subject. The method of prevention is a concept and not substantiated by any intrinsic or extrinsic evidence showing the method endpoint for the preventative application. 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 (Treatment)
9. Claims 28-30 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 treating melanoma and NSCLC cancer, in vivo, with FIT2019-86b and FIT2019-86b-51, respectively, does not reasonably provide enablement for treating any disease associated with impaired T-/NK-cell effector function and reduced immune response in any subject with any anti-CD122 x anti-CD132 bispecific antibody of claim 18. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and 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 28-30 are drawn to the treatment of any disease where a function of a T or NK cell is impaired and an immune response is downregulated in a subject in need thereof by administering a therapeutic effective amount of the bispecific antibody of claim 18.
Disclosure in the Specification
The extent of disclosure is limited to two clones tested in two different solid cancers in an animal model correlate for the same diseases.
[0019] FIG. 9 shows the tumor growth curve of a melanoma/PBMC co-implantation model in immune compromised M-NSG mice treated with FIT2019-86b (inverted triangle) and vehicle control (filled circle).
[0020] FIG. 10 shows the body weight change of a melanoma/PBMC co-implantation model in immune compromised M-NSG mice treated with FIT2019-86b (inverted triangle) and vehicle control (filled circle).
[0021] FIG. 11 shows the tumor growth curve of a melanoma/PBMC co-implantation model in immune compromised NCG mice treated with huFIT2019-86b-51 in four dosages of 1 mg/kg, 0.3 mg/kg, 0.1 mg/kg and 0.03 mg/kg, and vehicle control.
[0022] FIG. 12 shows the body weight change of a melanoma/PBMC co-implantation model in immune compromised NCG mice treated with huFIT2019-86b-51 in four dosages of 1 mg/kg, 0.3 mg/kg, 0.1 mg/kg and 0.03 mg/kg, and vehicle control.
[0023] FIG. 13 shows the tumor growth curve of a NSCLC cell/PBMC co-implantation model in immune compromised NCG mice treated with huFIT2019-86b-51 in two dosages of 1 mg/kg and 0.3 mg/kg, and vehicle control.
[0024] FIG. 14 shows the body weight change of a NSCLC cell/PBMC co-implantation model in immune compromised NCG mice treated with huFIT2019-86b-51 in two dosages of 1 mg/kg and 0.3 mg/kg, and vehicle control.
[0025] FIG. 15 shows the body weight change of mice treated with FIT2019-86b (inverted triangle), IL-2 (square) and vehicle control (circle).
[0026] FIG. 16 shows ratio of CD8+ vs. CD4+ T cells in PBMC on day 1 (solid), day 4 (open) and day 7 (horizontal striped) after injection of FIT2019-86b, IL-2 or PBS control. Each group of bars represents data from individual mouse, and all data were normalized to the respective ratio on day 1 of the same mouse.
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 much less the combination of 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).
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 antibodies as immunotherapeutic agents in vivo, one skilled in the art would reasonably conclude that the broadly claimed method invention was not fully supported in the specification, and thereby removing applicants from full possession of the invention.
Conclusion
10. No claims are allowed.
11. 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
