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 1-14 are the original claims filed 9/25/2023. In the preliminary amendment of 9/25/2023, claims 8-11 and 13-14 are amended. In the Response of 7/12/2026, claims 1-4, 6, 8, 10-11 and 13-14 are amended, claim 9 is canceled and new claims 15-20 are added.
Claims 1-8 and 10-20 are the pending claims.
Applicants amendment of the claims raises new grounds for objection and rejection. The Office Action is final.
Priority
2. USAN 18/552,407, filed 09/25/2023, is a National Stage entry of PCT/CN2021/ 106917, International Filing Date: 07/16/2021, and claims foreign priority to CN 202110202193.9, filed 02/24/2021, and claims foreign priority to CN 202110292998.7, filed 03/18/2021.
Information Disclosure Statement
3. As of 8/28/2026, three (3) IDS are filed: 9/25/2023; 10/25/2023; and 11/5/2023. The corresponding initialed and dated 1449 form is considered and of record.
Withdrawal of Objections
Specification
4. The objection to the abstract of the disclosure is withdrawn in view of the deletion of the term “new”.
5. The objection to the disclosure because of informalities is withdrawn.
a) The specification is amended to rectify the improper use of the term Sepharose, Biacore, NSG, celltiter-Glo, which is a trade name or a mark used in commerce.
Claim Objections
6. The objection to Claims 1-14 because of informalities is moot for canceled claim 9 and withdrawn for the pending claims.
a) Claims 1-8 and 10-14 are amended to replace SEQ ID NO: 19 with “RAN.”
b) Claim 1 and dependent claims 2, 4-5, 8, 10-14 are amended to recite:
An anti-human CD73 antibody, wherein the antibody comprises a light chain and a heavy chain, [and] wherein the light chain variable region of the light chain comprises the following three light chain CDRs: VL-CDR1 as shown in SEQ ID NO.: 18, VL-CDR2 as shown in SEQ ID NO.: 19, and VL-CDR3 as shown in SEQ ID NO.:20, 28, 29, 30, 31, 32 or 33; and wherein[,] the heavy chain variable region of the heavy chain comprises the following three heavy chain CDRs: VH-CDR1 as shown in SEQ ID NO.: 15 or 21, VH-CDR2 as shown in SEQ ID NO.: 16, and VH-CDR3 as shown in SEQ ID NO.: 17, 22, 23, 24, 25, 26 or 27.
c) Claim 2 is amended to recite “the light chain [CDR] CDRs” and “the heavy chain [CDR] CDRs.” d) Claim 3 is amended to recite to recite “wherein[,] the light chain” and “and wherein the heavy chain.”
e) Claim 4(b) is amended to delete to recite entirety of the “wherein” clause comprising the term “comprises[:]”.
f) Claim 6 is amended to recite “the light chain variable region” and “and wherein the heavy chain.”
g) Claim 8(b) is amended to recite “[and] wherein the coupling moiety.”
h) Claim 10(i) is amended to recite “(i) an active ingredient
i) Claim 11 is amended to recite (1) the antibody of claim 1; [or] (2) a recombinant protein of the antibody; and (3) a CAR construct of the antibody.
j) Claim 13 is amended to recite “[of] encoding the antibody.”
k) Claim 14 is amended to insert “and” between elements (1) and (2).
Withdrawal of Rejections
Claim Rejections - 35 USC § 112(b)
7. Claims 3-4 and 6-13 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) Claim 3 is amended to recite anti- human CD73 antibody.
b) Claim 4 is amended to recite the preparation is in contained form.
c) Claims 6-7 are amended to recite " scfv" in claim 6.
d) Claim 8 is amended to recite " a recombinant protein of the antibody".
e) claim 8(b) is amended to recite the broad recitation “drug”, and to delete “a toxin, a cytokine, a radionuclide, an enzyme”, which is the narrower statement of the range/limitation.
f) Claim 9 is canceled.
g) Claim 10 is amended to recite "a recombinant protein of the antibody, or a CAR construct of the antibody, a immune cell expressing the antibody, an antibody drug conjugate of the antibody, and a combination thereof.”
h) Claims 11-13 are amended to recite "(2) a CAR construct of the antibody" in claim 11.
i) Claim 13 is amended to recite "a polynucleotide".
Claim Rejections - 35 USC § 112(d)
8. The rejection of Claims 3, 6-7, 9, and 14 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent is moot for canceled claim 9 and withdrawn for the pending claims.
a) Claim 3 is amended to recite anti-human CD73 antibody.
b) Claims 6-7 are amended to recite anti-human CD73 antibody.
c) Claim 9 is canceled.
d) Claim 14 is amended to recite human CD73 protein.
Claim Rejections - 35 USC § 101
9. The rejection of Claim 9 under 35 U.S.C. 101 is moot for the canceled claim.
New Grounds for Objection
Claim Objections
10. Claims 15-16 and 19 are objected to because of the following informalities:
a) Amend claim 15 to recite “[[An]] The antibody drug conjugate of claim 8”.
b) Amend claim 16 to correct improper construction, for example,
“A method for treating a CD73-related diseasecomprising administering to a subject in need thereof, the antibody of claim 1, a drug conjugate of the antibody, or a CAR-T cell expressing the antibody, or a combination thereof
c) Claim 19 is objected to for reciting SEQ ID NO: 19 instead of “RAN.” Patent rules under 37 CFR 1.821 (and MPEP § 2422.01) apply to unbranched sequences of 4 or more specifically defined amino acids (or 10 or more nucleotides). Sequences with fewer than 4 amino acids are excluded from sequence listing requirements.
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d) Claim 19 is objected to for the designation of the elements as (Z1)-(Z8) that is unclear if the nomenclature refers to a laboratory name or is a typographical error intended to be (1)-(8). Note the distinction for new claim 20.
Appropriate correction is required.
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.
Scope of Enablement
11. Claim 16 is 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 the use of the CQ137, 137-2 and 137-3 anti-CD73 antibody clones in a therapeutic method for treating ovarian cancer or a melanoma associated with CD73 expression, does not reasonably provide enablement for preventing or treating just any CD73-related or expressing disease much less with the use of any combination of VH-CDR1-3 and VLCDR1-3 of instant claim 1. 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
Claim 16 drawn to a method of treating any CD73-related disease comprising administering to a subject I need thereof, the antibody of claim 1, a drug conjugate of the antibody, or a CAR-T cell expressing the antibody, or a combination thereof.
“CD73-relate disease”: the specification provides no generic definition for the meaning of the phrase. The specification refers to cancers or tumors associated with CD73-relate diseases at [0116]. Original claim 9 was drawn to “preventing and/or treating cancers or tumors associated with CD73-related diseases.”
“treatment”/ “treating”: the specification is unequivocal in teaching the meaning of the term to encompass both therapeutic and prophylactic outcomes at
[0170] “Treatment”, when applied to a human, animal, or research subject, refers to therapeutic, prophylactic or prophylactic measures, studies and diagnostics; and it comprises contact of an anti-CD73 antibody with a human or animal, subject, cell, tissue, physiological compartment, or physiological fluid.
The POSA could conclude that the claimed method includes any disease expressing CD73 administering any one of the anti-CD73 antibodies of claim 1 for therapy and prophylaxis.
Disclosure in the specification
The prototype antibody, CQ137, comprising SEQ ID NOs: 1, 2, 3 and 4 is used in the bioassays for those data showing in vitro and in vivo utility.
Example 3 CQ 137-Mediated CD73 Enzyme Activity Inhibition Detection
[0267] In this embodiment, CQ137 is mainly shown to inhibit CD73 protein and cell enzyme activity. Specifically, (1) CD73 Protease Activity Inhibition
[0268] The CD73 protein was diluted to a working concentration of 5 μg/mL, a CD73 antibody diluted with a triple gradient (0.001-10 μg/mL) was added, incubation was performed at 37° C. for 15 min, a mixed solution of 1 nM ATP and AMP was added, incubation was performed at 37° C. for 30 min, a CellTiter-GLo detection reagent (purchased from promega) was added in equal volumes, a self-luminescence value was read by an ELISA instrument, and the enzyme activity was calculated as 100% without the addition of antibody, and the change in rhCD73 activity was obtained, see FIG. 5.
[0269] The results show that CQ137 is superior to the control molecule MEDI-9447 in inhibiting the CD73 protease activity.
(2) Inhibition of CD73 Enzyme Activity on Human SK-OV-3 Cells 5×10.sup.4 SK-OV-3 cells were taken, triple gradient (0.009-20 μg/mL) dilution of antibody was added, incubated at 37° C. for 15 min, 1 nM AMP was added at 37° C. for 2 h, 1 nM ATP was added, and a CellTiter-GLo detection reagent was added immediately, a self-luminescence value was read by an ELISA instrument, and the enzyme activity was calculated as 100% without the addition of antibody, and the change in rhCD73 activity was obtained, see FIG. 6.
[0270] The results show that CQ137 can inhibit the CD73 enzyme activity on SK-OV-3 cells, and IC50 of CQ137 is 0.3708 μg/mL.
The POSA could conclude that CQ137 is capable of inhibiting CD73 enzyme activity in an ovarian cancer cell line, SK-OV-3.
Example 6 Inhibition Evaluation of CQ137 Humanized Enzyme Activity
[0291] In this embodiment, the humanized 137 antibody is mainly shown to inhibit CD73 protein and cell enzyme activity.
(2) Inhibition of CD73 Enzyme Activity on Human SK-OV-3 Cells
[0294] 5×10.sup.4 SK-OV-3 cells were taken, a gradient diluted humanized CD73 antibodies (137-1, 137-2, 137-3, 137-4, 137-5, 137-6, 137-7, 137-8, 137-9) were added, incubated at 37° C. for 15 min, 1 nM AMP was added at 37° ° C. for 2 h, 1 nM ATP was added, and a CellTiter-GLo detection reagent was added immediately, a self-luminescence value was read by an ELISA instrument, and the enzyme activity was calculated as 1 without the addition of antibody, and the change in rhCD73 activity was obtained, see FIG. 12 and FIG. 20.
[0295] The results show that the 9 humanized 137 antibodies can inhibit CD73 protein and CD73 enzyme activity on cell.
Example 7 Humanized 137 Antibody-Mediated Cell Internalization
[0296] 3×10.sup.5 SK-OV-3 cells were taken and incubated with 0.2 μg CD73 antibody at 37° C. The cells were incubated for 0, 1, 2, 3 hours and overnight. After incubation, an equal amount of corresponding humanized CD73 antibodies (137-1,137-2, 137-3, 137-4, 137-5, 137-6, 137-7, 137-8, 137-9) were added, after incubation for 1 h, Anti-Hfc-APC flow antibody was added, and detected by flow cytometer after incubation and elution. The relative fluorescence intensity (MFI) at 0 h is 1, and the calculated results are shown in FIG. 13 and FIG. 21.
[0297] Experimental results show that the 9 humanized antibodies of the present invention may also induce tumor cell internalization of CD73.
Example 8 Humanized 137 Antibodies Inhibit Proliferation of Human Melanoma Cells A375 in Mice
[0298] Mouse model NSG-A375 of human melanoma cells (A375) was constructed by NSG mice, and inoculated human PBMC laboratory mice and non-inoculated human PBMC control mice were prepared, administered every other day, and tumor volume was measured. Experimental mice were set with solvent PBS administration blank control, MEDI-9447 low dose (low dose is 0.5 mpk) administration, 137-2 high dose (3 mpk) and low dose, 137-3 high, medium and low doses (medium dose is 1 mpk), and experimental results were shown in FIG. 14. The mpk (Milligrams Per Kilocalms) is mg/kg.
[0299] The results show that the anti-tumor effects of 137-2 and 137-3 at low doses are all significantly higher than that of MEDI-9447.
The POSA could conclude that the anti-CD73 clones, 137-2 and 137-3, are effective in a therapeutic role in the treatment of melanoma, in vivo.
The POSA could conclude that NO examples of a CQ137 or CQ137 humanized antibody are shown to be prophylactic for any CD73 related disease.
The POSA could conclude that the entirety of the application does not enable the full breadth and scope of instant claim 16.
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 invention was not fully supported in the specification, and thereby removing applicants from full possession of the invention.
Conclusion
12. Claims 1-8,10-14,17-18 and 20 are allowed.
13. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
14. 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
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