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 1-42 are the original claims filed 4/24/2024. In the preliminary amendment of 7/1/2024, claims 1-42 are canceled and new claims 43-62 are added. Claims 43-62 are the pending claims.
Priority
2. USAN 18/644,825 filed 04/24/2024, is a Divisional of 17/141,406, filed 01/05/2021, now U.S. Patent # 11999790, 17/141,406 is a Divisional of 16/882,096, filed 05/22/2020, now U.S. Patent # 10934365, 16/882,096 is a Continuation of PCT/CN2017/11283, filed 11/24/2017.
Information Disclosure Statement
3. As of 9/16/2026, there is one IDS on file: 4/24/2024. The corresponding initialed and dated 1449 form is considered and entered.
Objections
Drawings
4. The drawing sheets for Figures 19-24 are objected to because of the use of the term Keytruda, which is a trade name or a mark used in commerce. 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.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
5. The abstract of the disclosure is objected to because it is less than 50 words. 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).
6. The disclosure is objected to because of the following informalities:
a) The use of the term Thalomid, Affinipure, 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.
Appropriate correction is required.
7. The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed. Amend the title to recite “Anti-human OX40 Antibodies and Uses Thereof” to comport with the abstract.
Claim Objections
8. Claims 43-62 are objected to because of the following informalities:
a) Claims 43-62 are drawn to the antibodies binding any OX40 protein. The specification does not support anything more than the claimed antibodies binding human OX40 protein:
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b) Amend claim 43 to recite “human TNF Receptor Superfamily Member 4(human OX40)”.
c) Amend claims 51 and 57 to recite “human OX40”.
Appropriate correction is required.
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
9. Claims 43-62 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, killing and reducing tumor growth of OX40-expressing colon cancer using 3 mg/kg for any one of the clones, 07-9H3, 07-9A4, 11-5C1, and 17-5D10, does not reasonably provide enablement for treating, killing and reducing tumor growth of any cancer much less any OX40-expressing cancer using any concentration of any one of the clones, 07-9H3, 07-9A4, 11-5C1, and 17-5D10. 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
Claims 43-50 are drawn to treating any cancer in a subject having the cancer with an anti-human OX40 antibody comprising the VH/VL CDR1-3 from the antibody clones, 9H3, 9A4, 5C1 or 5D10, irrespective of the cancer expressing OX40.
Claims 51-56 are drawn to decreasing the rate of growth for any tumor, comprising contacting the tumor cell with an anti-human OX40 antibody comprising the VH/VL CDR1-3 from the antibody clones, 9H3, 9A4, 5C1 or 5D10, irrespective of the tumor cell expressing OX40.
Claims 57-62 are drawn to killing any tumor cell comprising contacting the tumor cell with an anti-human OX40 antibody comprising the VH/VL CDR1-3 from the antibody clones, 9H3, 9A4, 5C1 or 5D10, irrespective of the tumor cell expressing OX40.
The treatment, decreasing and killing effects for the VH/VL CDR1-3 from the antibody clones, 9H3, 9A4, 5C1 or 5D10, encompasses any cancer/tumor so long as the amount of the antibody is effective.
“effective amount”:
[0220] As used herein, by an “effective amount” is meant an amount or dosage sufficient to effect beneficial or desired results including halting, slowing, retarding, or inhibiting progression of a disease, e.g., a cancer. An effective amount will vary depending upon, e.g., an age and a body weight of a subject to which the antibody, antigen binding fragment, antibody-encoding polynucleotide, vector comprising the polynucleotide, and/or compositions thereof is to be administered, a severity of symptoms and a route of administration, and thus administration can be determined on an individual basis.
[0221] An effective amount can be administered in one or more administrations. By way of example, an effective amount of an antibody or an antigen binding fragment is an amount sufficient to ameliorate, stop, stabilize, reverse, inhibit, slow and/or delay progression of a cancer in a patient or is an amount sufficient to ameliorate, stop, stabilize, reverse, slow and/or delay proliferation of a cell (e.g., a biopsied cell, any of the cancer cells described herein, or cell line (e.g., a cancer cell line)) in vitro. As is understood in the art, an effective amount of an antibody or antigen binding fragment may vary, depending on, inter alia, patient history as well as other factors such as the type (and/or dosage) of antibody used.
[0223] A typical daily dosage of an effective amount of an antibody is 0.01 mg/kg to 100 mg/kg. In some embodiments, the dosage can be less than 100 mg/kg, 10 mg/kg, 9 mg/kg, 8 mg/kg, 7 mg/kg, 6 mg/kg, 5 mg/kg, 4 mg/kg, 3 mg/kg, 2 mg/kg, 1 mg/kg, 0.5 mg/kg, or 0.1 mg/kg. In some embodiments, the dosage can be greater than 10 mg/kg, 9 mg/kg, 8 mg/kg, 7 mg/kg, 6 mg/kg, 5 mg/kg, 4 mg/kg, 3 mg/kg, 2 mg/kg, 1 mg/kg, 0.5 mg/kg, 0.1 mg/kg, 0.05 mg/kg, or 0.01 mg/kg. In some embodiments, the dosage is about 10 mg/kg, 9 mg/kg, 8 mg/kg, 7 mg/kg, 6 mg/kg, 5 mg/kg, 4 mg/kg, 3 mg/kg, 2 mg/kg, 1 mg/kg, 0.9 mg/kg, 0.8 mg/kg, 0.7 mg/kg, 0.6 mg/kg, 0.5 mg/kg, 0.4 mg/kg, 0.3 mg/kg, 0.2 mg/kg, or 0.1 mg/kg.
The instant specification defines therapeutically “effective amounts" for the anti- human OX40 clones in treating, killing or reducing cancers, in vitro or in vivo. However, the scope of the instant claimed cancers and the amount of the antagonist effective anti-human OX40 antibodies to achieve those results are not commensurate in scope with the instant claimed methods. (See In Alza Corp. v. Andrx Pharmaceuticals LLC, where the court held that claims construed to cover both osmotic and non-osmotic dosages were invalid for lack of enablement.[25] In this case, the court found that "the quantity of experimentation, lack of guidance in the specification, absence of working embodiments, and breadth of the claims demonstrates that. ... [the] patent specification fails to enable a person of ordinary skill to make and use nonosmotic oral dosage.).
Disclosure in the Specification
Example 8 in vivo testing of anti-hOX40 antibodies. [0291] The anti-hOX40 antibodies were tested to demonstrate their effect on tumor growth in vivo in a model of colon carcinoma, MC-38 cancer tumor cells (OX40-expressing colon adenocarcinoma cell). In Vivo Results for Mouse Anti-hOX40 Antibodies 07-9H3, 07-9A4, 11-5C1, 17-5D10, 08-6A11, and 14-7F11 [0296] Mouse anti-hOX40 antibodies 07-9H3, 07-9A4, 11-5C1, 17-5D10, 08-6A11, and 14-7F11 were administered to B-hOX40 humanized mice (OX40 humanized mice). The weight of the mice was monitored during the entire treatment period. The weight of mice in different groups all increased (FIG. 7, and FIG. 8). No significant difference in weight was observed between the control group and the anti-hOX40 treatment groups. The results showed that anti-hOX40 antibodies were well tolerated and not toxic to the mice.
[0297] The tumor size, however, showed significant difference in groups treated with antibodies 07-9H3, 07-9A4, 11-5C1, and 17-5D10. (FIG. 9).
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[0299] The result shows that 5C1 had the best TGI %. 6A11 and 7F11 were not effective in inhibiting tumor growth.
Example 9. In Vivo Testing of Humanized Anti-hOX40 Antibodies. [0305] The humanized anti-hOX40 antibodies were tested in OX40 humanized mice to demonstrate their effect on tumor growth in vivo. [0306] MC-38 cancer tumor cells (colon adenocarcinoma cell) were injected subcutaneously in B-hOX40 humanized mice. When the tumors in the mice reached a volume of 150 ± 50 mm3, the mice were randomly placed into different groups based on the volume of the tumor (8 mice in each group). [0307] The mice were then injected with human IgG (control) and anti-hOX40 antibodies by intraperitoneal injection at either 3 mg/kg or 1 mg/kg. The antibody was given on the first day and the fourth day of each week for 3 weeks (6 injections in total).
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[0311] The results above show that all anti-hOX40 antibodies can inhibit tumor growth. Among them, 9H3-H3K3-IgG1 (3 mg/kg) had the highest tumor growth inhibition percentage.
Notably, the humanized clone, 9H3, is the only instant claimed clone tested in the assays for OX40-expressing cancer tumor.
Example 10. Combination Therapy with Keytruda® (Pembrolizumab). [0317] To evaluate the efficacy of combination therapy, anti-hOX40 antibodies were administered to mice with some other therapeutic agents. In Vivo Results for 9H3 and Keytruda® for MC-38 Cancer Tumor Cells in Humanized Mice. [0318] MC-38 cancer tumor cells were injected subcutaneously in B-hOX40 humanized mice. When the tumors in the mice reached a volume of 150±50 mm3, the mice were randomly placed into different groups based on the volume of the tumor (6 mice in each group). The mice were then injected with (G1) PS (control), (G2) Keytruda® (0.3 mg/kg) (Merck), (G3) 9H3 (3 mg/kg), and (G4) Keytruda® (0.3 mg/kg) and 9H3 (3 mg/kg) by intraperitoneal injection. The antibody was given on the first day and the fourth day of each week for 3 weeks (6 injections in total). [0319] The weight of the mice was monitored during the entire treatment period. The weight of mice in different groups all increased (FIG. 19, and FIG. 20). No significant difference in weight was observed between the control group and the anti-hOX40 treatment groups. The results showed that these antibodies were well tolerated and not toxic to the mice.
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[0321] The result shows that 9H3 in combination with Keytruda® can improve tumor growth inhibition effects.
The specification does not support or enable the treatment, killing and/or growth reduction for just any cancer/tumor for any one of the VH/VL CDR1-3 from the anti-hOX40 clones defined in the claims.
The specification does not support or enable the treatment, killing and/or growth reduction for just any OX40-expressing cancer/tumor using just any VH/VL CDR1-3 from the instant claimed clones at just any effective amount.
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). "[T]o be enabling, the specification of a patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation.'" Genentech, Inc. v. Novo Nordisk, A/S, 108 F.3d 1361, 1365 (Fed. Cir. 1997) (quoting In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993)). 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).
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 in combination with the second agents, 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
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
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