DETAILED ACTION
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 .
Applicant’s election without traverse of group II and the species cancer, sarcoma, PD1, IL-17B, pembrolizumab, and an antibody directed against IL-17B in the reply filed on 1/20/26 is acknowledged.
The claims have been examined to the extent to which they read upon the above elections.
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.
Claim 19 recites the limitation "inhibitor of IL-17B or a receptor therof" in 3. There is insufficient antecedent basis for this limitation in the claim because claim 3 does not recite “inhibitor of IL-17B” and does not recite a receptor thereof.
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.
Claims 3-6, 9, 10, 15, 19, and 22 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 a method of inhibiting PD1 and IL-17B and to a method of treating fibrosarcoma, does not reasonably provide enablement for a method of treating any cancer via delivery of any anti-PD1 antibody and any IL-17B antibody. 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/or use the invention commensurate in scope with these claims.
Factors to be considered in a determination of lack of enablement include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)
The instant claims are directed to a method of treating any cancer via delivery of any PD1 antibody and any IL-17B antibody.
However, the specification does not draw an adequate nexus between inhibition of PD1 and inhibition of IL-17B and the predictable outcome of treating any possible cancer, which encompasses an enormous genus of cancers that have not been shown to be reliant upon PD1 or IL-17B alone.
The specification demonstrates i.p. injection of anti-PD1 antibody in IL-17B knockout mice in a MCA205 fibrosarcoma model with a significant tumor growth delay (Example 1); and treatment of mice subcutaneously grafted with MCA205 cells with anti-IL-17B antibody and anti-PD1 antibody with a significant increase to the response to anti-PD1 therapy alone (Example 3); and i.p. injection of anti-PD1 antibody in IL-17B knockout mice in a B16K1 melanoma model with a significant tumor growth delay (Example 4).
Treatment of fibrosarcoma with a combination of anti-IL-17B antibody and anti-PD1 antibody is not commensurate in scope with the treatment of any possible cancer. The knockout model of IL-17B is not commensurate in scope with any level of inhibition via delivery of any IL-7B antibody. Genetic knockout removes IL-17B expression entire4ly, which is not the same as antibody blockade.
For example, Bonnefoy et al. (WO 2020/201442 A1) demonstrate that the combination of an anti-PD1 antibody and an anti-IL-17B antibody did not eradicate tumors in all treated animals in the tumor model selected (Example 3). Mice bearing MCA205 fibrosarcoma were treated with the combination of antibodies and resulted in only 1 complete regression out of 10 animals, plus one additional long-term near-complete response. Therefore, about 80% of the animals did not have a complete or near-complete response, demonstrating that the combination is not universally effective even in the one fibrosarcoma model.
Bonnefoy et al. teach that the addition of the IL-17B antibody did not significantly affect MCA205 tumor growth, but increased response to anti-PD1 antibody in 2 out of 10 treated (Figure 3B, page 24).
Additionally, Qian et al. (Cytokine, 89, 2017, 34-44) teach that the effect of IL-17 is substantially dependent upon cancer type and microenvironment.
The art does not support that combined inhibition of PD-1 and IL-17B would be effective for treating any possible cancer in a predictable manner, much less every cancer encompassed by the claimed genus. Applicant’s own data (Bonnefoy et al. (WO 2020/201442 A1)) demonstrate that the instantly recited combined treatment produced complete regression in only 1 out of 10 subjects in a single cancer model, with only one additional near-complete response.
The scope of the claims in view of the specification as filed together do not reconcile the unpredictability in the art to enable one of skill in the art to make and/or use the claimed invention, namely a broad method of treating any cancer via delivery of any anti-PD1 antibody and any anti-IL-17B antibody encompassing in vivo effects.
MPEP 2164.01
Any analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention.
Also, MPEP 2164.01(a)
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Given the teachings of the specification as discussed above, one skilled in the art could not predict a priori whether introduction of any anti-PD1 antibody and any anti-IL-17B antibody in vivo would result in successful treatment of any possible cancer, each having its own etiology. To practice the claimed invention, one of skill in the art would have to de novo determine; the stability of the molecule in vivo, delivery of the molecule to the whole organism, specificity to the target tissue in vivo, dosage and toxicity in vivo, and entry of the molecule into the cell in vivo and the effective action therein. Without further guidance, one of skill in the art would have to practice a substantial amount of trial and error experimentation, an amount considered undue and not routine, to practice the instantly claimed invention.
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation (see MPEP 2164.01(a)).
Response to Arguments
Applicant argues that the claimed effect does not depend on the particular histology of a given tumor; rather, it derives from a common immunological mechanism - the PD1 immune checkpoint. As disclosed, the inventors discovered that IL-17B contributes to resistance against anti-PD1 therapeutics, such that inhibiting IL-17B restores or enhances the efficacy of PD1-axis blockade. Because PD1-axis blockade is efficacious across a broad range of cancers, the mechanism underlying the claimed combination is likewise applicable across cancers responsive to, or rendered resistant to, PD1-axis therapy. The specification further supports this generality with working examples in two distinct tumor models: a significant tumor-growth delay and increased survival following anti-PD1 antibody therapy in the absence of IL-17B in the MCA205 fibrosarcoma model (Examples 1 and 3), and a corresponding significant tumor-growth delay in the B16K1 melanoma model (Example 4).
The examples of the specification are not commensurate in scope with the treatment of any possible cancer. The partial and complete responses in IL-17B knockout animals (examples 2 and 4) is not representative of antibody treatment and is not representative of any possible cancer. The data of the specification regarding antibody treatment (example 3) demonstrate that the combination of an anti-PD1 antibody and an anti-IL-17B antibody did not eradicate tumors in all treated animals in the tumor model selected. Mice bearing MCA205 fibrosarcoma were treated with the combination of antibodies and resulted in only 1 complete regression out of 10 animals, plus one additional long-term near-complete response. Therefore, about 80% of the animals did not have a complete or near-complete response, demonstrating that the combination is not universally effective even in the one fibrosarcoma model.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 3-6, 9, 10, 15, 19, and 22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hoffman-La Roche et al. (WO 2016/044189 A1).
Hoffman-La Roche et al. teach: The present disclosure provides methods comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an IL-17 binding antagonist. Further provided are kits comprising a PD-1 axis binding antagonist, an IL-17 binding antagonist, or both, as well as instructions for use thereof (abstract).
Hoffman-La Roche et al. teach: [0010] The present disclosure describes a combination treatment comprising an effective amount of a PD-1 axis binding antagonist and an IL-17 binding antagonist.
Hoffman-La Roche et al. teach: [0011] In certain aspects, the present disclosure provides a method for treating or delaying progression of cancer in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an IL-17 binding antagonist. In another aspect, the present disclosure provides a method of enhancing immune function in an individual having cancer comprising administering an effective amount of a combination of a PD-1 axis binding antagonist and an IL-17 binding antagonist.
Hoffman-La Roche et al. teach: [0013] In some embodiments, the PD-1 axis binding antagonist is selected from the group consisting of a PD-1 binding antagonist, a PDL1 binding antagonist and a PDL2 binding antagonist.
Hoffman-La Roche et al. teach: [0014] In some embodiments, PD-1 binding antagonist is an antibody. In some embodiments, the anti-PD-1 antibody is a monoclonal antibody.
Hoffman-La Roche et al. teach: [0018] In some embodiments, the IL-17 binding antagonist inhibits the binding of IL-17 to the IL-17 receptor. In some embodiments, the IL-17 binding antagonist is an antibody. In some embodiments, the IL-17 binding antagonist is a monoclonal antibody.
Hoffman-La Roche et al. teach: [0146] "IL-17" as used herein refers to the IL-17 family of cytokines. Unless otherwise specified, a reference to an IL-17 may refer to one or more members of the IL-17 family of cytokines, including, e.g., IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F.
Therefore, it would have been obvious for the antibody of the method to be against any of IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, or IL-17F as a matter of design choice with reasonable expectation of the treatment effect taught by Hoffman-La Roche et al (instant claim 3).
Hoffman-La Roche et al. teach: [0026]In some embodiments, the cancer is selected from the group consisting of renal cell carcinoma, bladder cancer, non- small-cell lung cancer, squamous non- small-cell lung cancer, non-squamous non- small-cell lung cancer, colorectal cancer, melanoma, ovarian cancer, breast cancer, hormone receptor- positive breast cancer, HER2-positive breast cancer, and triple-negative breast cancer (instant claim 10).
Hoffman-La Roche et al. teach: [0325] In some embodiments, a cancer to be treated by the methods of the present disclosure includes, but is not limited to, colorectal cancer, renal cell cancer (e.g., renal cell carcinoma), melanoma, bladder cancer, ovarian cancer, breast cancer (e.g., triple-negative breast cancer, HER2-positive breast cancer, or hormone receptor-positive cancer), and non-small-cell lung cancer (e.g., squamous non-small-cell lung cancer or non-squamous non- small-cell lung cancer). In some embodiments, a cancer to be treated by the methods of the present disclosure includes, but is not limited to, a carcinoma, lymphoma, blastoma, sarcoma, and leukemia. In some embodiments, a cancer to be treated by the methods of the present disclosure includes, but is not limited to, squamous cell cancer, lung cancer (including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous carcinoma of the lung), melanoma, renal cell carcinoma, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer (including gastrointestinal cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, liver cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma and various types of head and neck cancer, as well as B-cell lymphoma (including low grade/follicular non-Hodgkin's lymphoma (NHL); small lymphocytic (SL) NHL; intermediate grade/follicular NHL; intermediate grade diffuse NHL; high grade immunoblastic NHL; high grade lymphoblastic NHL; high grade small non-cleaved cell NHL; bulky disease NHL; mantle cell lymphoma; AIDS-related lymphoma; and Waldenstrom's Macroglobulinemia); chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); Hairy cell leukemia; chronic myeloblastic leukemia; and post-transplant lymphoproliferative disorder (PTLD), as well as abnormal vascular proliferation associated with phakomatoses, edema (such as that associated with brain tumors), and Meigs' syndrome. In some embodiments, the cancer may be an early stage cancer or a late stage cancer. In some embodiments, the cancer may be a primary tumor. In some embodiments, the cancer may be a metastatic tumor at a second site derived from any of the above types of cancer.
Hoffman-La Roche et al. teach: [0028] In some embodiments, the IL-17 binding antagonist and/or the PD-1 axis binding antagonist is administered continuously or intermittently. In some embodiments, the IL-17 binding antagonist is administered before the PD-1 axis binding antagonist. In some embodiments, the IL-17 binding antagonist is administered simultaneously with the PD-1 axis binding antagonist. In some embodiments, the IL-17 binding antagonist and the PD-1 axis binding antagonist are formulated in the same composition. In some embodiments, the IL-17 binding antagonist is administered after the PD-1 axis binding antagonist. In some embodiments, the PD-1 axis binding antagonist or the IL-17 binding antagonist is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally (instant claims 4 and 15).
It is noted that claim 5 recites an outcome rather than a method step. The outcome would necessarily flow from the method step.
Hoffman-La Roche et al. teach: [0014] In some embodiments, PD-1 binding antagonist is nivolumab, pembrolizumab, CT-011, or AMP-224 (instant claim 22).
Hoffman-La Roche et al. teach: [0130] An "effective amount" is at least the minimum concentration required to effect a measurable improvement or prevention of a particular disorder. An effective amount herein may vary according to factors such as the disease state, age, sex, and weight of the patient, and the ability of the antibody to elicit a desired response in the individual. An effective amount is also one in which any toxic or detrimental effects of the treatment are outweighed by the therapeutically beneficial effects. For prophylactic use, beneficial or desired results include results such as eliminating or reducing the risk, lessening the severity, or delaying the onset of the disease, including biochemical, histological and/or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease. For therapeutic use, beneficial or desired results include clinical results such as decreasing one or more symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication such as via targeting, delaying the progression of the disease, and/or prolonging survival. In the case of cancer or tumor, an effective amount of the drug may have the effect in reducing the number of cancer cells; reducing the tumor size; inhibiting (i.e., slow to some extent or desirably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and desirably stop) tumor metastasis; inhibiting to some extent tumor growth; and/or relieving to some extent one or more of the symptoms associated with the disorder.
It would have been obvious to determine the effective amount of each agent as a matter of routine optimization. Clearly from the teachings of Hoffman-La Roche et al., it was known to determine the effective amount of each component dependent upon known factors (instant claim 19).
Hoffman-La Roche et al. teach: [0330] The appropriate dosage of the PD-1 axis binding antagonist and/or the IL- 17 binding antagonist may be determined based on the type of disease to be treated, the type of the PD-1 axis binding antagonist and the IL-17 binding antagonist, the severity and course of the disease, the clinical condition of the individual, the individual's clinical history and response to the treatment, and the discretion of the attending physician.
Additionally, instant claim 19 does not set forth any clear parameter for the amount required for the anti-PD1 antibody. The claim requires for it to be present in an amount inferior to its amount in a composition not comprising an inhibitor of IL-17B. If this is meant to require a lesser amount in combination than if it was being used alone for treatment, the claim does not specify what the threshold actually is to meet this criteria. However, it would have been obvious as a matter of design choice for each of the amounts to be less than if using for a monotherapy given that the patient can only tolerate a certain amount of treatment. Additionally, the claim is not directed to any specific amount in either of the compositions and there is no static known amount of the PD1 inhibitor in the monotherapy to compare the amount in the combination therapy to.
Hoffman-La Roche et al. teach: [0223] In some embodiments, the anti-PDLl antibody described herein is in a formulation comprising the antibody at an amount of about 60 mg/mL, histidine acetate in a concentration of about 20 mM, sucrose in a concentration of about 120 mM, and polysorbate (e.g., polysorbate 20) in a concentration of 0.04% (w/v), and the formulation has a pH of about 5.8. In some embodiments, the anti-PDLl antibody described herein is in a formulation comprising the antibody in an amount of about 125 mg/mL, histidine acetate in a concentration of about 20 mM, sucrose is in a concentration of about 240 mM, and polysorbate (e.g., polysorbate 20) in a concentration of 0.02% (w/v), and the formulation has a pH of about 5.5.
Hoffman-La Roche et al. do not teach the subject or the cancer is resistant to the anti-PD1 antibody (instant claims 6 and 9, respectively).
However, Hoffman-La Roche et al. do teach that in cancers such as bladder cancer and renal carcinoma, higher IL-17A/F expression correlated with stable or progressive disease on anti-PDL1 therapy. Hoffman-La Roche et al. teach IL-17A/F expression may be useful as a predictor of non-responsiveness to anti-PDL1 treatment. Therefore, if a tumor or subject comprising the tumor is predicted to be nonresponsive or resistant to PD-L1 blockade because it expresses IL-17A/F, it would have been obvious to add the IL-17 antagonist (including IL-17B) to overcome the poor response. The combination therapy is designed based upon this axis. The reference defines the PD-1 axis to include PD-1, PD-L1, and PD-L2. The reference offers a motivation to add an IL-17 (including IL-17B) antibody to a PD-1 axis antibody in tumors that response poorly to checkpoint blockade.
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Amy R Hudson whose telephone number is (571)272-0755. The examiner can normally be reached M-F 8:00am-6:00pm.
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/AMY ROSE HUDSON/Primary Examiner, Art Unit 1636
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