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 .
1. Claims 10 and 14-32 are pending and being examined.
Specification
2. 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. Examiner suggests a title relevant to the claimed invention of anti-TCTP antibody and methods of treating cancer.
Claim Objections
3. Claim 24 is objected to because of the following informalities: Claim 23 contains a typo. The acronym “(TIME)” should be amended to “(TME)” to represent “tumor microenvironment”. If Applicants intended to recite “tumor immune microenvironment”, then the word “immune” should be inserted into claim so that the current acronym reflects that. 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.
4. Claims 10, 14-22 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.
Claim 10 recites: An antibody or an antigen-binding fragment thereof, comprising: which is characterized in that the amino acid sequences of CDRs (complementarity determining regions) 1 to 3 satisfy any of the following (A), (B) or (C), or an antigen- binding fragment thereof:
a) a heavy chain variable domain (VH) that comprises a heavy chain complementarity-determining region (HCDR) 1 comprising the amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, and a light chain variable domain (VL) that comprises a light chain complementarity-determining region (LCDR) 1 comprising the amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 6,
b) a VH that comprises a HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 9, and a VL that comprises a LCDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 12, or
c) a VH that comprises a HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, and a VL that comprises a LCDR1 comprising the amino acid sequence of SEQ ID NO: 16, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 17, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 18.
The claim is unclear grammatically with regard to what is comprised by the claimed antibody or antigen-binding fragment thereof by reciting the antibody or antigen-binding fragment thereof “comprises: which is characterized in that the amino acid sequences of CDRs (complementarity determining regions) 1 to 3 satisfy any of the following (A), (B) or (C), or an antigen- binding fragment thereof:” and followed by options identified by lower case a), b), and c), which are not the capital (A), (B), and (C) identifiers recited in the preamble. Does the claimed antibody and antigen binding fragments thereof comprise 1 CDR listed, or one VH CDR1-3 listed, or both VH and VL CDR1-3 listed for each antibody? What (A), (B), and (C) criteria must the antibody satisfy? The claim as currently constituted is unclear, rendering its dependent claims unclear.
Examiner Suggestion: Amend claim 10 to recite: An antibody or an antigen-binding fragment thereof, comprising:
a) a heavy chain variable domain (VH) that comprises a heavy chain complementarity-determining region (HCDR) 1 comprising the amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, and a light chain variable domain (VL) that comprises a light chain complementarity-determining region (LCDR) 1 comprising the amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 6,
b) a VH that comprises a HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 9, and a VL that comprises a LCDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 12, or
c) a VH that comprises a HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, and a VL that comprises a LCDR1 comprising the amino acid sequence of SEQ ID NO: 16, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 17, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 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.
5. Claims 23-25, 27 and 29-32 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 written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a WRITTEN DESCRIPTION rejection.
The claims are drawn to a method for treating cancer in a subject in need thereof, comprising administering to the subject an agent that functions to:
suppress or inhibit the function of TCTP (claim 1);
treat cancer (claim 1); and
inhibit accumulation of myeloid-derived suppressor cells (MDSCs) in tumor microenvironment (TME) (claim 24).
Dependent claim 27 recites that the agent comprises an anti-TCTP antibody.
Thus, the claims identify the agent or antibody by function only. No agent or antibody structure is recited. The agent is critical to performing the claimed method.
The instant published specification discloses:
[0065] Examples of the substance that suppresses or inhibits the function of TCTP may include, but are not particularly limited to: antibodies, peptide aptamers, and the like that suppress or inhibit the function of TCTP; substances that decompose TCTP or induce decomposition of TCTP, such as, for example, dihydroartemisinin (DHA) and Sertraline; and substances that suppress or inhibit the expression of TCTP, such as, for example, siRNA and miRNA. Further examples of the substance that suppresses or inhibits the function of TCTP may also include substances that inhibit the binding of TCTP to a receptor thereof (TLR2), such as, for example, a TLR2 antagonist. This inhibitory substance may be a substance that interacts with TCTP or a receptor thereof (TLR2), or decomposes any one of them.
[0066] The inhibitor according to the present embodiment may comprise the above-described substance that suppresses or inhibits the function of TCTP.
[0067] A second embodiment of the present invention relates to an antibody that suppresses or inhibits the function of TCTP (hereinafter also referred to as “the anti-TCTP antibody according to the present embodiment”).
[0068] The “antibody” used in the present description is not particularly limited in terms of a preparation method thereof and a structure thereof, and examples of the present antibody may include all “antibodies” that each bind to a desired antigen based on desired properties, such as, for example, a monoclonal antibody, a polyclonal antibody, or a nanoantibody.
Thus, the instant specification discloses that the genus of claimed agents, or substances, that suppress or inhibit the function of TCTP is vast and may include, but are not particularly limited to: antibodies, peptide aptamers, and the like that suppress or inhibit the function of TCTP; substances that decompose TCTP or induce decomposition of TCTP, such as, for example, dihydroartemisinin (DHA) and Sertraline; and substances that suppress or inhibit the expression of TCTP, such as, for example, siRNA and miRNA. Substances that suppresses or inhibits the function of TCTP may also include substances that inhibit the binding of TCTP to a receptor thereof (TLR2), such as, for example, a TLR2 antagonist. The substance may be a substance that interacts with TCTP or a receptor thereof (TLR2), or decomposes any one of them.
With regard to anti-TCTP antibodies, the instant specification discloses three exemplary anti-TCTP mouse monoclonal antibodies 55F3, 44E1, and 51A9 that comprise the CDRs, VH, and VL sequences recited in instant claims 14-17 (see [87-107]; Example 1-18). The instant specification demonstrates in the Examples section 5, that the chemical DHA, and antibodies 55F3, 44E1, and 51A9 have anti-tumor activity.
Thus, the instant specification describes only three exemplary structurally distinct anti-TCTP monoclonal antibodies that function as claimed. Outside the genus of antibodies (i.e., agents), the instant specification discloses identifiable chemicals dihydroartemisinin (DHA) and sertraline as exemplary agents that suppress or inhibit the function of TCTP. The specification fails to disclose any other structure/sequence required of an anti-TCTP antibody or “agent” to possess the functions claimed and listed above.
To provide adequate written description and evidence of possession of the claimed antibody and agent genus required to practice the method, the instant specification can structurally describe representative agents and antibodies that function as claimed and listed above, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.). A disclosure that does not adequately describe a product itself logically cannot adequately describe a method of using that product.
Although Applicants may argue that it is possible to screen for antibodies that bind and inhibit the function of TCTP, and for agents that suppress or inhibit the function of TCTP, and function as claimed, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘requires a precise definition, such as by structure, formula, chemical name, or physical properties,’ not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future agents or antibodies yet to be discovered that may function as claimed. The TCTP antigen and its receptors (TLR2) provide no information about the structure of an antibody or agent that binds to it and inhibits or suppresses the function of TCTP.
In this case, the only factor present in the claims is a recitation of the antibody or agent function as listed above. The instant specification fails to describe structural features common to the members of the genus, which features constitute a substantial portion of the genus because the instant specification discloses only three exemplary monoclonal antibody sequences and two known chemicals that function as claimed. A definition by function does not suffice to define the genus because it is only an indication of what the antibody or agent does, rather than what it is. Other than for three defined monoclonal antibody sequences and two known chemical structures, the specification fails to provide the structural features coupled to the claimed functional characteristics for one to immediately envision members of the genus of agents required to practice the invention. The instant specification fails to describe a representative number of antibody sequences and agent structures for the genus of antibodies and agents that function as claimed. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus required to perform the claimed method.
With regard to the anti-TCTP antibody genus required to practice the invention, the specification discloses only three mouse monoclonal anti-TCTP antibodies that function as claimed, each antibody comprising six defined CDR SEQ ID NOs from the heavy and light chains that are critical to performing the claimed functions listed above. The specification does not disclose the sequence structure of any other antibodies that would predictably function as claimed. The claims broadly encompass any anti-TCTP antibody that functions as claimed and listed above. Applicants have not established any reasonable structure-function correlation with regards to the sequences in the variable domains or CDRs that can be altered and still maintain TCTP binding function and suppress/inhibit the function of TCTP, treat cancer, and inhibit accumulation of MDSCs in the TME. The instant specification does not describe representative examples to support the full scope of the claims because the instant specification discloses only three exemplary species of anti-TCTP antibody that function as claimed. Given the well-known high level of polymorphism of antibody CDR sequences and structure, the skilled artisan would not have been in possession of the vast repertoire of antibodies encompassed by the claimed invention. Therefore, one could not readily envision members of the broadly claimed genus required to practice the claimed invention.
Given the lack of representative examples to support the full scope of the claimed antibodies and agents used in the claimed method, and lack of reasonable structure-function correlation with regards to the unknown sequences/structures of antibodies and agents that perform the claimed functions, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of agents and anti-TCTP antibodies that is required to practice the claimed invention. Since the specification fails to adequately describe the product to which the claimed method uses, it also fails to adequately describe the method.
Examiner Suggestion: Amend claim 23 to recite administering structurally identifiable agents that are correlated to the claimed functions, for example:
Claim 23. A method of treating cancer in a subject in need thereof, comprising administering to the subject an agent that suppresses or inhibits the function of TCTP, wherein the agent is selected from dihydroartemisinin or an anti-TCTP antibody comprising:
a) a heavy chain variable domain (VH) that comprises a heavy chain complementarity-determining region (HCDR) 1 comprising the amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, and a light chain variable domain (VL) that comprises a light chain complementarity-determining region (LCDR) 1 comprising the amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 6,
b) a VH that comprises a HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 9, and a VL that comprises a LCDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 12, or
c) a VH that comprises a HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, and a VL that comprises a LCDR1 comprising the amino acid sequence of SEQ ID NO: 16, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 17, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 18.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
6. Claim(s) 23-26 and 30 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Duan et al (Nature Communications, 2019, 10:1899, internet pages 1-15), as evidenced by the instant specification.
Duan teaches a method of treating colorectal cancer in a subject, the method comprising administering to the subject dihydroartemisinin (DHA).
As evidenced by the instant specification, the DHA taught by Duan inherently functions to suppress or inhibit the function of TCTP and inhibit accumulation of myeloid-derived suppressor cells (MDSCs) in tumor microenvironment (TME), wherein the MDSCs are PMN-MDSCs.
7. Claim(s) 23, 27, and 30 are rejected under 35 U.S.C. 102(a)(1) as being anticipated WO 2012080509, Rochhi et al.
Rochhi teaches a method of treating cancer in a subject, the method comprising administering to the subject an antagonistic anti-TCTP antibody (p. 2-6), wherein the cancer comprises colorectal cancer (p. 12).
Claim Rejections - 35 USC § 103
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.
8. Claim(s) 23-26, 29 and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Duan et al (Nature Communications, 2019, 10:1899, internet pages 1-15), as evidenced by the instant specification; in view of Dosset et al (OncoImmunology, 2018, Vol 7, No. 6; e1433981 (14 pages)).
Duan teaches a method of successfully treating colorectal cancer in a subject, the method comprising administering to the subject a combination of dihydroartemisinin (DHA) + oxaliplatin + anti-PD-L1 antibody and explains the mechanism of why it is successful (abstract; Figures 6 and 9; p. 9, col. 1-2). Duan teaches (abstract):
Herein, we demonstrate effective immunotherapy of colorectal cancer via systemic delivery of an immunostimulatory chemotherapeutic combination in nanoscale coordination polymer (NCP) core-shell particles. Oxaliplatin and dihydroartemesinin have contrasting physicochemical properties but strong synergy in reactive oxygen species (ROS) generation and anticancer activity. The combined ROS generation is harnessed for immune activation to synergize with an anti-PD-L1 antibody for the treatment of murine colorectal cancer tumours. The favourable biodistribution and tumour uptake of NCPs and the absence of peripheral neuropathy allow for repeated dosing to afford 100% tumour eradication.
Duan teaches their combination therapy resulted in increased intratumoral infiltration of CD8+T cells. The oxaliplatin/DHA combination effectively generated a tumor-specific T cell response, which was further enhanced by the addition of anti-PD-L1 antibody (p. 10, col. 1-2).
Duan teaches clinical anti-PD-1 and anti-PD-L1 antibody therapy of CRC is known, explains why adding checkpoint inhibition to CRC chemotherapy is needed, and explains its mechanism of improving tumor immunogenicity and inducing CD8+ T cell infiltration into tumors to enhance immunotherapy. Duan teaches (p. 2, col. 1):
Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the US, with an approximate lifetime risk of 1 in 20 people1. The standard therapy of surgery plus adjuvant chemotherapies is often limited by the side effects of and resistance to chemotherapies2,3. Great emphasis has thus been placed on developing immunotherapies for CRC treatment4,5, particularly after the Food and Drug Administration’s approval of the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody ipilimumab in 20116, the programmed cell death protein 1 (PD-1) antibodies pembrolizumab and nivolumab in 20147, and the PD-1 ligand (PD-L1) antibody atezolizumab in 20158. Clinical trials of immune checkpoint inhibitors (α-CTLA-4, α-PD-1, α-PD-L1) have shown efficacy against many cancers, but limited effect in CRCs. A small subset of CRC patients having tumours with inherently high CD8+ T-cell infiltration and regulatory immune checkpoint overexpression have benefitted from α-PD-1 checkpoint blockade immunotherapy9,10,11,12. However, this cancer phenotype represents <5% of advanced stage CRC13,14. The PD-L1 antibody atezolizumab showed poor response in the predominant microsatellite stable form of CRC as a monotherapy, but improved overall response rates in combination with an MEK inhibitor or α-VEGF and standard folinic acid, 5-fluorouracil, and oxaliplatin (FOLFOX) chemotherapy15. There is thus an established need for therapies that can improve tumour immunogenicity and induce CD8+ T-cell infiltration to enhance immunotherapy for the broader population of CRC patients.
Duan explains that anti-PD-L1 antibody prevents the binding of tumor PD-L1 and T cell PD-1, thereby inhibiting deactivation of the T cells (Figure 9).
As evidenced by the instant specification, the DHA taught by Duan inherently functions to suppress or inhibit the function of TCTP and inhibit accumulation of myeloid-derived suppressor cells (MDSCs) in tumor microenvironment (TME), wherein the MDSCs are PMN-MDSCs.
Duan teaches administering an anti-PD-L1 antibody, but does not teach administering an anti-PD-1 antibody in their method.
Like Duan, Dosset also recognizes a need to enhance tumor immunogenicity and immunotherapy of CRC. Dosset teaches (p. 1):
“…combined chemotherapies such as 5-Fluorouracil plus Oxaliplatin (Folfox) are routinely used as first-line treatment for advanced CRC. However, the appearance of acquired pharmacological resistances to these therapies in most patients limits their antitumor effect, leading to tumor escape.”
Dosset teaches (abstract):
We demonstrated that 5-Fluorouracil plus Oxaliplatin (Folfox) drove complete tumor cure in mice when combined to anti-PD-1 treatment, while each monotherapy failed. This synergistic effect relies on the ability of Folfox to induce tumor infiltration by activated PD-1+ CD8 T cells in a T-cell dependent manner. This effect was concomitantly associated to the expression of PD-L1 on tumor cells driven by IFNγ secreted by PD-1+ CD8 T cells, indicating that Folfox triggers tumor adaptive immune resistance. Finally, we observed an induction of PD-L1 expression and high CD8 T cell infiltration in the tumor microenvironment of colorectal cancer patients treated by Folfox regimen. Our study delineates a molecular pathway involved in Folfox-induced adaptive immune resistance in colorectal cancer. The results strongly support the use of immune checkpoint blockade therapy in combination with chemotherapies like Folfox.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to add anti-PD-1 antibody, or to substitute anti-PD-1 antibody for the anti-PD-L1 antibody in the method of treating CRC taught by Duan. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Duan recognizes that anti-PD-1 and anti-PD-L1 antibody are already clinically used to treat CRC and enhance T cell responses; (2) Duan and Dosset both teach and demonstrate adding anti-PD-1/PD-L1 blockade to chemotherapy-based treatment comprising oxaliplatin or FOLFOX successfully enhances anti-tumor immune responses, CD8+T cell tumor infiltration, and CRC treatment; and (3) Duan and Dosset recognize that anti-PD-1 and anti-PD-L1 antibodies are functionally similar by blocking the same PD-1/PD-L1 pathway to enhance anti-tumor T cell responses.
9. Claim(s) 31 and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Duan et al (Nature Communications, 2019, 10:1899, internet pages 1-15), as evidenced by the instant specification; and Dosset et al (OncoImmunology, 2018, Vol 7, No. 6; e1433981 (14 pages)); as applied to claims 23-16, 29 and 30 above, and further in view of Bommer et al (Cell Communication and Signaling, 2017, 15:9, internet pages 1-15).
Duan and Dosset (the combined references) teach methods of treating CRC in a subject comprising administering combination therapy of DHA and oxaliplatin-based chemotherapy, wherein Dosset teaches the oxaliplatin-based chemotherapy for CRC is commonly FOLFOX (5-FU + oxaliplatin), as set forth above.
The combined references do not teach the method further comprising measuring the amount of TCTP protein in a tissue sample from the CRC subject.
Bommer teaches TCTP is a biomarker of CRC. TCTP is an anti-apoptotic protein frequently overexpressed in cancers, where high levels are often associated with poor patient outcome. TCTP may be involved in protecting cancer cells against the cytotoxic action of anti-cancer drugs. Bommer demonstrates detecting the early increase of TCTP levels in human colorectal cancer (CRC) and the regulation of TCTP expression in HCT116 colon cancer cells, in response to treatment with the anti-cancer drugs 5-FU and oxaliplatin. Bommer measured levels of TCTP protein in CRC patient tumor tissue samples and normal tissue utilizing immunohistochemistry. Bommer identified TCTP as a biomarker that is significantly increased in CRC compared to normal colon tissue, and increased significantly in early stages of CRC development. Bommer concludes that increased TCTP levels in CRC contribute to chemotherapy resistance to 5-FU/oxaliplatin treatment. Bommer suggests measuring levels of TCTP in CRC patients to monitor and prevent development of drug resistance (abstract; Discussion, Conclusion).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to additionally test for TCTP levels in the CRC patients treated by the combined references. One would have been motivated to, and have a reasonable expectation of success to, because: (1) the combined references and Bommer teach CRC is commonly treated with 5-FU/oxaliplatin; (2) Bommer established TCTP is a biomarker for the development and presence of CRC and for the resistance to 5-FU and oxaliplatin therapy; (3) Bommer suggests measuring TCTP in CRC patients in order assess CRC status and drug resistance; and (4) Bommer demonstrates successfully detecting protein levels of TCTP in CRC patient tumor tissues.
Examiner Suggestion: To obviate the prior art rejections, amend claim 23 to recite the specific anti-TCTP antibody claimed that is not taught by the prior art, for example:
Claim 23. A method of treating cancer in a subject in need thereof, comprising administering to the subject an anti-TCTP antibody comprising:
a) a heavy chain variable domain (VH) that comprises a heavy chain complementarity-determining region (HCDR) 1 comprising the amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, and a light chain variable domain (VL) that comprises a light chain complementarity-determining region (LCDR) 1 comprising the amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 6,
b) a VH that comprises a HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 9, and a VL that comprises a LCDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 12, or
c) a VH that comprises a HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, and a VL that comprises a LCDR1 comprising the amino acid sequence of SEQ ID NO: 16, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 17, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 18.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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10. Claims 10, 14, 18-25, 27-32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 12,329,814; in view of Bommer et al (Cell Communication and Signaling, 2017, 15:9, internet pages 1-15). Although the claims at issue are not identical, they are not patentably distinct from each other because the US Patent is claiming overlapping methods of treating the same cancer with an anti-TCTP antibody comprising the same CDR sequences instantly claimed, and in combination with anti-PD-1 antibody.
The US Patent claims:
1. A method for treating cancer in a patient in need thereof, comprising administering a combination comprising (1) a substance that suppresses or inhibits a function of extracellular translationally controlled tumor protein (TCTP) or its modified form, or a fragment or multimer thereof and (2) a cancer immunotherapeutic agent, to the patient,
wherein the substance that suppresses or inhibits the function of extracellular TCTP or its modified form, or a fragment or multimer thereof is an antibody or antigen-binding fragment thereof which specifically binds to TCTP or its modified form, or a fragment or multimer thereof, and the extracellular TCTP or its modified form, or a fragment or multimer thereof has been released from tumor cells,
wherein the cancer immunotherapeutic agent is an immune checkpoint inhibitor selected from an anti-PD-1 antibody and anti-CTLA-4 antibody, and
wherein the antibody or antigen-binding fragment thereof, which specifically binds to TCTP or its modified form, or a fragment or multimer thereof, and the extracellular TCTP or its modified form, or a fragment or multimer thereof, comprises complementarity-determining region (CDR)-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 selected from the group consisting of the following:
a) CDR-H1 of the sequence of SEQ ID NO: 1, CDR-H2 of the sequence of SEQ ID NO: 2, CDR-H3 of the sequence of SEQ ID NO: 3; CDR-L1 of the sequence of SEQ ID NO: 4, CDR-L2 of the sequence of SEQ ID NO: 5, and CDR-L3 of the sequence of SEQ ID NO: 6;
b) CDR-H1 of the sequence of SEQ ID NO: 7, CDR-H2 of the sequence of SEQ ID NO: 8, CDR-H3 of the sequence of SEQ ID NO: 9; CDR-L1 of the sequence of SEQ ID NO: 10, CDR-L2 of the sequence of SEQ ID NO: 11, and CDR-L3 of the sequence of SEQ ID NO: 12;
c) CDR-H1 of the sequence of SEQ ID NO: 13, CDR-H2 of the sequence of SEQ ID NO: 14, CDR-H3 of the sequence of SEQ ID NO: 15; CDR-L1 of the sequence of SEQ ID NO: 16, CDR-L2 of the sequence of SEQ ID NO: 17, and CDR-L3 of the sequence of SEQ ID NO: 18; and
d) CDR-H1 of the sequence of SEQ ID NO: 19, CDR-H2 of the sequence of SEQ ID NO: 20, CDR-H3 of the sequence of SEQ ID NO: 21; CDR-L1 of the sequence of SEQ ID NO: 22, CDR-L2 of the sequence of SEQ ID NO: 23, and CDR-L3 of the sequence of SEQ ID NO: 24.
2. The method according to claim 1, wherein the cancer is selected from the group consisting of colorectal cancer, melanoma, and fibrosarcoma.
3. The method according to claim 1, wherein the substance that suppresses or inhibits the function of extracellular TCTP or its modified form, or a fragment or multimer thereof alleviates, reverts or prevents immune suppression in the tumor immune microenvironment.
4. The method according to claim 1, wherein the substance that suppresses or inhibits the function of extracellular TCTP or its modified form, or a fragment or multimer thereof activates or enhances the functions of T cells and/or NK cells.
5. The method according to claim 1, wherein the substance that suppresses or inhibits the function of extracellular TCTP or its modified form, or a fragment or multimer thereof functions as an antagonist of myeloid-derived suppressor cells (MDSCs) in the tumor immune microenvironment.
6. The method according to claim 1, wherein the patient has shown or is likely to show no or limited response to immunotherapy for the treatment of cancer.
7. The method according to claim 1, wherein (1) the substance that suppresses or inhibits the function of extracellular TCTP or a modified form, or fragment or multimer thereof and (2) the cancer immunotherapeutic agent are administered simultaneously or sequentially.
8. The method according to claim 1, wherein the substance that suppresses or inhibits the function of extracellular TCTP or its modified form, or a fragment or multimer thereof, competitively inhibits binding of an anti-TCTP antibody to TCTP, wherein said anti-TCTP antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 selected from the group consisting of the following:
a) CDR-H1 of the sequence of SEQ ID NO: 1, CDR-H2 of the sequence of SEQ ID NO: 2, CDR-H3 of the sequence of SEQ ID NO: 3; CDR-L1 of the sequence of SEQ ID NO: 4, CDR-L2 of the sequence of SEQ ID NO: 5, and CDR-L3 of the sequence of SEQ ID NO: 6;
b) CDR-H1 of the sequence of SEQ ID NO: 7, CDR-H2 of the sequence of SEQ ID NO: 8, CDR-H3 of the sequence of SEQ ID NO: 9; CDR-L1 of the sequence of SEQ ID NO: 10, CDR-L2 of the sequence of SEQ ID NO: 11, and CDR-L3 of the sequence of SEQ ID NO: 12;
c) CDR-H1 of the sequence of SEQ ID NO: 13, CDR-H2 of the sequence of SEQ ID NO: 14, CDR-H3 of the sequence of SEQ ID NO: 15; CDR-L3 of the sequence of SEQ ID NO: 16, CDR-L2 of the sequence of SEQ ID NO: 17, and CDR-L3 of the sequence of SEQ ID NO: 18; and d) CDR-H1 of the sequence of SEQ ID NO: 19, CDR-H2 of the sequence of SEQ ID NO: 20, CDR-H3 of the sequence of SEQ ID NO: 21; CDR-L1 of the sequence of SEQ ID NO: 22, CDR-L2 of the sequence of SEQ ID NO: 23, and CDR-L3 of the sequence of SEQ ID NO: 24.
The US Patent claims reciting a pharmaceutical use of the anti-TCTP antibody or antigen-binding fragment thereof, and recites its CDR sequences, rendering obvious the instant anti-TCTP antibody of claims 10, 14, 18-22 comprising the same CDRs and comprised in a pharmaceutical composition.
With regard to claims 30 and 31, the US Patent does not claim further testing the colorectal cancer patient tissue for levels of TCTP protein expression.
As stated above, Bommer established TCTP protein expression is a biomarker of CRC progression and drug resistance, suggesting assessing the biomarker to determined cancer progression and drug resistance.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to additionally test for TCTP levels in the CRC patients treated by the method of the US Patent. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Bommer established TCTP is a biomarker for the development and presence of CRC and for the resistance to therapy; (2) Bommer suggests measuring TCTP in CRC patients in order assess CRC status and drug resistance; and (3) Bommer demonstrates successfully detecting protein levels of TCTP in CRC patient tumor tissues.
It is noted that the US Patent claims do not recite or render obvious the full VH and VL sequences of the anti-TCTP antibodies instantly claimed, and the VH and VL sequences are not obviated by prior art, therefore claims 15-17 are not rejected.
11. Conclusion: No claim is allowed.
12. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA B GODDARD whose telephone number is (571)272-8788. The examiner can normally be reached Mon-Fri, 7am-3:30pm.
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/Laura B Goddard/Primary Examiner, Art Unit 1642