“The reasons for the contradictory results of studies with PD-1 ligands are not known.”
“The transplanted tumor cells proliferation was completely inhibited in PD-1-deficient mice to which J558 cells had been transplanted (figure. 5(c)). These results present that inhibition of PD-L1 or PD-1 is effective on cancer treatment.”
“239. The specification must disclose the invention clearly enough and completely enough for it to be performed by a person skilled in the art. The key elements of this requirement which bear on the present case are these: i) the first step is to identify the invention and that is to be done by reading and construing the claims; ii) in the case of a product claim that means making or otherwise obtaining the product; iii) in the case of a process claim, it means working the process; iv) sufficiency of the disclosure must be assessed on the basis of the specification as a whole including the description and the claims; v) the disclosure is aimed at the skilled person who may use his common general knowledge to supplement the information contained in the specification; vi) the specification must be sufficient to allow the invention to be performed over the whole scope of the claim; vii) the specification must be sufficient to allow the invention to be so performed without undue burden.” i) the first step is to identify the invention and that is to be done by reading and construing the claims; ii) in the case of a product claim that means making or otherwise obtaining the product; iii) in the case of a process claim, it means working the process; iv) sufficiency of the disclosure must be assessed on the basis of the specification as a whole including the description and the claims; v) the disclosure is aimed at the skilled person who may use his common general knowledge to supplement the information contained in the specification; vi) the specification must be sufficient to allow the invention to be performed over the whole scope of the claim; vii) the specification must be sufficient to allow the invention to be so performed without undue burden.”
“However it is likely difficult to talk about all of tumor treatments by the PD-1/PD-L1 pathway because PD-L1 is not highly expressed in all of tumor tissues.”
“In the European Patent Office the view is taken that, with claims in either form, the actual achievement of the therapeutic effect is a functional technical feature of the claim, as opposed to a mere statement of purpose or intention.”
“The present invention is based, at least in part, on the discovery that PD-1 is a receptor for B7-4 molecules expressed on antigen presenting cells. PD-1 transmits a negative signal to immune cells, similar to CTLA-4. B7-4 molecules are expressed on the surface of antigen presenting cells and provide a co-stimulatory signal to immune cells and can transmit downregulatory signals to immune cells, depending upon the molecule to which they bind. Thus, modulation of PD-1, B7-4, and/or the interaction between B7-4 and PD-1 results in modulation of the immune response.”
“In another application, upregulation or enhancement of a B7-4 co-stimulatory function is useful in the induction of tumor immunity. Endogenous expression of wild-type B7-4 on tumor cells inhibits the immune response against tumor cells. Accordingly, inhibition of the interaction between B7-4 on tumor cells and PD-1 is useful in inducing tumor immunity. In one embodiment a PD-1 antagonist (e.g. a non-activating antibody against PD-1 or B7-4 or a small molecule PD-1 or B7-4 antagonist) is administered to a subject having or at risk of a tumor.”
"The question of obviousness must be considered on the facts of each case. The court must consider the weight to be attached to any particular factor in the light of all the relevant circumstances. These may include such matters as the motive to find a solution to the problem the patent addresses, the number and extent of the possible avenues of research, the effort involved in pursuing them and the expectation of success."
“Thus, we have described a subfamily of inhibitory molecules within the B7-CD28 family. The PD-L–PD-1 pathway may play a key role in the induction and/or maintenance of peripheral tolerance and autoimmune disease. The expression of PD-1 ligands in peripheral tissues suggests that this pathway may dampen inflammatory responses at these sites. It is worth noting that PD-L1 and PD-L2 mRNA expression are up-regulated in a variety of tumor cell lines. Cell surface expression of PD-L1 was confirmed in three of four human breast cancer lines examined. These findings give impetus to the investigation of whether PD-L expression on tumors attenuates anti-tumor responses as well as the role of the PD-1 pathway in the pathogenesis of human autoimmune disease. Because PD-L1 and PD-L2 can inhibit effector T cell proliferation and cytokine production, the PD-L–PD-1 pathway may be an attractive therapeutic target. Blocking the PD-1 pathway may enhance anti-tumor immunity, whereas stimulating this pathway may be useful for down-regulating ongoing immune responses in transplant rejection and autoimmune and allergic diseases.”
“13.3 Together [the findings disclosed in Latchman] indicated that the PD-1/PD-L pathway was one of nature’s important mechanisms for tolerance induction. They would provide immediate interest and impetus for the skilled person to block inhibitory signaling of the PD-L1/PD-L2-PD-1 pathway in order to induce anti-tumor immunity, as proposed in the last paragraph of the discussion of the Latchman paper. 13.4 It would have been obvious for the skilled person to test the effects of blocking PD-1 mediated signaling in an in vivo tumor model such as a mouse model in which a tumor is implanted or in mice which are known to develop tumors spontaneously. I believe the skilled person would have used an antibody against murine PD-1 or one of the murine PD-1 ligands as the blocking agent and would test its effect on tumor growth in that model. 13.5 In my opinion, the skilled person would in the first instance, choose to test an agent that blocked the signaling of PD-1, as opposed to a blocking agent against the ligands, because Latchman had shown that some tumors express PD-L1 and some express PD-L2. A blocking agent against PD-1 would be expected to prevent inhibitory signaling from either PD-L1 or PD-L2 from mediating their inhibitory effects through PD-1 on T cells. 13.6 I consider that in a transplanted tumor model an obvious tumor cell line to use would have been the P815 mastocytoma cell line. The results shown in Figure 3c of Latchman are that murine PD-L1 and PD-L2 mRNA are both expressed by P815 tumor cells; P815 had been extensively studied before and was well known to be immunogenic; and previous studies have documented that immunogenic tumor cells are the ones amenable to immune-based approaches for growth inhibition. Together these reasons made it a good candidate for the test of improving anti-tumor immunity by the blockade of PD-1 mediated inhibition. 13.7 Such mouse models and tumor cell lines were commercially available and easy to purchase by the skilled person in July 2002. 13.8 Methods for generating monoclonal antibodies would have been well known to the skilled person in July 2002 although a significant amount of practical work would have been required to generate an anti-PD-1 monoclonal antibody. However, such work would not have been unusual and would have been well within the norm for developing a therapeutic antibody at that time. For example …. 13.9 Before carrying out the mouse tumor model test, the skilled person, using standard assays known before July 2002, would have confirmed that a generated anti-PD-1 antibody binds to the PD-1 protein, blocks the binding of the PD-1 ligands to PD-1 and increases T cell responses as a result of blocking PD-1 signaling. 13.10 I consider that the generation and testing of an anti-PD-1 antibody in a mouse tumor model would have been logical and obvious for the skilled person to do based on the information in Latchman. For these reasons, I do not believe that this can be regarded as inventive or innovative in the light of what Latchman describes along with what the skilled person would have known from their common general knowledge. 13.11 The experiments in Latchman teach the skilled person that PD-L1 and PD-L2 through PD-1 mediate a potent inhibitory signal on antigen-specific mediated T cell activation, cell cycle progression and cytokine production. Although these experiments were not done in the context of tumors, they provide a strong expectation that blocking PD-1 mediated signaling would enhance anti-tumor immunity. There are a number of additional factors which would have made the skilled person expect a positive outcome: (1) The PD-L1/PD-L2 mediated inhibition seen in Latchman was observed in the context of moderate to low intensity TCR signals. Tumors are in general weakly immunogenic, thereby their low intensity TCR signaling would have a high chance of being inhibited by PD-1 and therefore PD-1 blockade would be expected to have a beneficial effect on anti-tumor immunity by enhancing T cell responses. (2) Antibodies to CTLA-4, which was considered to be a paradigm for PD-1, had already demonstrated that up-regulation of the immune response as a result of blocking signals which suppress T cell functions provides anti-tumor effects in mouse models. This prior work would have been very encouraging to the skilled person. (3) CTLA-4’s ligands, B7-1 and B7-2, were known not to be expressed on tumors. They are expressed on APCs. PD-1 ligands are expressed both on APCs and on tumors themselves suggesting that the PD-1 pathway might have greater relative importance as an immunosuppressive pathway that compromises anti-tumor immunity. Therefore blocking of this pathway would have a very high chance to enhance T cell responses against tumors.” (1) The PD-L1/PD-L2 mediated inhibition seen in Latchman was observed in the context of moderate to low intensity TCR signals. Tumors are in general weakly immunogenic, thereby their low intensity TCR signaling would have a high chance of being inhibited by PD-1 and therefore PD-1 blockade would be expected to have a beneficial effect on anti-tumor immunity by enhancing T cell responses. (2) Antibodies to CTLA-4, which was considered to be a paradigm for PD-1, had already demonstrated that up-regulation of the immune response as a result of blocking signals which suppress T cell functions provides anti-tumor effects in mouse models. This prior work would have been very encouraging to the skilled person. (3) CTLA-4’s ligands, B7-1 and B7-2, were known not to be expressed on tumors. They are expressed on APCs. PD-1 ligands are expressed both on APCs and on tumors themselves suggesting that the PD-1 pathway might have greater relative importance as an immunosuppressive pathway that compromises anti-tumor immunity. Therefore blocking of this pathway would have a very high chance to enhance T cell responses against tumors.”