Replies to post #279089 on Avid Bioservices Inc (CDMO)

[biopharm]

Biomarkers still King

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A better understanding of the reasons behind these differences, and insufficiencies, would significantly increase the therapeutic value of this new treatment modality.

One step in this direction would be biomarkers that help to identify patients who are most likely to respond to a given treatment, and least likely to experience side effects. While for some targeted therapies such companion diagnostics have already been developed (see, e.g., the anti-HER-2/neu antibody trastuzumab, where suitable tests define the HER-2 expression status, and thus predict therapy success in the treatment of breast cancer),31 in ICI the search for suitable biomarkers that reliably predict the efficacy of a therapy for a given patient is still ongoing.32,33

Nonetheless, many companies have already staked their claims in this field in terms of patent applications. Patents that protect the use of a particular biomarker, or a kit for detecting the same, can have tremendous commercial value, namely in case that, under the respective marketing authorization, a test for said biomarker is mandatory before an ICI can be prescribed, or its costs reimbursed, respectively.

In the above-mentioned case of trastuzumab, 10 tests for HER-2 expression status from 6 different suppliers (Ventana, Abbott, Biogenex, LifeTechnologies, Leica Biosystems, and DAKO) have been approved by the FDA.34 While use of one of these tests is mandatory,35 it becomes obvious that no supplier managed to monopolize this market, e.g., by obtaining broad enough patent protection. Nonetheless, there is still room for dispute, as, e.g., Dako and Abbott Molecular Inc. sued each other in 2005 for invalidity, or infringement, of UC California's patents US6596479 and US5447841, licensed to Abbott.36

With respect to anti-CTLA-4 therapy, numerous biomarkers have been suggested, namely, frequency of ICOS+ CD4 T cells, upregulation of HLA-DR/CD45RO, increase in tumor-infiltrating lymphocytes, forkhead box P3-positive and indoleamine 2,3-dioxygenase-positive tumors, presence of antibodies to cancer antigen NY-ESO-1, NY-ESO-1-specific T cell reactivity, high levels of IFN-?-related genes and decrease in genes associated with cellular proliferation and melanoma-specific antigens.37

Other authors38 report that absolute lymphocyte count, and baseline absolute eosinophil count and relative eosinophil count have also been associated with improved survival in these patients.

Compared to anti-CTLA-4 therapy, anti-PD-1 therapy is a relatively new field. Therefore, not surprisingly, the search for suitable biomarkers is not as advanced as in the anti-CTLA-4 area. While expression of PD-L1 seems to play a role in the responsiveness of a tumor to anti-PD-1 therapy, the results obtained are ambiguous,39 which may be due to variations in methodology, cancer type, primary vs. metastatic status, and treatment history, while, furthermore, PD-L1 expression has been shown to be dynamic, and associated with tumor-intrinsic and tumor-extrinsic factors.40

In October 2014, Merck's anti-PD-1 antibody pembrolizumab received a breakthrough therapy designation from FDA for the treatment of patients with EGFR mutation-negative, and ALK rearrangement-negative NSCLC whose disease has progressed on or following platinum-based chemotherapy. While the author could not retrieve a respective patent application assigned to Merck, it appears that Caris Life Sciences of Irving, TX, has established a patent estate, comprising, inter alia, international patent application WO2015116868A1 (Gatalica et al.) with priority of January 29, 2014, that might cover this embodiment (see Table 5).

Table 5.
Table 5.
Selected patents and patent applications related to biomarkers for anti-PD-1 and anti-CTLA-4 therapy
However, PD-L1 appears not be a binary indicator of potential durable benefit because, to date, no study has revealed a 0% response rate in patients with PD-L1-negative tumors either. 41 Despite this unclear situation, many patent applications exist already which relate to biomarkers or companion diagnostics for anti-CTLA-4 or anti-PD-1 therapies. Table 5 shows some selected patents and patent applications related to biomarkers for anti-PD-1 and anti-CTLA-4 therapy.

In this context, it is important to understand that, to meet the inventive step/non-obviousness criterion of a patent application, the requirements as to experimental evidence are regularly lower than in scientific literature, let alone than to obtain regulatory approval, where substantiation of therapeutic efficacy is required.42 To convince a patent examiner that a new compound has a particular effect, data obtained with relatively small sample sizes are usually sufficient, and statistical verification is usually not required. Further, in most cases non-clinical assay data are deemed sufficient.43 This means that patents can be obtained for a companion diagnostic that will never make it to the marketplace.

Further, when drafting patent applications related to biomarkers, care should be taken to account for particular requirements in the respective patent legislations. Under the EPC, claims related to a method of diagnosis are not patent eligible (Art 53 (c) EPC). In decision G1/04, the Enlarged Board of Appeal of the EPO has defined the criteria that make such methods of diagnosis exempt from patent protection. In particular, the patent claim must include the steps of: 1) examination involving the collection of data, 2) comparison of the data with standard values, 3) the finding of any significant deviation (i.e. a symptom), and 4) the attribution of the deviation to a particular clinical picture.

Methods that lack one of these steps do not qualify as diagnostic methods in the meaning of Art 53 (c) EPC. Thus, by omitting one of the 4 steps in the patent claim, this statutory exemption can be bypassed, provided the lacking feature is not essential to the method (which would result in an objection regarding lack of clarity or insufficient enablement). Other options to obtain protection for respective methods provide the claiming of a method of prediction of a therapy success, or prognosis of disease progression, both of which are not diagnosis in strictu sensu.

Further, under the EPC, use restrictions have no limiting effect on compound claims (with the exception of purpose-bound therapeutic claims, which are privileged under Art 54 (4) EPC). This means that a claim reciting “Biomarker X for use in the prediction of success of an anti-CTLA-4 treatment of cancer” would not be deemed novel in case the biomarker was already prior art. Suitable claim formats would be “Use of biomarker X for the prediction of success of an anti-CTLA-4 treatment of cancer,” or “Kit comprising labeled antibody X or nucleic acid probe Y,” provided the antibody or the probe is novel.

In the United States, diagnostic method claims in general, and biomarker claims in particular, are subject to extreme scrutiny by the United States Patent and Trademark Office (USPTO) after the new guidance which came into effect with 2 Supreme Court landmark decisions, Myriad and Prometheus.44 According to these 2 decisions, generally speaking, products of nature, including isolated genes, are deemed non-patent-eligible. This new policy led to a de-facto moratorium of allowances of patent applications related to diagnostic methods and biomarkers. 45 Table 5 shows selected patents and patent applications that claim biomarkers or companion diagnostics that their applicants deem predictive with respect to either anti-CTLA-4 or anti-PD-1 therapy.

Combination Therapies
Very early it became clear that the efficacy of ICI is likely to be increased when used in combination with other drugs.46 ICI combinations with other drugs are not necessarily reflected in the IP landscape in terms of explicit combination patents because very often a patent application devoted to a given ICI also claims, or discloses, with routine language, optional combinations thereof with other standard cancer drugs, even if such combination has not been experimentally tested.

One example is Ono's US patent US8728474 (see Table 2), claim 1 of which is directed to the treatment of a tumor by administering an anti-PD-1 monoclonal antibody, while claim 15 recites an optional combination thereof with an anti-CTLA-4 antibody. The combination of claims 1 and 15 thus encompasses, in particular, combinations of the 2. This patent therefore covers all combinations of either BMS's nivolumab or Merck's pembrolizumab with either BMS's ipilimumab or Pfizer's tremelimumab.

One rationale behind a combination therapy of an ICI with other drugs is that ICI therapy may require some time to take effect because the immune system has to be activated while the tumor is still growing. A combination involving, e.g., 1) a small molecular chemotherapeutic, or a targeted antibody, and 2) an ICI, may thus provide a short-term effect, in which the tumor growth is halted by the first component, and a long-term effect in which the immune system eliminates the tumor in response to the ICI therapy. Strictly speaking, such concept does not exactly rely on what patent professionals often call a “synergistic effect,” which is a code word when inventive step/obviousness issues of a given drug combination are discussed. The clue of this concept seems merely to bridge the time gap until the immunotherapy becomes effective. See the theoretical Kaplan-Meier curves in Fig. 1-2 for an explanation.
Figure 3.
Figure 3.
PD-1 is expressed on activated T-cells, while its ligand, PD-L1 is usually expressed on epithelial and endothelial cells. Binding to PD-1 deactivates the T-cell and thus protects the cells bearing PD-L1. Tumor cells do also express PD-L1, in order to ...
Figure 1.
Figure 1.
CTLA-4 is a T-cell specific inhibitory receptor which has higher affinity to B7-2, displayed on antigen presenting cells (APC), than the T-cell specific co-stimulatory receptor CD28, and suppresses CD28-mediated T cell activation. Blocking CTLA4 with ...
Figure 2.
Figure 2.
Actively binding B7-2 with a CTLA-4-Ig fusion protein, like abatacept, interrupts the interplay between CD28 and B7-2 and thus suppresses CD28-mediated T cell activation. This approach is applied in the treatment of autoimmune diseases.
A second rationale of ICI combinations with other drugs is where the combination develops a true synergistic effect in terms of efficacy.47 In the eyes of the EPO, synergy requires that “the functional interaction between the features achieves a combined technical effect which is different from, e.g., greater than, the sum of the technical effects of the individual features” (combination vs. juxtaposition).48 If sufficiently made plausible by an applicant, such synergistic effect is almost certainly a ticket for patent allowance.

However, even with one of the key arguments for inventive step/non-obviousness missing, patents can still be awarded for such type of combination therapy, namely when a true benefit is actually achieved, in particular if this effect was not entirely foreseeable from the prior art relating to the solo products, or to combinations thereof different to the actual combination. In practice, applicants should argue that the benefit shown was not foreseeable because, given the many disappointments and failures in the development of anti-cancer drugs, the increase in efficacy, or the decrease in side effects, could not be anticipated. Even if the effect of the 2 components lacks any synergistic effect, and is thus merely cumulative, applicants can argue that a novel combination of 2 drugs always bears the risk to develop a toxicity, or both compounds can reciprocally inhibit one another, thus rendering even the mere cumulative effect unforeseeable.

It needs to be said, however, that for many of the drug combinations in discussion that include an immune checkpoint inhibitor, a scientific rationale for study has not been found yet. Furthermore, it is difficult to decide where to look for hints of efficacy in view of so many potential combinations.49

One typical type of combination patents is assigned to small biotechnology companies. The above problem of finding a suitable pair in the haystack of drug candidates does not necessarily apply here because these companies sometimes seek to protect a combination of their key candidates with one or more ICI. In other words, the motivation to combine 2 drugs with one another is not always a scientific one, as it can sometimes simply reflect the mere pragmatic approach to combine what they have with what is supposed to be the next blockbuster. To successfully prosecute a respective patent to allowance, however, a benefit of such combination still needs to be demonstrated. This, of course, may also be helpful for subsequent approval and successful marketing. Table 6 shows some examples for such type of patents.

Table 6.
Table 6.
Patents protecting combinations comprising at least one ICI
These patents can serve as an entry ticket to enter into a research and development deal with large pharmaceutical companies, considering the high costs for the ICI already approved, plus the competition to enroll patients for clinical trials.50 However, large pharmaceutical companies have also discovered the potential of drug combinations that include ICI. Typically, the respective projects involve the combination of 2 or more proprietary molecules, comprising an ICI and one other agent, e.g., either another immune checkpoint inhibitor, a conventional antibody or a small molecule. Likewise typically, the second component can already be off-patent.

Other types of drug combinations comprising an immune checkpoint inhibitor are codeveloped by 2 or more large pharmaceutical companies. It has been postulated that this would be a typical indicator that the immune checkpoint inhibitor drug development pathway is already quite crowded.51 This development is not necessarily reflected in the IP landscape because, in such deals, each player contributes his particular candidate, which is already subject of a patent that also discloses or claims, optionally, the other component of the combination.

An overview of ongoing and discontinued projects exploring combinations of ICI with other drugs is shown in Table 6.

Commercial Conflicts or Litigation
Patents provide the right to sue a third party that the patent proprietor deems to illegitimately use the protected invention. The court's role in such dispute is to clarify whether such accusation is justified or not, and, in case it is, oblige the infringer to pay damages and/or stop the infringement. Because of the commercial potential of ICI, and the considerable expenses for ICI-related research and development, it is not surprising that sooner or later conflicts that escalated to court arose.
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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4966505/