!20160916  How KSR-unpatentable are structured-based drug discoveries?

---    How KSR-unpatentable are structured-based drug discoveries?

      Like it or not, patent law is governed by World War II-era thinking, the vomit illogic of Cuno Engineering, a 1941 Supreme Court decision that created the "flash of genius" test which stated that "mere exercise of skill" is not worthy of a patent, whatever the fruck "mere", "exercise" and "skill" meant. Result 70 years later:

Alice/Mayo - MERELY automating something supposedly well known - and no need to cite any prior art, no matter the efficiencies, is abstract and unpatentable.

KSR - MERELY exercising expected skills with a predictable outcome, is obvious and unpatentable.

So will patent lawyers please yell at their biochemistry clients, and tell them to stop bragging about how easy it is to use some drug-discovery tool to invent a new, useful drug? I am prompted once again to make this observation, because of yet another such paper in Nature:

Sttructure-based discovery of opioid analgesics with reduced side effects
Consortium from Stanford/UCSF/UNC
Nature, 8 September 2016

I highlight aspects of the Abstract that will be the basis for a KSR-predictable rejection (whatever the helk they didn't mean by "predictable" in KSR):

Abstract: Morphine is an alkaloid from the opium poppy used to treat pain. The potentially lethal side effects of morphine and related opioids -- which include fatal respiratory depression -- are thought to be mediated by μ-opioid-receptor (μOR) signalling through the β-arrestin pathway or by actions at other receptors. Conversely, G-protein μOR signalling is thought to confer analgesia. Here we computationally dock over 3 million molecules against the μOR structure and identify new scaffolds unrelated to known opioids. Structure-based optimization yields PZM21—a potent Gi activator with exceptional selectivity for μOR and minimal β-arrestin-2 recruitment. Unlike morphine, PZM21 is more efficacious for the affective component of analgesia versus the reflexive component and is devoid of both respiratory depression and morphine-like reinforcing activity in mice at equi-analgesic doses. PZM21 thus serves as both a probe to disentangle μOR signalling and a therapeutic lead that is devoid of many of the side effects of current opioids.

Let us consider then the four-step discovery process (yes, a discovery in the classic sense of the Constitution's granting patents for "discoveries", but that part of the Constitution is the one that the federal courts wipe their butts with):

  • 1. PHOSITAly, select something commercially interesting to make better (morphine).
  • 2. PHOSITAly, identify the problematic aspect of the something (β-arrestin-2 recruitment).
  • 3. PHOSITAly, automatically test zillions of candidate alternative structures (computationally dock over 3 million molecules).
  • 4. PHISITAly, identify some new versions of the something and skillfully test them (identify new scaffolds unrelated to known opioids)

Isn't the outcome of this PHOSITA-ish process predictable - they are going to find something or not? Let's look at a description of some of the steps.

We docked [using ZINC, an open-source discovery tool for PHOSITAs] over 3 million commercially available lead-like compounds against the orthosteric pocket of inactive μOR, prioritizing ligands (chemical with a metal atom) that interact with known affinity-determining residues and with putative [probable] specificity residues that differ among the four opioid receptor subtypes. For each compound, an average of 1.3 million configurations was evaluated [by a computer, not us] for complementarity to the receptor using the physics-based energy function in the DOCK3.6 [computer program]. As is common [for PHOSITAs] in docking and screening, the top ranking molecules were inspected for features not explicitly captured in the scoring function. We manually examined the top 2,500 docked molecules for their novelty, their interactions with key polar residues, and deprioritized those that showed conformational strain.

Yes, a lot of hard work, especially for my grandmother or a federal judge, but isn't this the type of routine planning and execution that PHOSITAs do with their tools? Result?

Ultimately, 23 high-scoring molecules with ranks ranging from 237 to 2095 out of over 3 million docked were selected for [routine] testing.

How much of that 3 million to 23 candidates was completely automated (no inventive contribution) - using the ZINC and DOCK programs and probably others, along with human selection expected of PHOSITAs? Now, the paper goes onto to describe the chemical analysis that was performed by the chemists as they evaluated their 23 candidates.. And some of the analysis required skilled observations of the chemistry involved, especially any new chemistry.

But thanks to the unconstitutionality of 35 USC 103 (in not defining "obvious" nor "skilled") and the unconstitutionality of KSR (in not defining "predictable", and worse citing caselaw (Adams) for introducing "predictable" where the caselaw nowhere mentions "predictable" - stare decrapisis) - thanks to these unconstitutional lack of guidances, we really don't know if what these scientists did was the predictable outcome of PHOSITAs using their tools and skills, or not, until a judge and a jury make a random decision based on their guts.

So I think a strong and steady warning should go out to anyone using drug discovery tools (or for that matter, EDA circuit design tools, optics design tools, etc.) - "Don't be so cavalier in describing how you used your skills and tools." You will get screwed by the patent offices and courts, for being a PHOSITA who is PHOSITAing using your PHOSITA skills and PHOSITA tools.

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Greg Aharonian
Internet Patent News Service
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