!20170505 Qualcomm/Apple/ITC; Are supercomputer-designed drugs KSR obvious?

     Financial chart of the day: How massive increases in the Fed balance sheet are propping up markets

see: www.zerohedge.com/news/2017-04-13/illusion-liquidity

One could almost argue that patents are contributing nothing to the economy, if the stock market (which used to rely on profits, profits often derived from patents) is being propped up solely by Federal Reserve manipulation (a few of whose economists love writing attacks on the patent system).

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When giants wrestle - Qualcomm asks ITC to block all imports of iPhones.   Bloomberg article at: https://www.bloomberg.com/news/articles/2017-05-03/qualcomm-said-to-seek-u-s-import-ban-for-iphones. A bit of advice for QualComm - winning at the ITC means nothing. Go ask ClearConnect (a case which destroyed all software method claims) - don't end up allowing the CAFC to destroy all cellphone claims.

2 year criminal sentence for false claim of copyright infringement.   A federal court in Massachusetts has given a cartoonist, Jayme Gordon, a 2-year sentence in prison, and a $3 million fine, for falsely claiming to have created Dreamwork's 'Kung Fu Panda' cartoon. For his false claims, which forced Dreamworks to spend $3 million in defense, Gordon was charged and found guilty of four counts of wire fraud and three counts of perjury (he destroyed some evidence involving cartoon drawings). Article at: www.masslive.com/news/index.ssf/2017/05/artist_must_pay_dreamworks_3_m.html. Time to jail patent trolls for mail fraud attached to filing patent infringement lawsuits based on false claims (that their crappy patents are anything but purely invalid crap).

Eagles sue the "Hotel California Todos Santos" for trademark infringement.   Newswires report that the Eagles have sued a Mexican hotel, Hotel California Todos Santos, for trademark infringement for selling tourist crap with cover art and the band's name linked to the song, "Hotel California", which they and some others have argued was inspired by the hotel. Yes, and "Along Came Mary" is about a pretty girl named Mary. Question - lawsuits involving rock music with drug connotations - should the judge, jury and lawyers be smoking a few joints during proceedings to truly create an environment of peers? Actually, would the Supreme Court and CAFC hate inventors less if they smoked a few joints while writing 101 caselaw? Article on the Eagles/Hotel at: www.washingtonpost.com/news/morning-mix/wp/2017/05/03/now-its-the-eagles-vs-hotel-california-in-a-federal-court/. Copy of the complaint at: www.scribd.com/document/347066691/Eagles-v-Hotel-California.

A perfect visual definition of "useful".   Science magazine has what should be a perfect visual definition of "useful", the definition being "Useful: what are vaccines". Graphic at: www.sciencemag.org/news/2017/04/heres-visual-proof-why-vaccines-do-more-good-harm.

How do you define a "sandwich"?   An amusing graphics chart, a table of what is, or maybe a sandwich. A BLT? Certainly a sandwich. A Pop-Tart? Maybe, to some. A good chart to use in talks on defining patent terms, including the patent term "sandwich". Chart at: https://flowingdata.com/2017/05/02/sandwich-alignment-chart/.

W.Virginia governor Jim Justice teaches me how to properly insult the complete uselessness of IPO's 101 amendment proposal.   I recently critiqued the idiotic proposal that oozed out of IPO, written mostly by a group of patent lawyers who want to make 101 caselaw worse for their clients, to then charge them more money fighting idiotic rejections, by using phrases such as "only in the human mind". The IPO proposal is riddled with so many new ill-defined terms and phrases and contradictions, as to sink 101 caselaw to lower levels of incoherence and constitutional abuse. Now, in reading these last two sentences, you are thinking, "Greg, a nice, almost proper, insult." No way, my insult is elementary school stuff. I turn to the beseiged Democratic governor of West Virginia, Jim Justice:

Gov. Jim Justice, a Democrat, strode into the Capitol rotunda here [in Charlestown, W.Va, a lovely town], denounced a series of budget cuts approved by Republican lawmakers and lifted the lid off a silver platter to reveal an aromatic pile of fresh bull manure atop a copy of the spending plan.
Yes, fresh bull manure atop a copy of the IPO bullshite amendment to 101. Article on Jim Justice at: www.nytimes.com/2017/05/01/us/jim-justice-west-virginia-governor.html. Hey, this smelly insult is useful. It, and the IPO 101 proposal, can be used to fertilize Pioneer Memorial Park.

Final end of the industrial revolution? Britain goes coal-less for one day.   Newswires report that on April 21st, for the first time since 1882, none of the electricity produced in Britain was from coal-fired plants. Renewables are the future, and someone should forcefully explain to President Trump that the U.S. coal industry is never coming back (especially if they keep on with the low levels of innovation - you think software patents are bad, look at some of the coal patents). Article at: www.nytimes.com/2017/04/21/world/europe/britain-burning-coal-electricity.html.

U.S. productivity suffering from shifting US profits/patents offshore?   There has been tons of commenting allover on the stagnation/decline of U.S. productivity. I myself argue that this can be so in the continuing low levels of patent quality (hi! Theranos, Tesla, ...) which reflect a lack of real innovation that can contribute to productivity and jobs. A CNBC article argues another aspect of this - that U.S. productivity measures are also hurt by U.S. companies moving their patents offshore, so that they can then move more of the profits offshore. "Similar [offshore] transfers are common among big tech companies like Microsoft and Google, as well as drug companies and other types of companies that can place a lot of value in intangible assets like brands and patents.". and "More than 90 percent of the missing output is being counted in 10 other countries, according to the paper. The Netherlands and Ireland were among the biggest recipients, which isn't surprising to anyone familiar with the "double Irish with a Dutch sandwich" corporate tax strategy.". Article at: http://www.cnbc.com/2017/04/28/foreign-countries-are-sapping-us-productivity-study-shows.html.

---    Are supercomputer-designed drugs KSR obvious?

      The University of Texas at Austin recently set out a press release touting its scientists use of supercomputers to find new, better cancer drugs. Great! I am sure anyone with cancer (or might get cancer) is heartened by such announcements. But these new drugs might never get to market, because the drug companies won't want to license new drugs that are unpatentable - solely because of the unconstitutional semantics of KSR, and its idiotic, undefined "predictable" test for "mere" obviousness. Excerpts of the article are below, with some parts bolded that could be evidentiary admissions that what these scientists are doing are nothing more than PHOSITAs using their tools "merely" in "predictable" ways. New deposition question: "When searching for your new drug, did you use a supercomputer?". "Yes? Hey judge, here's our summary motion of invalidity for obviousness."

The semantic nonsense of undefined terms, constitutional inequities and contradictory logic - that plagues much of 101 and 103 caselaw - must end. This nonsense costs patent applicants to waste hundreds of millions of dollars a year defending their inventions, and has led to hundreds of millions of dollars of true invention being denied protection. That this does not concern the patent bar in the least is an outrage.

---    U.Texas supercomputers assist in search for new, better cancer drugs

     by Aaron Dubrow, TACC PR Office, 01 May 2017

Surgery and radiation remove, kill, or damage cancer cells in a certain area. But chemotherapy — which uses medicines or drugs to treat cancer — can work throughout the whole body, killing cancer cells that have spread far from the original tumor.

Finding new drugs that can more effectively kill cancer cells or disrupt the growth of tumors is one way to improve survival rates for ailing patients.

Increasingly, researchers looking to uncover and test new drugs use powerful supercomputers like those developed and deployed by the Texas Advanced Computing Center (TACC).

"Advanced computing is a cornerstone of drug design and the theoretical testing of drugs," said Matt Vaughn, TACC's Director of Life Science Computing. "The sheer number of potential combinations that can be screened in parallel before you ever go in the laboratory makes resources like those at TACC invaluable for cancer research."

Three projects powered by TACC supercomputer, which use virtual screening, molecular modeling and evolutionary analyses, respectively, to explore chemotherapeutic compounds, exemplify the type of cancer research advanced computing enables.

Virtual Screening

Shuxing Zhang, a researcher in the Department of Experimental Therapeutics at the University of Texas MD Anderson Cancer Center, leads a lab dedicated to computer-assisted rational drug design and discovery of novel targeted therapeutic agents.

The group develops new computational methods, using artificial intelligence and high-performance computing-based virtual screening strategies, that help the entire field of cancer drug discovery and development.

Identifying a new drug by intuition or trial and error is expensive and time consuming. Virtual screening, on the other hand, uses computer simulations to explore how a large number of small molecule compounds "dock", or bind, to a target to determine if they may be candidates for future drugs.

"In silico virtual screening is an invaluable tool in the early stages of drug discovery," said Joe Allen, a research associate at TACC. "It paints a clear picture not only of what types of molecules may bind to a receptor, but also what types of molecules would not bind, saving a lot of time in the lab."

One specific biological target that Zhang's group investigates is called TNIK (TRAF2- and NCK-interacting kinase). TNIK is an enzyme that plays a key role in cell signaling related to colon cancer. Silencing TNIK, it is believed, may suppress the proliferation of colorectal cancer cells.

Writing in Nature Scientific Reports in September 2016, Zhang, Tan and Chen reported the results of a study that investigated known compounds with desirable properties that might act as TNIK inhibitors.

Using the Lonestar supercomputer at TACC, they screened 1,448 Food and Drug Administration-approved small molecule drugs to determine which had the molecular features needed to bind and inhibit TNIK.

They discovered that one — mebendazole, an approved drug that fights parasites — could effectively bind to the target. After testing it experimentally, they further found that the drug could also selectively inhibit TNIK's enzymatic activity.

Greg note: here is the troubling question for all drug patentees - was the automatic finding that this one drug out of 1448 inhibits TNIK - the predictable result of a PHOSITA using his or her Ordinary Skills with now Ordinary Tools? Is this admission of easy discovery - an admission of obviousness? Is anyone in the USPTO or patent bar paying attention to this troubling development, all due to the Supreme Court's unconstitutional usurping of Congressional power, by using KSR to nullify the tail language of 35 USC 103?
As an FDA-approved drug that can be used at higher dosages without severe side effects, mebendazole may is a strong candidate for further exploration and may even exhibit a ‘synergic anti-tumor effect' when used with other anti-cancer drugs.

"Such advantages render the possibility of quickly translating the discovery into a clinical setting for cancer treatment in the near future," Zhang and Tan wrote.

In separate research published in Cell in 2013, Zhang's group used Lonestar to virtually screen an even greater number of novel inhibitors of Skp2, a critical oncogene that controls the cell cycle and is frequently observed as being overexpressed in human cancer.

"Molecular docking is a computationally-expensive process and the screening of 3 million drug-like compounds needs more than 2,000 days on a single CPU [computer processing unit]," Zhang said. "By running the process on a high-performance computing cluster, we were able to screen millions of compounds within days instead of years."

Their computational approaches identified a specific Skp2 inhibitor that can selectively impair Skp2 activity and functions, thereby exhibiting potent anti-tumor activity.
Greg note: a just as troubling question for all drug patentees - was the automatic finding that this one drug out of 3,000,000 - the predictable result of a PHOSITA using his or her Ordinary Skills with now Ordinary Tools? Is this admission of easy discovery - an admission of obviousness? Since to a computer, there is little difference between 1,448 and 3,000,000, or 3,000,000,000 - as the drug design computer software (or the electronic circuit design computer software) becomes more powerful, does it increasingly prevent PHOSITA users of the software from patenting their inventions?
"Our work at TACC has resulted in multiple potential drug candidates currently at the different stages of preclinical and clinical studies," said Zhang. "We hope to continue using the resources to identify more effective and less toxic therapeutics."

Molecular Modeling

Described as "the guardian of the genome", tumor protein 53 (p53) plays a crucial role in multicellular organisms, conserving the stability of DNA by preventing mutations and thereby acting as a tumor suppressor.

However, in approximately 50 percent of all human cancers, p53 is mutated and rendered inactive. Therefore, reactivation of mutant p53 using small molecules has been a long-sought-after anticancer therapeutic strategy.

Rommie Amaro, professor of Chemistry and Biochemistry at the University of California, San Diego has been studying this important molecule for years trying to understand how it works.

In September 2016, writing in the journal Oncogene, she reported results from the largest atomic-level simulation of the tumor suppression protein to date — comprising more than 1.5 million atoms.

The simulations helped to identify new "pockets" — binding sites on the surface of the protein — where it may be possible to insert a small molecule that could reactivate p53. They revealed a level of complexity that is very difficult, if not impossible, to experimentally test.

"We could see how when the full-length p53 was bound to a DNA sequence that was a recognition sequence, the tetramer clamps down and grips onto the DNA – which was unexpected," Amaro said.

In contrast, with the negative control DNA, p53 stays more open. "It actually relaxes and loosens its grip on the DNA," she said. "It suggested a mechanism by which this molecule could actually change its dynamics depending on the exact sequence of DNA."

According to Amaro, computing provides a better understanding of cancer mechanisms and ways to develop possible novel therapeutic avenues.

"When most people think about cancer research they probably don't think about computers, but biophysical models are getting to the point where they have a great impact on the science," she said.

Evolutionary Comparisons

Chemicals created by plants are the basis for the majority of the medicines used today. One such plant, the periwinkle (Catharanthus roseus), is used in chemotherapy protocols for leukemia and Hodgkin's lymphoma.

A completely different approach to drug discovery involves studying the evolution of plants that are known to be effective chemotherapeutic agents and their genetic relatives, since plants that share an evolutionary history often share related collections of chemical compounds.

University of Texas researchers — working with researchers from King Abdulaziz University in Saudi Arabia, the University of Ottawa and Université de Montréal — have been studying Rhazya stricta, an environmentally stressed, poisonous evergreen shrub found in Saudi Arabia that is a member of the family that includes the periwinkle.

To understand the genome and evolutionary history of Rhayza stricta, the researchers performed genome assemblies and analyses on TACC's Lonestar, Stampede and Wrangler systems. According Robert Jansen, professor of Integrative Biology at UT and lead researcher on the project, the computational resources at TACC were essential for constructing and studying the plant's genome.

The results were published in Nature Scientific Reports in September 2016.

"These analyses allowed the identification of genes involved in the monoterpene indole alkaloid pathway, and in some cases expansions of gene families were detected," he said.

The monoterpene indole alkaloid pathway produces compounds that have known therapeutic properties against cancer.

From the annotated Rhazya genome, the researchers developed a metabolic pathway database, RhaCyc, that can serve as a community resource and help identify new chemotherapeutic molecules.

Jansen and his team hope that by better characterizing the genome and evolutionary history using advanced computational methods, and making the metabolic pathway database available as a community resource, they can speed the development of new medicines in the future.

"There are a nearly infinite number of possible drug compounds," Vaughn said. "But knowing the principles of what a good drug might look like – how it might bind to a certain pocket or what it might need to resemble – helps narrow the scope immensely, accelerating discoveries, while reducing costs."

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