The increasing importance of monoclonal antibody as a therapeutic modality is exemplified by Genentech’s $256 million worth of royalty in 2007 and a projected growth of 15% to 25% in 2008 as reported by the WSJ.  The royalty income is based mostly on a single patent generally known as the Cabilly II patent which have been the subjects of my previous blogs.  The Cabilly II patent relates to the basic methods for making monoclonal antibody using recombinant DNA technology.  As such, if you are importing, selling, or manufacturing monoclonal antibody drugs in the US, the chances are you will have to pay royalty to Genentech.

The latest development in this high stake game is that Genentech and MedImmune has reached a settlement with undisclosed terms.  This litigation is rather complicated and goes back to 2003.  MedImmune had licensed certain intellectual property rights from Genentech, but challenged the validity of one of the licensed patents from Genentech. The litigation revolves around the assertion that MedImmune did not breach its license agreement with Genentech by such a challenge.  For more detail discussion please see this article from law.com.

The Cabilly Controversy

Genentech’s Cabilly II Is Revoked

Genentech the owner of the Cabilly patent announced on Monday February 25, 2008 that it has received notification from USPTO that the patentability of the claims in the Cabilly patent has been rejected.  This is a high stake game with millions of royalty payment at stake.

As discussed in my previous blogs, the Cabilly patent (also known as the Cabilly II patent for this particular case) covers the method of making monoclonal antibodies and antibody fragments.  Genentech in addition to using the technology to make it own drugs (Avastin, Herceptin and Rituxan) also license the technology to other companies.  Many billion dollar drugs such as Humira and Remicade for rheumatoid arthritis (Abbot and J&J) and Erbitux for colorectal cancer (Imclone) need the Cabilly patent for their manufacture.

This notification is in the form of a Final Office Action does not mean the end of the Cabilly patent.  Because of the huge amount of royalty is affected, Genentech will no doubt appeal the decision to the Board of Appeals of USPTO.  In the meantime the patent is deemed to be still valid pending the Appeal and this may take up to 2 to 3 years and Genentech can continue to enforce the patent and collect royalties.

Read my previous posts on Cabilly Patents
Cabilly I
Cabilly II

FDA is an agency within the United States Department of Health and Human Services and is mandated to regulate through its subdivisions Center for Devices and Radiological Health (CDHR) for medical devices and Center for Drug Evaluation and Research (CDER) for drugs with respect to safety and efficacy.  In addition to safety and efficacy, FDA regulates almost every facet of prescription drugs and use of medical devices, including testing, manufacturing, labeling, advertising and marketing.   The intent is to protect the public against fraudulent claims and to ensure safety of the consumers.  The intent of FDA is not to regulate the practice of medicine.  Within this context, a drug or medical device that has been approved by FDA for a specific use can at the discretion of the physician be legally used for conditions other than those approved by FDA.  Such practice is called the off-label use of an FDA approved product and the rules of the game are changing, at least for the companies. 

Companies have in the past have been prohibited to promote drugs or medical devices for uses that have not been specifically approved by FDA.  The leeway for companies to make such promotions may widen slightly.  The new guidelines (draft for public comments) would permit manufacturers and companies to distribute reprints from peer-reviewed journal articles.  Several categories of reprints are prohibited under this guideline including special supplements, letters to the editor, early-stage trials in healthy patients, and articles that are “inconsistent with the weight of credible evidence.”

This move by FDA is not without controversy.  As reported in WSJ Health Blog Randall Lutter, FDA deputy commissioner for policy stated that  ”Articles that discuss unapproved uses of FDA-approved drugs and devices can contribute to the practice of medicine and may even constitute a medically recognized standard of care,”.  Lutter maintained that “This guidance also safeguards against off-label promotion.”

Not everyone agrees with this latest intended move by FDA to what some deemed as facilitation of off-label use.  A particularly vocal opponent of this FDA initiative is Congressman Henry Waxman, a California Democrat.  He wrote a cautionary letter to the FDA citing danger of such a move as potentially short circuiting the FDA regulatory process and opens the door to abusive marketing.  He quoted Senator Estes Kefauver warning that if promotion of unapproved uses was allowed, “the expectation would be that the initial claim would tend to be quite limited, which, of course, would expedite approval of the new drug application.”  The implication here is that companies would then “promote” and “widen” the unapproved indications through the distribution of reprints from peer-reviewed journal articles touting the off-label use of such drug or device.  The controversy remains if this is after all necessarily a bad thing and not to the interest of the public.

Wall Street Journal has an excellent article on this issue.

Each year Time Magazine in conjunction with CNN come up with a list of best inventions for various categories.  Because of the large number of categories and each invention is listed on separate page (I guess for more advertising opportunities), it is cumbersome to go through all of them.  I have condensed the best inventions on the Health category into a single page.  The best invention in my opinion for the health category is….

1. PowerFoot One, is the world’s first actively powered foot ankle prosthesis.  The inventor an MIT professor is himself a double amputee.  The secret to long battery life is to recapture energy during walking.
   Time Link       iWalk
2. Schizophrenic mouse.  Akira Sawa of John Hopkins has been studying how variants of a gene called DISC1 increase the risk of schizophrenia.  The Sawa Laboratory has developed a schizophrenic mouse model that will some day lead to better understanding and perhaps better treatment for this debilitating form of mental illness.  This research group is trying to match findings obtained in patients with schizophrenia with those from animal models using MRI and PET.
   Time Link       Sawa Laboratory
3. Blood Type Conversion System.  Group O blood is highly desirable for blood transfusion because the red blood cells do not have A antigen or B antigen on their cell surfaces.  As such it can be transfused to patients with Group A, Group B or Group AB blood type and of course also to patients with Group O.  Therefore Group O blood type is also known as universal donor blood.  Danish scientists have discovered two bacterial enzymes that will cleave the sugar molecules eliminating the A and B antigens and thus converting the blood essentially to Group O blood.
   Time Link       ZymeQuest
4. Do it Right.  In the heat of a CPR resuscitation one can over compress or under compress the chest.  Worst still because of the intensity of the situation at hand (pardon the pun), we tend to compress the chest at a higher rate than is usually recommended.  A group of final year engineering student from McMaster University came up with a simple and elegant solution to this problem.  Sensors embedded in neoprene glove detect the pressure exerted by the palm and also keep track of the rate of compression.  The data feed back to the machine is used to determine the type of verbal cues offered to the resuscitator such as “compress faster”.
   Time Link       CPRGolove
5. Prognosticating Cancer Recurrence.  Amsterdam-based Agendia molecular diagnostics was one of the first companies to be approved under FDA’s new In Vitro Diagnostic Multivariate Index Assay (IVDMIA) Guidelines for their diagnostic kit for breast cancer prognosis.  Agendia’s proprietary gene expression analysis can identify older breast cancer patients at low risk for metastatic disease.  This valuable information can be use clinically to decide which treatment regime to use for specific breast cancer patients.
   Time Link       Agendia

My favorite invention this year is the cprGlove.  Simple and elegant solution to an unmet need.

Jim Larrick, MD PhD runs a private research institute called Panorama Research in Mountain View, California (a stone throw from Google headquarter).  This private research institute competes on equal terms with academic institutions for research grants from NIH and other federal agencies including SBIR grants.  Jim has founded 14 biotech companies out of Panorama Research of which 4 have gone IPO (some through mergers).  This is not a bad record for a private research institute.  Many universities would have love such a track record.

Jim is first and foremost a maverick; not the type that will fit well in an academic institution.  He is not only an entrepreneur but also a consummate scientist with a solid track record of having published over 240 peer review journal articles.  He published one of the first books on oncogene with Ed Liu, currently the Executive Director of the Genome Institute of Singapore.

He was recently in Africa with the Sanofa Center for African Dance & Culture.  The purpose of this trip was to promote AIDS awareness through the medium of dance.  Jim’s production company, Slick Production (no kidding), produced a moving documentary in HDTV format about this trip.  You can view a sample of the documentary from here and a new trailer from here.

I have procrastinated for three months before I finally decided to re-visit my previous blog on RNAi. I want to use this Blog to illustrate two points. Firstly how fundamental research can lead to patentable platform technology which Christensen called “disruptive technology”. Secondly, I would like to use this case as an illustration on how to look up information related to an issued patent that would not be apparent in the patent itself. Shortly after my blog on RNAi in September 2006, it was announced in October 2006 that Andrew Fire and Craig Mello were the recipient of the Nobel Prize in Physiology or Medicine for their work on RNAi. Their discovery that double-stranded RNA when injected into worms would silence the gene with the complimentary sequence was published in Nature in 1998. Underscoring the importance of this discovery is the fact that the Nobel Prize was awarded only eight years later after the initial discovery.

It is of interest to review the sequence of events between the landmark publication in Nature and the subsequent filing and issue of a US Patent covering this subject matter. The manuscript for the paper was received by Nature on Sep 16, 1997 and was accepted for publication on November 24, 1997. This seminal paper was published by Nature on Feb 19, 1998 with the title “Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans”. A patent on this subject matter was not filed till Dec 18, 1998 almost 10 months after the initial publication. My guess is that someone at the technology transfer office at Carnegie Institution of Washington was not quite sure about the application of such fundamental scientific discovery.

Genetic inhibition by double-stranded RNA US Patent 6,506,559
Abstract:
A process is provided of introducing an RNA into a living cell to inhibit gene expression of a target gene in that cell. The process may be practiced ex vivo or in vivo. The RNA has a region with double-stranded structure. Inhibition is sequence-specific in that the nucleotide sequences of the duplex region of the RNA and of a portion of the target gene are identical. The present invention is distinguished from prior art interference in gene expression by antisense or triple-strand methods.

The above patent abstract written in 1998 succinctly and elegantly defined the essence of the technology. This patent was filed in December 18, 1998 and only issued in January of 2003. What happened? Why does it take four years for the patent to be issued? Although patent are public document, you will not find the background information on the process that lead to the issue of this patent. To find this information you will have to look at the “File Wrapper”. The folder in which the U.S. Patent and Trademark Office maintains the application papers is referred to as a file wrapper. In it contains the “office action” notifications and responses from the patent attorney amongst other documents. I view the patent application exercise as a bargaining process between the patent attorney and the examiner. Your patent attorney drafts the specifications of the patent according to information supplied by you. His responsibility include drafting claims that are as broad as possible consistent with the specifications. In addition making sure that the patent application meets all statutory requirements, the patent examiner has to ensure that the claims are not overly broad beyond what the specifications can support. In critical cases of due diligence for freedom to operate, it is also essential to review the file wrapper.

Patent Application Information Retrieval (PAIR) is an electronic service provided by USPTO for information on issued or published patent application status. Also available at PAIR are file wrapper document images. For convenience, the electronic copies of file wrappers can also be ordered from USPTO. Other commercial suppliers include Advanced Patent Services and Access Patent Group. In the software (WizPatent Manager and WizPatent Express) that we have developed and knowing the importance of information from file wrapper, we have provided links to PAIR all US Patents downloaded. This makes looking up file wrapper information on PAIR a breeze.

However the PAIR portal is far from perfect. Not infrequently the portal is down. In other cases, the images are not available and you have to order them commercially. This usually cost about a $100 and the average size of the file wrapper is between 50 to a 100 pages.

 

  

This year Time Magazine’s Best Inventions 2006 has selected an invention which I felt is very relevant to the holiday season.  TruTouch technology has come up with a really bright idea (pardon the pun) of using near infrared spectroscopy to detect alcohol level transcutaneously.  This non-invasive method reportedly will detect alcohol level in 60 seconds flat.   

 

Alcohol monitoring technology that uses near-infrared (NIR) reflectance spectroscopy to noninvasively measure alcohol transcutaneously is a recent advance in optical testing method.  To translate laboratory results to a system such as the one shown above that will function reliable in the field is no small feat (see OE Magazine).  The TruTouch system uses NIR spectroscopy to measure unique spectral absorption signatures. A specific spectral absorption signature is determined by the molecular structure of the chemical compound of interest.  As opposed to measuring a given concentration of a pure compound in the laboratory, direct measurement of alcohol level transcutaneously is not possible due to the variation in skin structure and the presence of a myriad of other compounds.  To overcome such difficulty indirect multivariate calibrations such as partial-least-squares regression (PLS) is used.  These and other technical details are given in an article in OE Magazine. 

Looks like the unit above can be made compact and robust enough to fit into the arm rest of a car and electronically linked to the ignition system.  For a person who has a restricted driving license due prior drunk driving conviction, the car is programmed not to start unless he is sober.

Happy Holiday and safe driving.            

Other Best Inventions of note are:

Good for Girls

Gardasil is a vaccine for immunizing adolescents against the sexually transmitted human papillomavirus, a major risk factor for cervical cancer.

Hypoallergenic Cats

A naturally hypoallergenic breed of cat that do not secrete protein in their saliva that can trigger an allergic reaction in humans.

Water Machine

A water-harvesting machine, which can pull up to 500 gal. of drinkable water per day out of thin air.

Whether you are doing clinical trials for drug or medical device you need to be aware of a safe harbor provision in the
US patent.  This exemption from infringement is known as Section 271(e)(1) and is especially important for the pharmaceutical industry.  This issue is made famous by the Merck vs. Integra case. The Supreme Court reviewed a decision of the court of Appeals for the Federal Circuit and held that Merck was not guilty of patent infringement for using Integra’s patents for clinical research.   

 

Integra Lifesciences purchased all the patents from a company called Telios Inc. in a bankruptcy sale for $20 million. Merck & Co., Inc. a United States pharmaceutical company used one of those patents to conduct clinical research in order to submit an Investigational New Drug Application (“IND”) to the FDA.  The patent in question relates to peptides involved in interactions between cell surfaces and the extra-cellular matrix namely the RGD peptide.

 

The Supreme Court concluded that Merck’s actions fell safely within an exception enacted by the congress especially for the pharmaceutical industry. This exception known as the “§271(e)(1) exception” states :

‘It shall not be an act of infringement to make, use, offer to sell, or sell within the United States or import into the United States a patented invention …solely for uses reasonably related to the development and submission of information under the Federal law which regulates the manufacture, use, or sale of drugs or veterinary biological products.’

In brief the exception provides a “safe-harbor” from patent infringement for research reasonably related to an FDA submission.

 

Integra argued that Merck conducted pre-clinical studies related to efficacy, mechanism of action, pharmokinetics, and the pharmacology and not just on the toxicology as required by the IND application and hence had conducted research outside the exemption. The Supreme Court however dismissed the argument by saying that FDA specifically asks if the clinical trial poses an “unreasonable risk” for which to be assessed requires the tests conducted by Merck to be done. They also concluded that as long as there is reasonable basis for believing that the experiments will produce the information that are relevant to an IND or NDA (Non Disclosure Agreement) it falls under the exception. 

 

The broader issue relates to research exception at universities for patented technologies.  Prior to the Bayh-Dole act it can be argued that academic research is for the purpose of “philosophical experimentation” with no “intent to use for profit.”  However almost all universities have a technology transfer office and it is hard to argue that there is no intent to commercialize the research result.

 

However some questions do remain unanswered. The “§271(e)(1) exception uses the term “patented invention” and not just “patented drug” or “patented compound” and so the limits of this exception are not clearly defined.

 

Links
 

Merck v. Integra : The Supreme Court’s Take On The Research Exception To Patent Infringement , Les Nouvelles, June 2006

 

Supreme Ct. to Hear Merck Case – SMITH HOPEN INTELLECTUAL PROPERTY LAW

Merck vs. Integra – Letters from Babylon

 

Why did a technology that was hailed as the “Breakthrough of the Year” in 2002 by the journal Science did not succeed commercially, at least not yet?  There was high hope that RNAi maybe the next class of miracle drug.  So much so that in February 2004, MIT’s Technology Review listed it as one of the “10 Emerging Technologies That Will Change Your World”.  It was believed that modern ailments such as heart disease, hepatitis, diabetes, Alzheimer’s disease, cancer and AIDS that are triggered by “errant genes”, could be arrested or cured by turning off the genes by using RNAi.  

What is RNAi?

RNA interference (RNAi) was discovered by biochemist Thomas Tuschl. RNAi is a mechanism where fragments of double-stranded RNA (dsRNA) interfere with the expression of a particular gene. RNAi was primarily used extensively in reducing expression in plants. In simple terms, RNAi is a gene silencing process commonly referred to as a “knockdown” to differentiate it from processes where the gene is removed (“knockout”). Experiments have shown that RNAi involves perfectly base-paired dsRNA molecules (complimentary to the target mRNA) inducing mRNA cleavage. RNAi is thought to play a role in the immune response to viruses and other foreign genetic material.  A year after Tuschl first presented his findings in
Tokyo in 2001, the technique received universal acceptance and many major drug companies became interested in the technique.

 

From Tusch’s original patent US 7,056,704 RNA interference mediating small RNA molecules

 

What is the problem?

 

RNAi was first used in clinical studies involving the treatment of macular degeneration (a medical condition where the light sensing cells in the macula malfunction and over time cease to work). RNAi also showed to reverse induced liver failure in mouse models but caused a significant number of cases of heart failure in the mice due to high dosage.  

In order for RNAi to be used as a successful drug there are certain obstacles it needs to overcome. RNAi drugs should manufactured at reasonable costs, it should reach target cells, and it should be potent enough to improve the health of the person. Since RNAi is a charged oligonucleotide it will not pass through a lipid bi-layer of the cell. When injected into the blood stream, unmodified RNA is rapidly excreted by the kidneys or degraded by enzymes. Although attempts have been made to complex the RNA with a lipid or modifying the RNA phosphate backbone to minimize charge, delivery to the cell is still a problem. Even if the delivery problem is solved, questions with regards to toxicity still exist.

 

The Continuing saga….

 

Pharmaceutical companies such as Sirna, Alnylam, Ambion and others are continuing to develop RNAi therapy despite the unsolved problems. Regulations are in the preliminary stages as clinical trials have just started. Many of the patents are still pending. Since no RNAi-based product is in clinical development the market for RNAi is not clearly defined. It is estimated that the drug discovery market based on RNAi may increase up to $1 billion in 2010.

 

 

Links :

 

10 Emerging Technologies That Will Change Your World – Technology Review February 2004

 

Wikipedia Article on RNAi 

 

RNAi- Interference RNA , University of Miami   

In 1989, Genentech was issued the first ‘Cabilly’ patent (named after the inventor Shmuel Cabilly and others). The Cabilly patent (US 4,816,567) claims methods for making monoclonal antibodies using recombinant DNA technology. In the same year Celltech was issued a similar ‘Boss’ patent (named after the inventor Michael Boss and others). The Cabilly patent claims also included the claims in the Boss patent (
US 4,816,397). As a result the two companies entered into a lengthly interference dispute that was resolved in 2001.

 

 

An interference is a legal proceeding unique to U.S. patent law where the Patent Trademark Office (PTO) resolves which party, if any, is entitled to priority of invention where the same subject matter is allegedly invented by the two different parties. The agreement led to the issuing of a second Cabilly patent (US 6,331,415) that is not set to expire until 2018. This meant that the total length of patent protection for Genentech was a whopping 29 years.

 

Genentech receives an estimated $300 million each year in patent royalties for the licencing of the Cabilly patent from companies such as Johnson & Johnson, MedImmune, and Amgen. In 2003, MedImmune filed a lawsuit against Genentech and Celltech claiming violations for antitrust, patent and unfair competition laws. MedImmune challenged the validity and the enforceability of the Cabilly II patent which contains the same claims as Celltech’s Boss patent. On October 18^th 2003, the U.S. Court of Appeals in Washington  D.C., ruled against MedImmune’s appeal.  

 

Following an anonymous third party request, the Cabilly II patent is being re-examined to determine if Cabilly II covers the same inventions as Cabilly I which expired in March 2006. In a preliminary ruling, examiners rejected the Cabilly II patent. Genentech appealed and as a result a re-examination is in process which could take many years, all through which the Cabilly II patent remains valid. This means that companies developing antibody drugs have to continue to pay royalty for the licensing of the technology until the re-examination is complete.

 

Links

Genentech Tries to Calm Cabilly Worries – TheStreet.com

It Lives for 29 Years – Legal Times, November 2003