Thursday, April 2, 2015

Attachment B: Research Plan



                                  



                                                              ATTACHMENT “B”

THE PATENT IS THE PRODUCT

                                             RESEARCH PLAN FOR PATENT FILING

            U.S. Patent law establishes a blueprint for research aimed at patenting a new chemical compound with medicinal properties in humans.  The compound must be novel, which means that it must be chemically identified, and then a patent search, as well as a Chemical Abstract search, must show that no similar compound has been synthesized and characterized anywhere in the world in the last 150 years.  The specific tests to positively identify a given compound will vary according to the atomic signature of the compound, but general categories of compounds require similar tests.

A patentable compound must have demonstrable utility, which in the case of medicinal compounds, has been defined by court ruling to mean both successful in vitro tests and successful animal tests.  A  U.S. Appeals Court ruling [In re Brana 51 F.3d 1560 (Fed. Cir. 1995), 34 U.S.P.Q. 2d 1436] has established that reduction to practice for a medicinal compound occurs only after successful completion of appropriate animal tests, so any patent filing submitted without such data will fail on grounds of non-utility. Clinical trials showing utility in humans are not necessary to obtain a valid U.S. patent. 

There also exists the patent concept of broad versus narrow patents.  A broad patent is granted to a novel group of compounds in which a new area of chemical entities with novel properties has been discovered.  A narrow patent is granted where a new use for a known compound is sought.  Broad patents have more commercial value than narrow patents.  With broad patents, the rule is:  show three examples, and claim the world.  Therefore, a search for closely related compounds with biological activity is mandatory if a broad patent is desired.  Effectiveness against a range of organisms allows broad claims of utility against entire classes of organisms.

With these considerations in mind, a sequential course of action would include the following steps:

 Year One:

Set up the corporate structure to retain the rights to any patents filed by the corporate entity.    Retain a patent lawyer to review the provisional patent as already written by Bayless.  A prior art search of the drug discovery is the first step.  A provisional patent should then be filed, as revised by the attorney.  Provisional patents are used a place-holders.  If the actual patent filing goes beyond the provisional patent in scope, the Patent Office will disallow the broader claims, so the provisional patent should be as broad as possible.  Provisional patents are good for one year.  If the formal patent is not filed within the one year period, a second or third provisional patent can be filed, but the priority filing date of the first or second provisional patent is lost. 

Cost: $50,000.


SYNTHESIS OF COMPOUNDS: 

Once the provisional patent is filed, a preclinical drug discovery company that specializes in synthesis and testing of compounds will be located and hired (See Southern Research Institute at end for example).   An NDA should be signed by the companies selected, but the provisional patent does not have to be shared with them until after a deal is signed.  Once the legal requirements are in place, synthesis of active ingredients will be conducted with the original compound as well as its analogs, as selected by Bayless.  Following synthesis, precipitation and/or freeze-drying, the purification of active ingredients will occur.  Synthesis of compounds will be an on-going process that may require two to four years to complete.  Any subsequent in vitro and animal testing will have to be done with a fully characterized active compound.  Thus this step is first.  Research is not a linear process, but a series of hop-scotch steps forward and back and sideways, so it is hard to forecast how long is long enough.         
    
            Cost:  $950,000.


Year Two:     

            Biological testing should begin.  As compounds are synthesized, they should be tested in vitro against a range of micro-organisms in order to select metabolically active compounds for further review.         A biological testing lab will have to be selected and hired to conduct such tests.  (See Accugen Labs for example at end)   Here again, the extent of in vitro testing necessary to evaluate synthesized compounds is difficult to forecast at this time.  The obvious endpoint is when sufficient testing is completed to support a broad patent.  The patent attorney should have input here.

   IN VITRO BIOLOGICAL TESTS:

1.     Tests of synthesized compounds should be run to identify which of
them possess inhibitory properties.  Growth Inhibition Curves in liquid media against a range of bacteria will accomplish this task.

2.     Toxicity screens of active compounds in yeast will reveal toxicity profiles and provide the Therapeutic Index on each candidate, and allow the selection those that are both active and non-toxic.

3.     Additional tests, including Minimum Inhibitory Concentration determinations as well as Growth Inhibition Curves in liquid media, and Zone of Inhibition tests using solid media against a range of pathogenic Gram-positive and Gram-negative organisms, both aerobic and non-aerobic, will establish which compounds are worth the time and expense of further characterization.
     
     Cost:  $1,000,000.


Year Three:

            Compounds which have in vitro activity against bacteria, and a satisfactory Therapeutic Index, will then be fully characterized by an Analytical Chemist.  The same lab that does the synthesis may perform the characterization, or a different lab may be selected.

ANALYTICAL METHODS:

            Once the activity and toxicity profiles of active compounds have been established, chemical characterization should occur.  By following this sequence, only active compounds go through the expense of lab identification.  Following identification, a Chemical Abstract search by the patent attorney will confirm the novelty of the group of compounds.  Typical tests for this group of compounds include:

1.     Ultraviolet spectroscopy with water as solvent.

2.     Paper chromatography,
      using the ascending technique with propanol-ethanol-water (40:40:20).

3.     Various forms of spectroscopy to determine the molecular composition of the compounds.

4.     Nuclear magnetic resonance to determine the structure of the compounds.

5.   Mass spectrometry for detection and identification of components.

                  Cost:  $1.000,000.


Year Four:

                  Once the compounds have been synthesized, tested in vitro, and fully characterized, they should be tested in animals to provide evidenced for utility.  An animal testing facility will have to be located to conduct such testing.  (See Idexx Bioresearch for example at end).



ANIMAL TESTING:

Animal models for human disease exist, and appropriate animals should be selected to demonstrate the ability of the compounds to prevent death from pathogenic bacteria. Typically, animal testing first involves establishing dosing levels, and then challenging the animal with pathogenic bacteria while providing the drug to see if the animal survives. 

Therefore:

 1.   Determine maximum tolerated oral dose in the selected animal models.

2.     Perform Staphylococcus aureus (MRSA) and Escherichia coli (diarrhea) challenge test in mouse and rabbit, and Francisella tularensis (Tularemia) and Pasteurella mutocida (cholera) tests in rabbits.  Dogs, cats, and pigs are also candidates for testing.


ADDITIONAL IN VITRO TESTS:

3.    Inhibition screening on at least three normal human cell lines to provide          a Therapeutic Index for human cells.                                                           
           
          4.    Inhibition screening on lung, breast, and prostate human tumor cell lines.

5.     Inhibition tests on at least three species of protists in liquid media.

          6.   Inhibition tests on Canine Distemper, Measles, and Ebola viruses in vitro.

                  Cost:  $1,000,000.


Year Five:

      Patent Filing.

Once the various synthesis, purification, analytical and biological techniques are completed, U.S. patent(s) must be filed.  Estimated time to completion from the provisional filing: four years.  PCT patent(s) must be filed within one year of a U.S. patent application.

Once the patent is filed, potential licensing partners can be contacted.  A marketing manager should be hired to lead this effort.  Mid-level drug development companies have the financial means to carry a drug candidate through the FDA process.  Once the FDA process is complete, licensing to major drug firms should occur.  Up-front money is usually paid at signing, with royalty payments as negotiated.  Joint ventures with major pharmaceutical companies should be investigated as a possible alternative.  Out-right sale is also possible, although licensing and subsequent royalties generally result in more money to investors over time.   
         
             Cost:  $1,000,000.




SOUTHERN RESEARCH INSTITUTE

BIRMINGHAM, Ala. —Southern Research Institute conducts both contract research and basic research for clients, providing preclinical drug discovery, development, and clinical trial support services in cancer, infectious diseases, and CNS/neurological disease to pharmaceutical and biotechnology companies. Scientists conduct translational science to invent small molecules and advance them from the design stage to the clinic. Services available include medicinal chemistry, molecular biology, biochemistry, high-throughput screening and a full set of in-house GLP development services including toxicology, ADME/PK, animal models, formulations, and bioanalytical services.
About Southern Research
Southern Research Institute is a not-for-profit 501(c)(3) scientific research organization founded in 1941 that conducts preclinical drug discovery and development, advanced engineering research in materials, systems development, and environment and energy research. More than 550 scientific and engineering team members support clients and partners in the pharmaceutical, biotechnology, defense, aerospace, environmental and energy industries. Southern Research is headquartered in Birmingham, Ala., with facilities in Wilsonville, Ala., Frederick, Md., and Durham, NC and offices in Huntsville, Ala., New Orleans, La., and Washington, DC.


ACCUGEN LABS
Accugen is a FDA registered, independent contract microbiology laboratory. We offer full microbiological testing and analyze products from a wide variety of industries. Our microbiological testing laboratory is comprised of a highly experienced team of microbiologists who are experts in testing ASTM, AOAC, AATCC, FDA, EPA, USDA, USP, CTFA, JIS, ISO and other methods of analysis. Our competent professionals have decades of experience in routine microbiological analysis, special microbiology, research microbiology, and a variety of other microbiological testing. We are considered leading authorities in microbial testing. Accugen has provided impeccable microbiological services to pharmaceutical, disinfectant, cosmetic, food, personal care, household, medical device, antimicrobial, paint, paper, plastic, textile and other miscellaneous industries. At Accugen, we understand the challenges presented by a changing market place and our goal is to maintain the cost effective and highest quality microbiological testing services.


IDEXX BIORESEARCH

Preclinical and Veterinary Clinical Testing

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Researchers in the top pharmaceutical organizations, biotechnology companies, and academic institutions trust IDEXX BioResearch to deliver the highest caliber of out-sourced lab results. Consider how we can bring your studies to a successful conclusion. 
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