Patentable and Non Patentable Biotech Inventions

1
Patentable and Non Patentable Biotech Inventions

• A Presentation
• By
• D. Calab Gabriel
• Senior Partner
• K S Partners, Gurgaon

2
Scope

• Patent Law
• What is non patentable
• Product patent
• Case studies Product Patent
• Process Patent
• Case studies- Process Patent

3
Patent law

• Patents Act 1970
• Patentable inventions
• any product or process which is
• novel
• not obvious to a person skilled in the art
• capable of industrial application

4
WHAT IS NOT PATENTABLE? (section 3)

• (d) New use of known substance/process
• Polymorphs, esters, salts, combinations,
  derivatives that do not show enhanced therapeutic
  efficacy over known main substance
• (e) Mere admixtures (as opposed in synergistic
  mixtures) and processes thereof
• Method of treatment of human beings/animals
• (j) Plants, animals parts thereof

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WHAT IS NOT PATENTABLE? (section 3)

• Section 3(d)
• 3(d) The mere discovery of a new form of a known
  substance which does not result in the
  enhancement of the known efficacy of that
  substance or the mere discovery of any new
  property or new use for a known substance or of
  the mere use of a known process, machine or
  apparatus unless such known process results in a
  new product or employs at least one new reactant.

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WHAT IS NOT PATENTABLE? (section 3)

• Section 3(d) (cont.)
• Explanation For the purpose of this clause,
  salts, esters, ethers, polymorphs, metabolites,
  pure from, particle size, isomers, mixtures of
  isomers, complexes, combinations and other
  derivatives of known substance shall be
  considered to be the same substance, unless they
  differ significantly in properties with regard to
  efficacy.
• Examples
• Toxic non-toxic
• Stable shelf life

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WHAT IS NOT PATENTABLE? (section 3)

• (e) a substance obtained by a mere admixture
  resulting only in the aggregation of the
  properties of the components thereof

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WHAT IS NOT PATENTABLE? (section 3)

• (i) any process for the medicinal / surgical /
  curative, prophylactic/diagnostic/therapeutic or
  other treatment of human beings or similar such
  process for treatment in animals.
• IN VITRO methods?

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WHAT IS NOT PATENTABLE? (section 3)

• (j) Plants and animals in whole or in part
  thereof other than microorganisms but including
  seeds, varieties and species and essentially
  biological processes for production or
  propagation of plants and animals.
• Cell per se?

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SECOND MEDICAL USE
Section 3(d)New Use of a Known substance
Section 3(e)Mere admixture
Section 3(i)Method of Treatment
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A FEW OF ACCEPTED CASES INSPITE OF 3(d) OBJECTION
S. no Application Nos. Section 3(d) Allowed different Efficacy subject matter.
1 2807/DELNP/2004 (Salt) Far better physiochemical properties i.e. Solubility, non hygroscopicity, distribution coefficient, formulation processability and photo-stability.
2 0844/DELNP/2005 (Salt) Better physiochemical Properties i.e. better photostability.
3 1046/CAL/1995 (Polymorph,new form) Better thermal Stability
4 INPCT/2002/00845 (hydrate) Better stability of heptahydrate over hydrate form
5 0457/KOLNP/2005 (Derivative) Enhanced Efficacy in Various test procedures and bioassays
6 0609/KOLNP/2003 (Derivative) Lesser Toxicity and better therapeutic Index
7 0482/KOLNP/2005 (Polymorph) More crystalline form to impart better thermodynamic stability, and purity
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A FEW OF ACCEPTED CASES INSPITE OF 3(d)
OBJECTION - contd
S. No Application Nos. Section 3(d) Allowed different Efficacy subject matter.
8 1342/KOLNP/2005 (Derivative) Improved oral Bioavailability
9 1180/MUMNP/2003 (Complex) Better stability, easily isolated and processed with minimal degradation.
10 656/DELNP/2005 (Polymorph, new forms a- and ß- Form) Form having better Stability under High temperature and relative humidity conditions
11 4719/DELNP/2005 (Polymorph, new forms a- and ß- Form) Forms having better Stability under High temperature and relative humidity conditions
12 30/DELNP/2003 (Derivative) Higher magnitude of biological activity against various cancer cells
13 842/DELNP/2005 (Polymorph) Higher stability (in terms of oral delivery)
14 1599/DELNP/2005 (Derivative) Higher pharmacotherapeutics properties like higher potency and significantly reduced brain access.
13
GLIVEC

• Test of 3(d) and the product patent regime.
• Novartis AG filed patent application No.
  1602/MAS/98 on July 17, 1998 for crystal
  modification of A N-Phenyl-2-Pyrimidineamine
  derivative, processes for its manufacture and its
  use
• Specifically beta form of N-5-4-(4-Methyl-pipera
  zino-methyl)-benzoylamido-2-methyl-phenyl-4-(3-p
  yridyl)-2-pyrimidine-amine salt.
• ( ß form of methanesulfonic acid addition salt
  of a pyrimidine compound and XRD pattern of ß
  form was provided)

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GLIVEC
X-RD of Beta Form
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GLIVEC

• Notable statement in specification It goes
  without saying that all the indicated inhibitory
  and pharmacological effects of ß form are also
  found with the free base.
• No enhanced efficacy shown
• Established ß form was pre-existing
• Application was rejected by the Patent Office
• Limited appeal to DB Chennai, case rejected
• Limited issue before IPAB-case rejected
• Challenged IPAB decision by way of write in SC

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TYPICAL BIOTECH INVENTION
Genomic DNA (plant)
Vector
Ligate
Recombinant clone in plasmid vector
Patentable
Protein product
Micro-organism, variants
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PRODUCT PATENTS

• All products of molecular biology whether for
  use as drug or food product
• Novel micro-organism (isolated/genetically
  engineered)
• Novel gene and peptide sequences
• Promoter, Marker
• Novel cassette, construct
• Vaccine
• New viral strain

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Micro-organisms

• Not defined by Act
• Possibly includes yeast, bacteria, recombinants,
  DNA sequences, vectors
• Are isolated microbes and colonies mere
  discovery ??
• Isolates, if characterized, deposited in ID and
  utility found - patentable
• Genetically modified organisms patentable
• Source and origin of Biological material to be
  provided in specification

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Genes

• Gene sequences if isolated and utility found,
  patentable
• Are they part of animal or human being ?
• Antibodies, including chimeric antibodies are
  patentable

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Nucleotide sequences

• Nucleic Acids
• molecules containing A, G, C and T residues
  (DNA)
• molecules containing A, G, C and U residues (RNA)
  
• DNA is transcribed into RNA
• RNA is translated into Proteins
• Proteins are molecules containing up to 20
  different amino acid residues A (ala), C (cys),
  D (asp), E (glu), F (phe), G (gly), H (his), I
  (ile), K (lys), L (leu), M (met), N (asn), P
  (pro), Q (gln), R (arg), S (ser), T (thr), V
  (val), W (trp)
• 3 nucleic acid residues code for
• one amino acid residue

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Isolated DNA EP Position

• What is a DNA sequence ? Can it be patented?
• Held in RELAXIN CASE Isolated DNA sequence is a
  chemical compound can be patented

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Isolated DNA US Position

• patentable
• An isolated and purified DNA molecule, RNA
  molecule, or amino acid molecule
• isolated chemical compounds
• Full-Length Genetic Sequences patentable
• Corresponding amino acid sequence patentable

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US position- Contd

• ESTs
• Partial nucleic acid sequences if proved useful
  (eg as encoding protein responsible for
  diagnosis of a specific disease) patentable

• DNA fragment encoding a full ORF
• May be useful if homology to existing nucleic
  acids or proteins (with an established utility)
  is at least 95

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BOTTOM-LINE

• Nucleotide sequences
• The sequence must be isolated and purified from
  its natural environment
• raw sequences with no known use are not
  patentable
• India
• Product patent regime just introduced
• So far few patents granted for nucleotide
  sequences
• Sequences patentable provided
• Isolated from natural surrounding
• Utility proven

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BOTTOM-LINE

• Nucleotide sequences
• TTT ATT TGT CCT ATT TAA CCT CGT GCT CAT GCT
• phe ile cys pro ile stp pro arg ala his ala
• Claim
• 1.An isolated nucleic acid sequence bearing SEQ
  ID 1

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Micro-organisms EP position

• EP case T396/93
• Micro-organism includes bacteria, yeast, fungi,
  algae, protozoa, virus.
• Biotechnology Directive
• Defines biological material not micro-organism
• Includes microbes, cell lines, viruses.
• Excludes cell lines used for modifying germ line
  of human beings

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Micro-organisms US position

• Diamond v. Chakrabarty, 447 U.S. 303 (1980)
• genetically engineered bacteria are patentable
• anything under the sun that is made by man
• Patents granted for
• Yeast lines,
• Virus, hybridoma, oyester
• Harvard Mouse

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Micro-organisms Indian position

• Section 3
• Plants, animals and human beings except
  micro-organism not patentable
• No distinction between isolated and genetically
  modified micro-organism
• Many argue Isolated micro-organism is no
  invention, only GM

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ISOLATED MICROORGANISM

• Micro-organism
• Isolated ?
• Mutant ?
• Genetically modified ?
• Deposit in international depository prior to date
  of Indian filing

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LIFE SCIENCES

• Micro-organism
• Also describe source and origin of biological
  material
• Bring out utility
• If mutated set out conditions, details

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CHARECTERISATION OF YEAST STRAIN

• Ex Mere mention of deposit of yeast strain in
  a depository without setting out its
  characteristics in the specification is
  inadequate description
• Pfizers Application 1974 RPC 689

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LIFE SCIENCES

• DNA/Protein Sequences
• Describe fully how sequence was derived
• If mutated, how?
• Utility/applications of sequence
• Products comprising sequence
• Sequence listing to be submitted

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USE OF NEW SUBSTANCE

• A novel compound X useful for treatment of cancer
• Use of compound X for treating cancer
• A novel compound X to prepare a medicament Y for
  treating cancer
• Use of compound X to manufacture medicament Y for
  management of cancer

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BIO-PRODUCTS

• Indicate the class and specific chemicals used
• Ex All the oxidants that would enable the
  invention, all alkali/acids that would help to
  work the invention

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EXAMPLE
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US PATENT NO. 6,764,824

• What is claimed is 1. The primers of SEQ ID
  NO 1 and 2 useful for screening human beings for
  a pre-disposition to schizophrenia.
• 2. A method of screening human beings for a
  pre-disposition to schizophrenia by identifying
  non-sense mutation of codon TGG coding for amino
  acid tryptophan substituted with TAG, a non-sense
  codon, at nucleotide No. 825 from 5' end in exon
  2 and its allelic variants in synaptogyrin 1 gene
  of chromosome 22q11-13, said method comprising
  (a) isolating DNA from blood leukocytes, (b)
  amplifying isolated DNA by PCR using primers of
  SEQ ID NO 1 and/or 2 of enclosed sequence
  listing, specific for exons of synaptogyrin 1
  gene, (c) sequencing the amplified DNA, (d)
  comparing the sequenced DNA with that of normal
  synaptogyrin 1 gene, (e) identifying the said
  mutation, (f) designing oligonucleotide primer
  and/or probe of SEQ ID NO 3 of enclosed sequence
  listing with its 3' end extending up to
  penultimate position of said mutation, (g)
  screening for said non-sense mutation using
  primer and/or probe of step (f), and (h)
  screening of said allelic variation for said
  non-sense mutation using appropriate allele
  specific oligonucleotide probes and/or primers
  selected from the group consisting of SEQ ID NO
  4 to 7 of enclosed sequence listing.

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US PATENT NO. 6,958,224

• A chimeric protein aBNAC, of SEQ ID NO2.
• A chimeric protein as claimed in claim 1, wherein
  said chimeric protein is consists of a total of
  177 amino acids.
• A chimeric protein as claimed in claim 1,
  wherein the net charge of each unit of said
  chimeric protein is -5.
• A chimeric protein as claimed in claim 1,
  wherein said chimeric protein forms beta-sheet
  structure.
• A chimeric protein as claimed in claim 1,
  wherein the N-terminal domain of said chimeric
  protein contains nine proline residues.

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US PATENT NO. 6,616,950

• What is claimed is 1. A fermented fruit based
  herbal health drink composition useful as an
  antioxidant, cardio-tonic, diuretic, digestive,
  choleretic, nervine relaxant and immuno-modulant,
  comprising extract from plant Andrographis with
  concentration ranging between 0.5 to 10 in the
  total herbal health drink, extract from fruit,
  and ethanol ranging between 3 to 13 in the total
  herbal health drink, optionally extract from
  plant Tinospora and other additives.

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US PATENT NO. 6,558,940

• A biologically pure culture of Streptomyces sp.
  CIMAP A.sub.1 strain bearing ATCC Accession No.
  PTA-4131 and capable of inhibiting the growth of
  phytopathogenic fungi.

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US PATENT NO. 6,696,284

• 1. A biological filter for the purification of
  waste gases, comprising a housing with at least
  one inlet and at least one outlet, and a bed of
  active micro-organisms contained in a carrier
  material consisting of pith extracted from
  coconut husks, the carrier material being
  provided in the housing such that the waste gases
  flowing in through the at least one inlet contact
  the bed of carrier material before exiting
  through the at least one outlet.

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US PATENT NO. 6,548,746

• 1. A new and distinct high alkaloid producing
  Catharanthus roseus plant called Dhawal having
  NCIMB accession number 41147, and having the
  following combination of characteristics (a)
  plant height of 65-75 cm, (b) light green to
  grayish green (emerald green 758/1 color
  designation from the "Horticultural Colour Chart
  II") pubescent leaves with distinctly undulating
  leaf margin, (c) green stem, (d) white
  flowers, (e) field resistance to die back
  disease, (f) high leaf yield of 1352 to 2557
  kg/ha, (g) 0.89 to 1.40 of total alkaloids in
  leaves, (h) 1.60 to 2.22 of total alkaloids in
  roots, (i) a randomly amplified polymorphic DNA
  (RAPD) profile distinct from the variety Nirmal
  when the DNA is polymerase chain reaction (PCR)
  amplified by four primers selected from the group
  consisting of OPT 06, 09, 16 and 17, and (j)
  higher herbage and alkaloid yield as compared to
  the variety Nirmal.

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PROCESS PATENTS

• Any in vitro process
• Method of protein purification, downstream
  processing
• Process using micro-organisms to obtain
  chemicals

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Screening Assays

• Usually patentable
• Diagnostic assays grey area
• Is it ex-vivo or in-vivo?
• Does the result of the method indicate that
  subject is suffering from a disorder?
• If yes, not patentable

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Examples PATENTABLE PROCESS

• PCR process
• Process using microbe
• Novel fermentation products,
• novel techniques
• - RFLP, AFLP, fingerprinting etc

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US PATENT 7247291
Nano sized sulfide compounds of cerium and a
process for the preparation thereof

• A bioprocess for the preparation of a sulfide
  compound of cerium, which comprises the
  steps of
• a) treating trivalent Cerium salt, optionally in
  combination with 0.005-0.1 w/v, of sodium
  sulfate, with a culture broth of sulfate-reducing
  bacteria (SRB), containing 0.05-1 v/v, of
  chloroform, under an inert atmosphere, at a
  temperature ranging between 25-40 C., at pH of 2
  to 6 for a period in the range of 3 to 45 days in
  single or several installments such that a
  concentration of trivalent Cerium ions does not
  exceed 0.1 w/v at any point of time, to obtain a
  biomass,
• b) concentrating the biomass as obtained in step
  a) at a temperature ranging between 60 to 150 C.
  for a period in the range of 1 to 6 hours to
  obtain a concentrated biomass, and
• c) treating the concentrated biomass as obtained
  in step b) at a temperature between 600 to 1500
  C. for a period in the range of 5 to 400 minutes
  followed by separation to obtain a sulfide of
  Cerium.

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US PATENT 4960429
Chromium free process for the tanning of hides  

• A chromium free process for the tanning of
  animal hides which includes, after the standard
  pretreatment of the hide, covalently modifying
  the skin collagen of said hide by a process ..

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U.S. PATENT 6777219
PROCESS FOR THE PREPARATION OF ALKALINE
PROTEASE  

• A process for the preparation of alkaline
  protease which comprises growing a fungal strain
  Conidiobolus coronatus isolated from Anekal,
  Karnataka, India and deposited in American Type
  Cell Culture (ATCC) depository under Accession
  Number PTA-4132, in a medium having pH 6.0 to
  9.0, a carbon source and a nitrogen source under
  aerobic conditions in submerged culture, at a
  temperature ranging between 20 to 30 C., for a
  period ranging between 2 to 6 days, harvesting
  the medium and separating the enzyme in liquid
  phase.

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Australian Patent Application no 2003217445

• A method for unhairing animal skins or hides
  using a total lime and sulfide free enzymatic
  solution comprising
• preparing an enzymatic solution from animal or
  plant tissue,
• optionally presoaking of skins or hides in water
  at 10C to 60C for 2 to 6 hours,
• removing the soaking liquor,
• applying the enzymatic solution by pasting or
  spraying on the flesh side of the skin or hide
  and left for 10-24 hours at a temperature ranging
  between 10C to 60C, wherein the skins or hides
  are arranged flesh side to the flesh side or
  grain side to grain side,
• floating the skins or hides in liquid comprising
  the enzymatic solution, vi. removing
• the skins or hides from the liquid comprising
  enzymatic solution to produce an effluent and,
• unhairing of the skins or hides either by
  scraping the hair with a curved knife on a wooden
  beam or by an using unhairing machine.

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Method for regeneration of organs

• A method for regenerating organs in humans using
• stem cells
• from contiguous embryonic peritoneal layer
• formation of mesodermal organs in vitro
• avoids use of exogenous tissue
• 5 organs regenerated

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Method for regenerating organs

• Patent Act, 1970
• sec 3(i) any process for the medical, surgical,
  . treatment of human beings or render them free
  of disease
• invention in question hit by above provision
• currently not patentable in India
• US 6,227,202 obtained

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Method for regeneration of organs

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Ureter regenerated
53

• ?

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