Mapping Biologics to Diseases

One simple way to understand the importance of biologic drugs is to map them to the diseases they treat. In the process of identifying priority public health important biologics the first step is to ascertain whether they are protected by a patent monopoly, a patent monopoly grants market exclusivity for a limited period of time thereby exclude competitors in the market and allow the patentee to price these patented biologics exorbitantly. Considering a complex technology and a higher manufacturing standards required for producing biologics, they always come with a prohibitive price tag. For instance, when a late stage breast cancer drugs Kadycla and Perjeta was launched in 2015 in India, the launch price for 200ml dosage of Kadycla was Rs.2,10,000 amounting to 12 lakh and Perjeta per dosage was priced at Rs.2,49,000 amounting up to 30 lakh for 9 months treatment¹, Over the past decade or so there has been an increase in the use of biologics for diseases otherwise left untreated by small molecule drugs (chemical / pharmaceutical drugs). These protein based biologics considered as specialty therapies are the go to drugs to treat various diseases and at present are being used in the treatment of rheumatoid arthritis, Crohn’s disease, Psoriasis, psoriatic arthritis, allergic asthma, breast cancer, ulcerative colitis, multiple myeloma, pneumonia (vaccine) etc.². In India, many biosimilar drugs (follow-on biologics) are already available and marketed such as bevacizumab, rituximab, etanercept, infliximab, adalimumab, insulin glargine, trastuzumab, etc. There are different therapeutic categories in biologics such as monoclonal antibodies, recombinant hormones/proteins, cell therapy, gene therapy, interferons, antisense, growth factors, vaccines etc. The International Patent Classification (IPC) for biologics are A61K39/00, in particular for antibodies/antigens it is A61K2039/505, C07K16/08, C07K16/34, C07K16/30, Y10S530/808 etc. The most widely exploited therapeutic category of biologics for its targeted specificity and extensive applicability is monoclonal antibodies (mAbs). mAbs have been the highlight of major discoveries and have rendered possible solutions in precision medicine with over 100 mAbs approved as drugs since 1985³.

Monoclonal antibodies

Every individual’s immune system is intrinsically equipped to produce antibodies to fight against antigens. Those antibodies, which can be produced and mass synthesized in the laboratory are known as monoclonal antibodies (mAbs). In the initial years these were made from hybridoma cells by using recombinant DNA technology however with advance in biotechnology various mAbs are currently being designed and produced, the four main types are murine, chimeric, humanized and human mAbs. The monoclonal antibodies (mAb) discovered way back in 1980’s has paved way to multiple advancements both in diagnostic and therapeutic fields in addressing various challenges in new age diseases. The first therapeutic mAb, Muromonab-CD3 (Orthoclone, OKT3) was approved by FDA in 1986 and since then many mAbs have been discovered and approved for medical use such as adalimumab, abciximab, trastuzumab, alemtuzumab, cetuximab, bevacizumab, rituximab, ipilimumab, omalizumab, nivolumab, tocilizumab, etc and many more are under development and clinical investigation⁴.

Kohler’s Technology

Ironically, Dr. Georges Kohler and Dr. Cesar Milstein, discoverers of the process of producing monoclonal antibodies in 1975 who also went on to receive Nobel Prize for their work on producing monoclonal antibodies did not patent protect their technology. Kohler didn’t believe in protecting the technology with patents and while sharing the X63 myeloma cell line with other scientists had categorically insisted on not seeking patent protection for products produced through this technology⁵. The first ever patent for mAbs against tumors and influenza antigens was respectively granted in the years 1979 and 1980 to Hilary Koprowski, Carlo Croce and Walter Gerhard⁶. These mAbs were actually created using X63 myeloma cell line originally developed and supplied from Milstein to Koprowski in 1976. Since then there have been different types of mAbs developed and patented both for diagnostic and therapeutic use. The first ever patent on monoclonal antibodies was for the method of producing tumour antibodies⁷. The claims pertained to method of producing malignant tumour antibodies from fused cell hybridoma technology. Over the year’s patents on mAbs have been granted to various types of claims comprising antibodies, antigen specificity, antibody targets, amino acid sequence of antibody, antibody specific functionalities, epitope on antigens and paratopes on antibodies etc Numerous patents on mAb drugs such as pertuzumab, trastuzumab emtansine T-DM1, obinutuzumab, nivolumab, ipilimumab, pembrolizumab, margetuximab have been granted in many countries, including India. As we explore the vast field of mAbs for therapeutic purposes, it is also important to emphasize the need to accord patent protection for genuine inventions which would advance the therapeutic benefits and at the same time ensure patent protection does not lead to cost barriers in accessing these wonder drugs.

Method of Producing Antibodies

The first ever patent claims for monoclonal antibodies was that of “Method of Producing Tumour Antibodies” [US4172124A]

1. A method of producing malignant tumour antibodies comprising immunizing an animal with tumour cells, forming fused cell hybrids between antibody producing cells from said animal and myeloma cells, cloning said hybrids and selecting clones which produce antibodies that demonstrate a specificity for tumour cells.

Analysis: The underlined sentence pertains to process, sentence in bold pertains to technology and italicized sentence pertains to the product. An independent claim covering the method of producing malignant tumour antibodies by immunizing and fusing the cell hybrids between mouse cells and myeloma cells. These cell hybrids are then cloned to produce antibodies with specificity for tumour cells.

10. process of claim 1, wherein said hybrid is introduced into an animal selected from the group consisting of a histocompatible animal and athymic nude mice and cultured in vivo.

11. A method according to claim 1 wherein a mouse is immunized with tumor cells and a fused cell hybrid is formed between the spleen cells of said mouse and mouse myeloma cells.

16. A method according to claim 1 wherein a mouse is immunized with tumor cells and a fused cell hybrid is formed between the spleen cells of said mouse and mouse myeloma cells.

Analysis: The dependent claim covers the process of culturing the hybrid cells in vivo selected from histocompatible animal and athymic nude mice. The method involves making of fused cell by immunizing the mouse with tumour cells to form a hybrid cell with spleen cells and mouse myeloma cells. The in vivo culturing of hybrids is in the animal selected from the group consisting of a histocompatible animal and athymic nude mice.

Another important mAb used in the treatment, of HER2-positive breast cancer patients in combination with other chemotherapeutic drugs (trastuzumab and docetaxel) is pertuzumab. This is an important drug used in cases where the present regimen of Herceptin treatment fails in breast cancer patients causing a relapse⁸.

A patent for pharmaceutical formulation with Pertuzumab is patented in India⁹.

“Pharmaceutical Formulation Comprising HER2 Antibody” [IN268632]

Claims¹⁰

1. An aqueous pharmaceutical formulation comprising Pertuzumab in an amount from 20mg/mL to 40mg/mL, histidine acetate buffer at a concentration from 10mM to 40mM, sucrose at a concentration from 60mM to 250mM, and polysorbate 20 at a concentration from 0.01% to 0.1%, wherein the pH of the formulation is from 5.5 to 6.5

Analysis: The underlined sentence in the claim pertains to composition, sentence in bold pertains to product comprising mAb, excipients at specific concentration and italicized sentence pertains to the properties of the formulation. An independent claim covering a pharmaceutical composition in aqueous form consisting of pertuzumab (mAb), histidine acetate buffer, sucrose and polysorbate with a pH range of 5.5 to 6.5. The patentee was able to overcome the objections raised under Section 2(1)(j), 3(d) and 3(i) by showing that the claimed concentration of the mAb and excipients in particular histidine acetate buffer is specific to this formulation as it displayed better superior properties compared with histidine-Hcl, histidine-Hcl is the standard buffer used in the preparation of previous mAbs (trastuzumab, theomaliumab, thepalivizumab etc) and the present formulation includes histidine acetate buffer. The claimed concentration and ratio of constituents used in the present formulation exhibits superior properties by preventing particle formulation when stored in stainless steel tanks leading to corrosion and leaching of metal irons thereby avoiding potential immunogenicity which in turn could impact the therapeutic efficacy of the claimed formulation. Thereby through lower particle formation and aggregation during the manufacturing process of the formulation, the patent claims better pharmaceutical formulation comprising pertuzumab antibody.

Conclusion:

With the advent of hybridoma technology and discovery of mAbs the diagnosis and realisation for new age therapies to address multiple diseases and disorders has been achievable. mAbs have revolutionised treatment for cancer with their specificity and targeted approach, for example breast cancer and Alzheimer’s disease. As the technology for identifying and developing mAbs evolves and continues we can look forward to treating incurable diseases such as autoimmune diseases, genetic disorders (Mogamulizumab, Lanadelumab-flyo), infectious diseases and certain types of cancers. The scope of the claims for mAbs will also be expanded and from the above two claim analysis it is evident that patent protection will be claimed and granted for every aspect of this technology. The scope of the claims can include process, pharmaceutical composition/formulation, specific concentration of the excipients, specificity of the antibody, properties of the pharmaceutical composition, combination of different mAbs, method of treatment, the technology involved in producing mAbs and finally the product.