API and IP Newsletter
Contents
Recent FDA approval: Palovarotene
We follow FDA approvals. We cover chemistry, very brief regulatory and IP situation in this write-up.
On 16 August 2023 FDA approved Palovarotene, 10 MG capsule.
Palovarotene, sold under the brand name Sohonos, is a medication used for the treatment of heterotopic ossification and fibrodysplasia ossificans progressiva. It is a highly selective retinoic acid receptor gamma (RARγ) agonist.
Ipsen estimated palovarotene peak annual sales of $400 million in chronic and flare-up FOP indications, plus significant upside from approval in multiple osteochondromas here.
It was approved for medical use in Canada in June 2022. So, before US approvals, generics would have innovator samples available for reverse engineering.
Claim 39 in WO2002028810A2 represents the compound.
Example 20 in WO2002028810A2 describes synthesis of 4-[(1E)-2-(5,5,8,8-Tetramethyl-3-pyrazol-1-ylmethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-vinyl]benzoic acid ie Palovarotene
NCE-1 date would be 16 August 2027. An equivalent of compound patent is expired in US. All OB listed patents are related to method of use. Generally whenever there is no compound patent protection, one could see many ANDA filers on NCE-1 date. So, in this case also one would expect many ANDA filers on NCE-1 date, though we have not studied strength of all OB listed patents.
Raw material (RM) required for synthesis of Palovarotene would be very common. One of the RM is 2,5-Dimethyl-2,5-hexanediol it is imported by Emcure, Rampex, BDR and Matrix.
Another RM is 1-Methylpyrrolidine. It is also very common RM, Aurigene, DRL, GVK, Sai, Syngene, Avra have recently imported it in a small quantity. These companies might be active in development of generic Palovarotene.
General information
Artificial Intelligence in Drug Development: Patent Considerations
Abstract ideas, mental steps, and mathematical algorithms are not patentable.
The transformative potential of AI, encompassing machine learning and generative capabilities, holds great promise for revolutionising drug discovery and development. This promising horizon is accompanied by intricate challenges.
News here.
Japan approves Alzheimer's drug developed by Eisai, Biogen
Japan's health ministry on Monday approved the manufacture and sale of a drug for Alzheimer's developed by Japanese pharmaceutical company Eisai and U.S. company Biogen.
Lecanemab, branded Leqembi, will be the first drug in Japan to both treat the underlying cause of Alzheimer's disease and slow the development of its symptoms.
News here
Intellectual Property
Teva vs Eli Lilly
This is a dispute between two anti-migraine products. Emgality of Eli Lilly and Ajovy of Teva.
Emgality’s sale hit $650m in 2022, and is expected to reach $1.3bn by 2029. Ajovy’s sale was $342m last year, and is forecasted to reach $719m by 2029.
The Court was moved by Teva. Matter was in United States District Court District of Massachusetts.
The Patents-in-Suit are
US 8,586,045,
US 9,884,907 and
US 9,884,908 relate to a method for treating headache by blocking the binding function of the CGRP protein
These patents are issued or license to Teva and Teva believed Eli Lilly’s product Emgality infringes these patents.
Background:
Teva and Lilly both developed antibodies capable of treating headache disorders associated with calcitonin gene-related peptide (“CGRP”).
In the instant case, Teva alleged that Lilly induced infringement and contributorily and wilfully infringed three of its above listed patents
Lilly, in turn, alleged that the Patents-in-Suit are invalid for lack of written description and enablement.
From 18 October 2022 through 09 November 2022, the parties presented their cases to a jury, which returned a verdict in favour of Teva and awarded $90,000,000 in lost profits damages, $36,740,000 (or 5%) in reasonable royalty damages, and $49,800,000 in future lost profits damages.
The matter was before the single Judge bench for the bench trial.
Brief science is explained below
CGRP is a protein found in humans. When CGRP binds, or attaches, to certain cells, the cells expand, causing increased blood flow through blood vessels, which is associated with headache.
The Patents-in-Suit, relate to a method for treating headache by blocking the binding function of the CGRP protein.
More specifically, the Patents-in-Suit relate to a method for using humanized anti CGRP antibodies to bind to CGRP, and block the CGRP protein from itself binding to cells in a way that causes headache.
Antibodies and antigens are both proteins. Antibodies are proteins produced by the immune system to fight disease and infection by identifying and binding to antigens.
A humanized antibody is an antibody engineered in a laboratory. Humanizing an antibody means taking an antibody from a non-human species, like a mouse or rat, and converting it to an antibody that the human immune system will not reject.
The makeup and shape of an antibody (a protein) is relevant to how the antibody functions. Proteins are made up of amino acids. There are approximately 20 amino acids found in the human body. These individual amino acids combine together in chains linked together in a head-to-tail fashion, to form a protein.
When amino acids combine in a chain to make a protein, they form a shape, and the shape of the protein determines the protein’s function. The relevant antibodies here are generally depicted with a Y-shape.
Typical full-length antibodies are made up of four chains two light chains and two heavy chains and each of the four chains has two regions, a constant region and a variable region.
The constant regions are largely the same across all antibodies, and the variable regions are different in different antibodies.
The variable regions, or variable domains, can be categorized into V-gene families.
Different V-gene families are defined by their sequence, or makeup, of amino acids.
A V-gene family’s sequence of amino acids determines the variable region of the antibody’s structure, or shape.
Inside the variable regions are complimentary determining regions (CDRs), which are structures with a distinct sequence of amino acids.
The CDRs are the parts of an antibody that bind to an antigen.
The CDRs have a particular shape based on their amino acid sequence, and when a CDR’s shape matches the shape of a binding site on an antigen (called the epitope region of the antigen), the antibody can bind to the antigen.
These antibodies are called humanized anti-CGRP antagonist antibodies because when they bind to the protein CGRP (when the CDR of the antibody binds with the epitope of CGRP), they antagonize, or block, CGRP from functioning in a way that causes headache.
Dr. Jorg Zeller and his team are the inventors of the Patents-in-Suit.
Arguments by parties
Teva argued that evidence at trial confirmed that before Zeller and his team developed the Patents-in-Suit, a connection between CGRP and headache had been established, and both clinically-effective small molecule drugs targeting the CGRP pathway and anti-CGRP antagonist antibodies had been described in the scientific literature, but a [person of ordinary skill in that art (a “POSA”)] did not yet know whether the antibodies could be used to prevent headache.
For example, Teva cited to an inventor of the Patents-in-Suit’s testimony that as early as 2001, he and others knew that if you inject CGRP into human, you elicit pain. People actually did this experiment, they injected CGRP into human that elicited an acute migraine.
That inventor further testified that in 2003, an executive at his company made a public presentation showing that blocking the CGRP receptor leads to partial reversal of migraine pain, and that research on this same topic was published just under a year after 2004.
All of the asserted claims require the use of a humanized anti-CGRP antagonist antibody. In addition, the asserted claims cover a method for treating headache by administering the humanized anti-CGRP antagonist antibodies.
Lilly contended that Teva’s specification discloses just a single humanized anti-CGRP antagonist antibody within the scope of the asserted claims. Teva’s CGRP antibody is called G1.
Although the specifications disclose 84 variants of the humanized anti-CGRP antagonist antibody G1, Lilly contends that the 84 variants are not within the scope of the ’907 and ’908 Patents because they are antibody fragments, not full-length antibodies.
In contrast, Teva argued that the specifications disclose experimental data for 97 different humanized and murine anti-CGRP antibodies, including antibody G1.
Teva’s anti-CGRP product is called Ajovy®. The active ingredient in Ajovy® is the G1 antibody disclosed in the Patents-in-Suit, which is also called fremanezumab (fmab).
Lilly’s alleged infringing product is Emgality®, and the active ingredient in Emgality® is the anti-CGRP antagonist antibody galcanezumab (gmab). Lilly argued there are several differences between G1 and gmab.
As mentioned earlier from 18 October 2022 through 09 November 2022, the parties presented their cases to a jury, which returned a verdict in favour of Teva. A jury awarded Teva $ 176.5 million damage and rejected Lilly’s argument that patents are invalid.
Lilly filed the instant motion for judgment as a matter of law (JMOL) and/or a new trial on 27 January 2023.
Lilly argued that it is entitled to JMOL and/or a new trial because the asserted claims are invalid for two reasons: (1) lack of written description and (2) lack of enablement.
Lilly also pleaded that it is entitled JMOL and/or a new trial on the issue of future lost profits. The Court addressed each issue in turn.
A District Court Judge overturned Jury verdict and $176.5m damage award. The Hon Judge agreed Emgality, utilises a similar mechanism for mitigating migraines, inhibiting calcitonin gene-related peptides (CGRP) that cause pain.
However, the case hinged on whether Teva had the right to patent CGRP antibodies as a whole based on it being the first company to prove and then commercialise its ability to treat migraines with its G1 antibody.
According to the Judge, Eli Lilly argued successfully that its own antibody, galcanezumab, was substantively different to G1, and that the process used to create these antibodies was widely known in the industry.
The active ingredients are only around 50%-60% similar and given the mind-bogglingly larger number of antibodies that could fit within the asserted claim, it was ruled unreasonable to classify galcanezumab, and therefore Emgality, as covered by the patent.
Finally Hon. Judge reversed the Jury’s validity decision and concluded that Teva’s patents are overly broad and did not enable scientist to recreate the antibodies without undue experimentation.
Decision here
