Viewing the patent layout strategy of combination therapy from the cooperation between Hengrui and Cornerstone

In the field of tumor treatment, in recent years, the obvious development trend is to shift from single treatment to combined treatment
.
Specifically in immunotherapy, the combined inhibition of CTLA-4 target and PD-1 target has become a classic match
.
Recently, Hengrui Pharmaceuticals chose to purchase CS1002 CTLA-4 monoclonal antibody CS1002 from CStone Pharmaceuticals, which also confirmed the development trend of combination drugs
.
CStone Pharmaceuticals has taken combination medication as one of its company's development strategies
.
In this article, the author will analyze the direction of CS1002 that may obtain patents for joint use in the future
.
01 CS1002 and Ipilimumab (Yervoy™) CTLA-4 are popular targets.
There are dozens of drugs under development, and more than 20 are in the registration/critical clinical trial stage
.
Bristol-Myers Squibb (BMS) product ipilimumab is the only drug on the market in the world for this target
.
In the Chinese market, the core patents of Yervoy antibodies (CN1371416B & CN102766210B) have expired in 2020
.
CS1002 from CStone Pharmaceuticals is an analog of Yervoy antibody and its amino acid sequence is the same as Yervoy
.
As the core patent of BMS has expired, the major patent obstacles in front of CS1002 have been removed
.
02 Combination of CS1002 and CS1003 As mentioned above, tumor immunotherapy is a research and development strategy that CStone has been emphasizing
.
CS1002 should be developed to enrich the product pipeline to better implement the strategy of combination therapy
.
For CTLA-4 targets, current research focuses on the combination of CTLA-4 and PD-1/PD-L1 antibodies
.
In the fourth quarter of 2020, CStone Pharmaceuticals submitted an IND application in China for the combination therapy of CS1002 and CS1003 (CS1003 independently developed PD-1 antibody)
.
From a patent point of view, the combination therapy of CS1002 and CS1003 can be simply divided into two levels: (1) CS1002+CS1003 combination, that is, if CS1002+CS1003 is brand new, this combination can be protected; (2) CS1002+ CS1003 is used for disease X, that is, if the combination treatment of disease X is brand new, the application of the combination CS1002+CS1003 for treatment of disease X can be protected
.
CS1002+CS1003 patent application for the combination of CS1002+CS1003, although CS1003 is a self-developed PD-1 antibody developed by CStone, which has a sequence different from the existing PD-1 antibody, the combination may be novel; but PD-1 When the combination of antibody and CTLA-4 antibody has become the mainstream of treatment, the combination of CS1002+CS1003 is likely to have the problem of lack of creativity
.
If it is hoped that the combination can obtain patent protection, it may be necessary to prove that it has better effects than the existing similar combination, which is quite difficult
.
According to the public patent examination information, the author also did not find that CStone Pharmaceuticals has submitted patent application information for this combination.
It also shows that CStone Pharmaceuticals has no intention to deploy because of the low degree of patentability of this combination
.
CS1002+CS1003 combination is used to treat disease X.
There is not much public information related to CS1002 at present, but according to the announcement of CStone Pharmaceuticals and Hengrui Pharmaceuticals, we can still take a look
.
In the announcement, Zhang Lianshan, President of Global R&D of Hengrui Pharmaceuticals, stated that “CS1002’s excellent early clinical data and differentiated dosing regimens further demonstrate its excellent R&D capabilities.
” It can be inferred that CStone Pharmaceuticals should adjust the dosing regimen.
Highlight the advantages of CTLA-4 antibody therapy
.
Unfortunately, in the current practice of patent examination in China, it is usually difficult to obtain patent protection for dosing regimens
.
The claims of the Chinese patent for medical use adopt Swiss-type claims, that is, the application of substance A in the preparation of drugs for the treatment of disease X
.
The dosing interval feature is usually regarded as a technical feature of the medication process, which cannot be linked to the pharmaceutical process, and thus will be regarded as unlimited
.
In the following, the author will analyze the identification of drug characteristics in China's patent examination through specific cases of patent administrative disputes
.
03 Applicant for case retrial (plaintiff in the first instance, appellant in the second instance): Kabis Pharmaceutical Co.
, Ltd.
Respondent (defendant in the first instance, appellee in the second instance): Patent Reexamination Board On November 19, 2013, the Supreme People’s Court took issue with Kabis An administrative ruling was made in the case of invalid administrative dispute between the Special Pharmaceutical Company and the Patent Reexamination Board concerning the patent number 99812498 and the invention patent named "Antibiotic administration method", and Kabist Pharmaceutical Company's application for reexamination was rejected
.
In the ruling, the Supreme People's Court held that the characteristics of the patent administration dosage, time interval and other features have no limiting effect on the medical use claims
.
The claims of the patent in question are as follows: 1.
The use of latentomycin in the preparation of a medicament for treating bacterial infections in patients in need without causing skeletal muscle toxicity, wherein the dose used for the treatment is 3 to 75 mg/ kg of latentomycin, wherein the dose is repeatedly administered, and the dose interval is once every 24 hours to once every 48 hours
.
Obviously, the claim relates to the technical features of the dosage and time interval; in the Supreme People’s Court’s decision, it was pointed out that since such claims restrict the manufacturing behavior of the manufacturer that manufactures a drug for a certain purpose, the method should still be followed.
Analyze its technical features from the perspective of claims
.
In this case, Carbis Pharmaceutical Company was able to prevent latentomycin from producing skeletal muscle toxicity through the use of a specific dosing regimen.
This solution is undoubtedly a major discovery regardless of whether it is from a market or R&D perspective.
Before the discovery of this dosing regimen, it was generally believed that a small amount of latentomycin could not be used for treatment, and a larger dose would cause skeletal muscle toxicity, leaving latentomycin in a tasteless state
.
However, it is based on Swiss-type claims, so the dosage regimen does not affect the raw materials, preparation steps and process conditions, drug product form or composition, and equipment, etc.

.
In the end, the technical solution of the patent is considered to be an improvement in the dosage and time interval of administration, without changing the antibacterial mechanism, antibacterial spectrum and bactericidal activity of latentomycin, and does not change the known use of latentomycin in treating diseases.
Furthermore, the patentability of the patent is denied
.
It can be seen from this that even CStone Pharmaceuticals may be able to improve the efficacy of the CS1002+CS1003 combination from a therapeutic point of view through a differentiated dosing program.
According to the current practice of Chinese patent law review, if the efficacy improvement cannot be linked to the pharmaceutical process, this dosing program It’s more difficult to be recognized by the Chinese Patent Office for its innovativeness
.
On the other hand, if you try to protect the dosing regimen in China, you must actively try to establish a connection between the dosing regimen and the pharmaceutical process during the research process, and provide sufficient data to prove this connection when applying
.
Of course, because the United States patent law protects therapies, there are no restrictions on the practice of Chinese patent review in the dosing regimen in the United States
.
Similarly, although early Europe adopted a Swiss-type claim approach similar to China’s, the European Patent Office has completely denied the rationality of Swiss-type claims since 2011, and adopted a second medical use claim instead.
(For example, Compound A for use in the treatment of cancer), that is to say, the dosage, method of administration, etc.
can also be protected in Europe
.
Therefore, based on the current information disclosed by CStone Pharmaceuticals, the combination of CS1002 and CS1003 may be difficult for China to obtain exclusive patent rights, but there is still room for Europe and the United States
.
In addition, CStone Pharmaceuticals can also actively expand the combination program to new cancer types, and can obtain patent rights for the combination program to treat specific diseases
.
In addition, in the announcement, Zhang Lianshan, President of Hengrui Pharmaceuticals Global R&D, also stated that “CS1002 is an important supplement to the pipeline layout and has important drug combination potential.
” Therefore, Hengrui Pharmaceuticals also introduced CS1002 based on the combination of drugs.

.
Therefore, for Hengrui Pharmaceuticals, the above conclusion on the patentability of the combination therapy is also applicable to Hengrui.
If Hengrui hopes to obtain certain exclusive patent rights on CS1002, it may be necessary to consider CTLA-4 antibodies and non-PD- 1/PD-L1 antibody combination, or actively expand new indications for the combination of CTLA-4+PD-1/PD-L1
.
04 Conclusion In general, in the combination of PD-1/PD-L1 antibody and CTLA-4 antibody, if you want to obtain patent protection, the basic directions that the applicant can consider are: (1) The combination can provide significant Better than other existing combinations; (2) Expand combinations for new indications
.