Synthetic lethal FIC encounters ineffective blockbuster drug IP will be besieged?

TextMedicine Crazy

Recently, Warwick Pharma challenged AstraZeneca's olaparib crystal form patent to be partially invalid, which touched the intellectual property sensitive nerve of the domestic pharmaceutical industry for a long time
.

The "Mao" and "Shield" of intellectual property have once again had a fruitful confrontation with the domestic pharmaceutical battlefield.

01 Background of PARP inhibitors

01 Background of PARP inhibitors

Olaparib, what drug?

This is a landmark FIC, the first listed PARP inhibitor, and the first listed drug under the concept of "synthetic lethality"
.

Olaparib was first listed in 2014, and then Rucaparib, Niraparib, and Talazoparib were listed successively; in China, Hengrui Medicine's Fluzoparib was approved in 2020
.

In 2020, Parley drugs have a market share of nearly 2 billion to 3 billion US dollars, and the clinical indications mainly point to ovarian cancer and breast cancer

Figure 1.
1 The structure of the 5 Parli drugs that have been marketed

(Image source: J.
Med.
Chem.
2020, 63, 14151-14183)

02This patent invalidation target

02This patent invalidation target

Target Patent, "Polymorphism of 4-[3-(4-Cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one", Patent Application No.
200780038855.
1, the priority date is October 17, 2006, the authorization announcement date is June 6, 2012, and the patentee is "Kodos Pharmaceutical Co.
, Ltd.
"
.

The initiator of this patent invalidation, that is, the invalidation requester, is "Nanjing Huawei Pharmaceutical Technology Group Co.
, Ltd.
".
According to information on Nanjing Huawei's official website, the company "actively initiated the invalidation challenge of the A crystal patent while developing the new crystal form of olaparib.
, to avoid patent disputes"
.

Further inquiries about the domestic registration application information of olaparib found that in addition to AstraZeneca’s declaration of the product as an original research import in 2013, many domestic pharmaceutical companies have registered and declared the product, and most of them are Chemical drugs category 3.
1, the specific sponsors include Shandong Luoxin Pharmaceutical, Lianyungang Hongchuang Pharmaceutical, Jiangsu Hansoh Pharmaceutical, CSPC Zhongqi Pharmaceutical, Sichuan Kelun, Beijing Kelaibo Pharmaceutical, Beijing Kanglisheng Pharmaceutical, Ruiyang Pharmaceutical, Chia Tai Tianqing, Lianyungang Runzhong Pharmaceutical, etc.
; and most of them have been approved for clinical use
.

03 Patent invalidation process

03 Patent invalidation process

This patent is invalid, and the decision number is 53361.
The legal basis for the invalidation of the patent is "Article 26, paragraph 4 of the Patent Law" and "Article 22, paragraph 3 of the Patent Law".
If the technical solution is obtained or summarized from the content fully disclosed in the description, and there is no reason and/or evidence enough to suspect that the invention or utility model is not practicable within the scope of the claims, the claims shall be considered to be supported by the description.

”

Nanjing Huawei Pharmaceutical Technology Group Co.

, Ltd.

Table 3.
1 Evidence provided by Nanjing Huawei

At this time, the applicant believes that: Compound 168 in Example 9 of Evidence 3 discloses the compound structure of olaparib, and the crystal form A protected in claim 1 does not have unexpected uses or effects, so it does not have an inventive step; Claims 2 and 3 protect the preparation method of olaparib crystal form A.
Evidence 4 discloses methods known in the art to control the transformation of drug crystal forms, including selecting an appropriate crystallization solvent, and controlling an appropriate temperature to obtain different Evidence 5 discloses that crystal phase transition may occur when the crystal form is heated to the transition temperature; the crystal form transition phenomenon often occurs during the storage process of the suspension liquid preparation.
On the basis that claim 1 is not inventive, the right to Requirements 2 and 3 are also not inventive
.

Claims 4 to 16 protect the pharmaceutical composition comprising olaparib crystal form A and the use of olaparib crystal form A.

After the normal process, the patentee presented the following counter-evidence:

Table 3.
2 Evidence provided by the patentee

In the reply, the patentee believes that: the 10 characteristic peaks defined in claim 1 are sufficient to distinguish the protected crystal form from other crystal forms, and the powder XRD pattern of crystal form L in evidence 2 exists with the crystal form A of the patent involved There is a significant difference, and the claims can be supported by the description; the technical problem actually solved by the patent involved is to provide a solvent-free and stable crystalline form of olaparib, and it is difficult to provide a crystalline form of olaparib without solvent.
The discovery and formulation of the problem is itself non-obvious
.

The petitioner submitted a statement of opinion and evidence 7 to 9 on September 16, 2021:

Table 3.
3 Nanjing Huawei continues to provide evidence

Subsequently, the petitioner reiterated the reasons why claim 1 was not supported by the description and did not have inventiveness, and evidence 7 could prove that the polymorphism of solid drugs is ubiquitous, and evidence 8 could prove that drug solvates are ubiquitous, and cannot It is considered that providing a solvent-free olaparib crystal is a new technical problem to be solved
.

The preparation process of the solvent-free crystal form A is a conventional technology in the art.

After that, an oral trial will be conducted.
The key information of the oral trial is as follows:

The petitioner abandons the use of evidence 8 and evidence 6 as reference materials, and the patentee recognizes the authenticity and publicity of evidences 1 to 5, 7 and 9; the petitioner clarifies that evidence 9 uses pages 39-40, about page 39 3.
1 Paragraphs 1-2 under the heading, page 40, on the choice and specific operation of mixed solvents
.

Regarding the counter-evidence, the petitioner recognized the accuracy of the translation of counter-evidence 1 and the authenticity and openness of counter-evidence 2, but did not agree with the authenticity of counter-evidence 1, on the grounds that the witness who gave the testimony of counter-evidence 1 was an employee of the patentee and had an interest in it.
, and did not appear in court to testify, the time of the spectrum in counter-evidence 1 can be changed at will, and the date displayed on the spectrum is later than the priority date of the patent involved
.

The patentee claimed that the witness who issued the counter-evidence 1 was unable to log in to the remote trial system and could not testify in court after many efforts, and remotely displayed the original notarized documents of the counter-evidence 1; , only the employees of the patentee can testify; with regard to time, since the content of counter-evidence 1 is used to prove that the solvate is obtained according to the usual method, it has been recorded in the description of the patent involved, and the content of counter-evidence 1 is recorded later The completed experimental results further verify the above conclusion, and the experimental evidence completed later should be able to be used for the above-mentioned proof purpose;

The petitioner clarifies that the combination of evidence on inventive step is the same as the request for invalidation, and evidence 9 is used as common knowledge for the inventiveness evaluation of claims 2 and 3.
The patentee believes that claim 2 is not addressed in the petitioner's written opinion on invalidation and 3 ways of combining evidence with common knowledge
.

Petitioner filed an after-court statement on November 17, 2021

04 The final result of this invalidation

04 The final result of this invalidation

Based on the above content, the collegial panel finally decided: "Declare claims 1, 3-16 of the invention patent No.
200780038855.
1 invalid, and continue to maintain the validity of the patent on the basis of claim 2 in the text of the authorization announcement
.

"

The reasons for making the above decision are mainly composed of the following information:

First, this invalidation request examination decision is made on the basis of the text of this patent grant announcement;

The collegiate panel does not recognize the authenticity of counter-evidence 1;

Insufficient disclosure of the problem, in the art, select several characteristic peaks to define a specific crystal form, usually based on a certain purpose for comprehensive consideration, without strict restrictions, those skilled in the art can clearly claim 1 to request the protection of the crystal.
Form A, according to the characteristic peaks listed in claim 1, can distinguish Form A from other solvate crystal forms
.

Therefore, the protection scope of claim 1 is to protect the crystal form A, and the reason that the claim 1 cannot be supported by the description put forward by the petitioner cannot be established

The problem of inventive step, the solvent described in paragraph [0040] of the patent specification involved by the patentee and the crystallization method described in counter-evidence 1 to obtain olaparib solvate are not enough to prevent those skilled in the art from not using other methods and other methods.
Solvent to further study the crystal form of olaparib, but also could not prove that there is a technical barrier to obtain the crystal form of olaparib, and as mentioned above, steps (c) and (c) of Example 3 in paragraphs [0211]-[0233] of the description (d) It is recorded that olaparib crystal form A was also obtained by suspending, stirring, heating and refluxing in methanol aqueous solution and ethanol aqueous solution, and recrystallization, which further proves that those skilled in the art can try various methods to obtain olaparib.
The crystal form
A.
Therefore, the panel does not support the patentee's claim
.

For claims 4-16, on the basis that evidence 3 has disclosed the pharmaceutical composition of the compound and related pharmaceutical uses, in the case where the cited claim 1 does not have an inventive step, since the crystal form A of claim 1 does not have an inventive step , the corresponding pharmaceutical compositions and related pharmaceutical uses are not inventive
.
Therefore, claims 4-16 are also not inventive
.

For claim 3, for those skilled in the art, for the purpose of finding a more convenient and quick preparation process or improving the stability of a pharmaceutical compound, those skilled in the art are motivated to try to prepare a crystal form in combination with other existing technologies and common knowledge
.
Therefore, claim 3 is not inventive compared to the combination of evidence 3, evidence 4 and evidence 5 and common knowledge, and does not meet the provisions of Article 22, paragraph 3 of the Patent Law
.

Last point, claim 2
.
In the preparation method of the scheme 1 defined in claim 2, recrystallization is performed from a solvent selected from dichloromethane and acetonitrile; the crystallized olaparib is first treated with ethanol; the crystallized olaparib is treated with water to remove the trapped ethanol : Evidence 4, Evidence 5 and Evidence 9 only generally describe some possible conditions affecting the crystal form, as well as the basic principle of recrystallization and the optional mixed solvent
.
The petitioner does not claim that the above-mentioned evidence provides specific guidance on the preparation steps of the olaparib crystal form A of claim 2.
The steps and conditions in the solution 1 are conventional technical means in the art, and the reason that the claim 2 is not inventive according to the applicant cannot be established
.

05Summary and discussion

05Summary and discussion

First of all, the victory of the intellectual property department of Warwick Pharmaceuticals at this stage is very worthy of recognition.
This is a successful attempt in the domestic patent invalidation battlefield, and at the same time, it has played a positive role in the commercialization of its own products
.
Another blockbuster drug encounters patent invalidation, which will almost be an inevitable process
.

Second, let's analyze it from a technical point of view
.

It is an indisputable fact in the industry that it is difficult to maintain the general direction in the field of crystal form patents; if we look back at all crystal form patents ten years ago, if we look at the patent texts presented ten years ago with the ability of those skilled in the art at this stage, If you fight seriously, the shield is hard not to break
.

During the review process, both those skilled in the art and the reviewers have already possessed a high level of technical ability in the field; and at the same time, there is a "motivation" to make a practical attempt on the finished product of a compound or drug.
This "motivation" , can be said to be both happy and sad
.

In the future, how to prevent crystal patents? How to prevent further expansion to the most important compound patents? It is a very important problem that must be continuously updated for the researchers of the current domestic innovative drug sponsors
.
Although, to a certain extent, it is the process of the integration of products and intellectual property to promote innovation, but it is also a true portrayal of the increasingly fierce competition in the industry
.
For the current domestic generic drug centralized procurement and innovative drug involution environment, it will undoubtedly increase the competitiveness of this industry and the tension of practitioners
.
However, this is the current stage of China's pharmaceutical industry, and I believe that it will be more difficult in the future, but only by continuously creating and strengthening the soft and hard power of enterprises and practitioners can we withstand the various challenges brought by the environment!

References:

1.
Nanjing Huawei official website http:// J.
Med.
Chem.
2020, 63, 14151-14183

3.
Sina Pharmaceutical's "Synthetic death: PARP inhibitor market rises, who will share in the future? 》

4.
http://36.
112.
95.
124/reexam_out2020New/searchdoc/decidedetail.
jsp?jdh=53361&lx=wx

5.
Patent reexamination and invalidation http://