Acceptance of Post-filing Data for Pharmaceutical Patents in Patent Examination Practice: Cases Study

Tag:intellectual property-patents,healthcare and pharmaceuticals

The technical effect is a crucial factor in determination of inventiveness for pharmaceutical patents, and it relies heavily on experimental data. The presence and quality of experimental data can directly affect the grant or reject of a patent. Therefore, the acceptance of post-filing data has always been a matter of great concern.

In accordance with the first-to-file principle under China's Patent Law, experimental data should be disclosed in the original patent application documents. However, due to factors such as the unpredictability of the prior art references cited by examiners and invalidation petitioners, the specific drafting of claims under the Markush system, and the diversity of experimental parameters, applicants often find it necessary to supplement experimental data after the application date to address challenges related to inventiveness and insufficient disclosure during prosecution and invalidation proceedings.

Chapter 10, Section 3.5.1 of the latest “Guidelines for Patent Examination” amended in 2021 clearly outlines the examination principles for post-filing data, i.e. “Examiners should review experimental data submitted by applicants after the application date to satisfy the requirements of Article 22, Paragraph 3, and Article 26, Paragraph 3 of the Patent Law. The technical effect demonstrated by the post-filing data should be something that a person skilled in the art can derive from the content disclosed in the patent application.”

Section 3.5.2 further specifies the standard for examination of “post-filing data for pharmaceutical patent applications” and provides examination examples related to pharmaceutical patent applications.

[Example 1]: The claims set forth compound A, and the specification sets forth the preparation examples of compound A, the hypotensive effect of compound A, and the experimental method for determining the hypotensive activity, but does not set forth the result data. The applicant submits post-filing data on the hypotensive effect of compound A in order to demonstrate sufficient disclosure of the specification. For person skilled in the art, the hypotensive effect of compound A has been disclosed in the original application, and the technical effect proved by post-filing data can be obtained from the disclosure of the application document. Note that the post-filing data should also be considered in the examination of inventiveness.

[Example 2]: The claims set forth compounds of general formula I. The specification sets forth compounds of general formula I and its preparation method, the preparation examples of several specific compounds A and B of general formula I, and the antitumor effect of compounds of general formula I, the experimental methods for the determination of antitumor activity and the result data. The experimental results disclose that IC50 values of the example compounds for tumor cells are in the range of 10-100 nm. To demonstrate the inventiveness of the claims, the applicant submitted comparative experimental data showing an IC50 value of 15nM for compound A and 87nM for compound of reference document 1. For a person skilled in the art, compound A and its antitumor effect are disclosed in the original application, and the technical effects demonstrated by post-filing data can be obtained from the application document. Kindly note that the examiner still needs to further analyze whether the technical solution of the claim meets the requirements for inventiveness in combination with the post-filing data. 

The above two examples as set forth in the Guidelines for Patent Examination provide more specific insights into determining the “technical effect that can be obtained from the content disclosed in the patent application.” We may interpret the acceptance standard for post-filing data as set forth in the Guidelines for Patent Examination as follows:

The essence of [Example 1] can be summarized as: if the original specification discloses the preparation method, structure, identification data, and a technical effect but without actual data to the technical effect, to a compound, it indicates that the applicant had already paid attention to the technical effect of the specific compound A before the application date.  In this case, the experimental data submitted by the applicant after the application date serves to strengthen the preliminary indication of the technical effect in the specification. In short, the post-filing data are accepted because the technical effect to be further confirmed by the data can be obtained from the content disclosed in the patent application. 

In [Example 2], the original specification discloses the preparation method, specific structure, identification data, and specific assay methods of genus compounds, along with relevant technical effect data in a range to some compounds. If the effect data values of the compound supplemented in the post-filing data fall within the corresponding effect range mentioned in the original specification, it can be considered that the technical effect of the post-filing data can be obtained from the content disclosed in the patent application, based on the preliminary disclosure of the technical effect in the original specification.

In addition, on September 12, 2020, the Supreme People's Court also issued the “Provisions of the Supreme People's Court on Several Issues Concerning the Application of Law in the Trial of Administrative Precedents of Patent Authorization and Confirmation (I)”, and Article 10 provides that: “If a pharmaceutical patent applicant submits post-filing data after the application date and claims that the patent application complies with the provisions of Article 22.3, Article 26.3, and etc. of the Patent Law based on this data, the People's Court shall review it.” Subsequently, in the “Interpretation and Application of the Provisions of the Supreme People's Court on Several Issues Concerning the Application of Law in the Trial of Administrative Precedents of Patent Authorization and Confirmation (I),” the Supreme People's Court further elaborated that, “Regarding Article 10 of the 'Provisions,' which relates to 'pharmaceutical patent applicants submitting post-filing data after the application date,' it is not inherently a part of the patent specification. When the People's Court conducts review, it must pay attention to the unique characteristics and rules of pharmaceutical research and development, while also adhering to the principles of the first-to-file system and 'disclosure in exchange for protection' as stipulated in Patent Law.  It should protect innovative achievements in accordance with the law and prevent applicants from obtaining undue benefits by supplementing experimental data after the application date, ensuring a balance between public interests and incentives for innovation.”

Comparing the “Guidelines for Patent Examination” with the judicial examination standards, it becomes apparent that the standards are consistent. Specifically, the technical effect demonstrated by post-filing data should be something that a person skilled in the art can derive from the content disclosed in the patent application, while also upholding the principles of the first-to-file system and “disclosure in exchange for protection” as stipulated in Patent Law. In recent years, with the publication of some typical precedents of reexamination or invalidation proceedings, it appears that the China National Intellectual Property Administration (CNIPA) may have adopted a more flexible approach toward post-filing data in pharmaceutical patents. However, such post-filing data should not violate the first-to-file system by encompassing content that was undisclosed or incomplete on the application date or priority date, thereby maintaining a balance between the rights of patentees and public interests.

The following will look at the degree of acceptance of post-filing data for pharmaceutical patents in practice from the aspect of CNIPA precedents. Typically, if the cases related to the submitted post-filing data are similar to the two examples provided in the “Guidelines for Patent Examination” ([Example 1]: Cases I, IV, and VI; [Example 2]: Case III), the CNIPA is likely to accept the post-filing data. Even if the original application discloses a technical effect, if it is merely a “general” technical effect and not the “unexpected” technical effect that the post-filing data aims to demonstrate, then the post-filing data may not be accepted (Case II).  However, if the original application discloses a specific unexpected technical effect, and it can be reasonably expected that this technical effect was achieved before the application date, then the post-filing data can be accepted (Case V).

Case I - “Lenvatinib” Invalidation Case[1]

[Patent No.] ZL01819710.8

[Patentee] Eisai R&D Management Co., Ltd.

[Invalidation Requester] Chia Tai Tianqing Pharmaceutical Group Co., Ltd.

[Invalidation Decision No.] 50111

[Post-filing Data]

Specification of Original Application: The application document provides a detailed description of the preparation method, structure, confirmation data, and results of activity experiments for Lenvatinib. These experiments include tests for inhibiting invasive lumen formation induced by a mixture of various angiogenic factors and tests for inhibitory activity on receptor kinases. According to the data disclosed in the specification, Lenvatinib compounds exhibit activity as multi-pathway inhibitors. Pharmacological test Example 1 demonstrates that Lenvatinib has inhibitory effects on invasive lumen formation in endothelial cells induced by various angiogenic factors (including VEGF and FGF2 among five different angiogenic factors). Pharmacological test Example 3 discloses the results of in vitro assays of receptor tyrosine kinase activity. It includes methods for determining the inhibitory capacity on several kinase activities, including VEGFR2 and FGFR1, and documents the experimental results of Lenvatinib compounds, among dozens of other compounds, on the inhibitory effect of VEGFR2 kinase.

Supplementary Data: The supplementary experiments used the testing methods for VEGFR2 and FGFR1 receptor kinase activity as outlined in pharmacological test Example 3. The results of the experiments not only reaffirm the data regarding VEGFR2 receptor kinase activity as disclosed in the patent specification but also provide additional data on FGFR1 receptor kinase activity.

Conclusion: Accepted.

[Invalidation Decision]

The results of pharmacological test Example 1 confirm that the patented compound inhibits invasive lumen formation in endothelial cells induced by a mixture of various angiogenic factors, indicating that the patented compound preliminarily proves Lenvatinib to be a multi-pathway angiogenesis inhibitor. Pharmacological test Example 3, from the perspective of receptors, investigates the inhibitory effects of the patented compounds, including Lenvatinib, on different receptors such as VEGFR2 and FGFR1 and discloses the activity data of VEGFR2 kinase receptors. The post-filing data submitted by the patentee demonstrates, from the perspective of receptors, that Lenvatinib is not just a VEGF single-pathway inhibitor. The post-filing data supports the technical effect disclosed in the specification that Lenvatinib is a multi-pathway angiogenesis inhibitor, which is something that a person skilled in the art can derive from the content disclosed in the patent application.  Therefore, the panel accepted the “post-filing data submitted after the application date” and upheld the validity of the patent.

Case II - Hypertension Drug Composition Invalidation Case[2]

[Patent No.] ZL01822113.0

[Patentee] Daiichi Sankyo Co., Ltd.

[Invalidation Requester] Shanghai SynCores Technologies, Inc.

[Invalidation Decision No.] 50045

[Post-filing Data]

Specification of Original Application: The drug composition containing specific angiotensin II receptor antagonists such as CS-866 and diuretics exhibits excellent antihypertensive effects and can be used for the prevention and/or treatment of hypertension.  The combination of these drugs shows superior efficacy compared to each single agent.  Example 1 is a test of the antihypertensive effects of the combination of CS-866 and hydrochlorothiazide (HCTZ), and the conclusion is that the combined administration of HCTZ and CS-866 (Group 4) demonstrates a significantly better antihypertensive effect than each single agent (Group 2 or Group 3). The content disclosed in the patent application indicates that the technical solution of the patent in question has an excellent antihypertensive effect and that the combined administration of both drugs is superior to the administration of each drug individually. However, it does not explicitly state that the combination of HCTZ and CS-866 has a synergistic effect.

Supplementary Data: The post-filing data aims to demonstrate that various dose combinations of CS-866 and hydrochlorothiazide have a synergistic effect, and expert testimony has been submitted to prove the synergistic effect of the combination therapy.

Conclusion: Not accepted.

[Invalidation Decision]

The expert testimony of Counter-evidence 13 explicitly states that their evaluation method requires an examination of whether there is a statistically significant difference between A+D and B+C.  However, both the Counter-evidence 13 and the on-site statements of expert witness of Counter-evidence 13 indicate that the numerical differences reflected in Example 1 are not significant. Therefore, those skilled in the art cannot conclude that the combination of hydrochlorothiazide and CS-866 has a synergistic effect based on Example 1. In summary, the patent in question does not explicitly state that the combination of hydrochlorothiazide and CS-866 has a synergistic effect, and those skilled in the art cannot derive the conclusion of a synergistic effect from the content disclosed in the patent application. Therefore, the post-filing data submitted by the patentee to prove the synergistic effect cannot be accepted. The patent is invalidated as a whole.

Case III - Copanlisep Reexamination Case[3]

[Application number] 200780044849.7

[Reexamination Requester] Bayer Intellectual Property Co., Ltd.

[Reexamination Decision No.] 323552

[Post-filing Data]

Specification of Original Application: The 2,3-dihydroimidazo[1,2-c]quinazoline compounds disclosed can be used to inhibit phosphoinositide 3-kinase (PI3K) and treat diseases associated with PI3K activity, particularly diseases characterized by excessive proliferation and/or angiogenesis. According to the examples, the specific compound sought to be protected in the present application, Copanlisep, exemplified by the compound as in Example 13, is described. The specification details test methods for the in vitro inhibition activity of each specific compound against the three PI3K isoforms, PI3K-α, PI3K-β, and PI3K-γ, and provides partial specific compounds, including the compound from Example 13, with average IC50 values below 10nM for the inhibition of PI3K-α and PI3K-β, with no data provided for PI3K-γ inhibition.

Supplementary Data: The post-filing data includes comparative data on the in vitro inhibition activity of the compounds of the present application (i.e., Example 13 compound) and prior art compounds against the three isoforms of PI3K. The specific inhibition values for PI3K-α and PI3K-β in the post-filing data are 0.496nM and 3.72nM, respectively.

Conclusion: Accepted.

[Reexamination Decision]

For PI3K-α and PI3K-β, according to the disclosures in the original application, the technical effect of the inhibitory activity of the compounds of the present application against the various isoforms of PI3K has been publicly disclosed, and a range of in vitro inhibition activity values for PI3K-α and PI3K-β isoforms <10nM has been disclosed. The specific inhibition values for PI3K-α and PI3K-β in the post-filing data are 0.496nM and 3.72nM, respectively, and all of these specific values fall within the range of in vitro inhibition activity values as disclosed in the specification for the above-mentioned isoforms. Therefore, the post-filing data submitted by the requester in the reexamination, regarding the inhibitory activity of PI3K-α and PI3K-β, is something that a person skilled in the art can derive from the content disclosed in the patent application. Based on this, the panel accepted the “post-filing data submitted after the application date.”

Case IV - Empagliflozin ineffective case[4]

[Patent No.] ZL201310424724.4

[Patentee] Beringer Ingelheim International Co., Ltd.

[Invalidation Requester]Chia Tai Tianqing Pharmaceutical Group Co., Ltd.

[Invalidation Decision No.] 51799

[Post-filing Data]

Specification of Original Application: Compounds of Formula I according to the present invention have an EC50 below 1000nM, preferably below 200nM, and most preferably below 50nM. The specification lists the chemical names of 17 specific compounds, including compound (3), which is the empagliflozin compound.  The specification also provides methods for preparing 57 specific compounds, including the preparation method for empagliflozin. The specification further describes that compounds of Formula I have inhibitory activity against various subtypes of SGLT, such as SGLT-1 and SGLT-2. However, it expresses a preference for superior SGLT-2 inhibitory activity relative to both subtypes but does not exclude its inhibitory activity against SGLT-1. The activity tests described in the specification are also for SGLT-1 and SGLT-2, and no specific compounds are provided for the assays.

Supplementary Data: The post-filing data aims to demonstrate that empagliflozin has lower SGLT-1 inhibitory activity compared to similar compounds in the prior art, resulting in significantly improved SGLT-2/SGLT-1 selectivity.

Conclusion: Not accepted.

[Invalidation Decision]

The facts that can be proven by the supplementary experimental evidence in this case should be those that can be determined based on the prior art and the application documents at the priority date. That is, empagliflozin has SGLT-2 activity and selectivity similar to the prior art at the priority date; it cannot be used to prove the unexpected high technical effect of SGLT-2/SGLT-1 selectivity due to extremely low SGLT-1 inhibition that could not have been determined at the priority date. Although this patent specification does not provide any specific experimental data, the prior art has already disclosed compounds with similar structure and activity. Therefore, those skilled in the art can expect that the phenyl-derived compounds with pyranose glucose substitution disclosed in the patent also have a similar level of SGLT-2 inhibitory activity based on the aforementioned prior art. If the patentee insists that the compounds of this patent have a significantly reduced SGLT-1 inhibitory effect compared to similar compounds disclosed in the prior art, since the patent specification does not clearly disclose the technical issue raised by the patentee and does not provide any experimental data, those skilled in the art cannot determine, based on the content disclosed in the specification, that the specific compounds claimed in this patent application had the specific technical effect asserted by the patentee before the application date. The patent is partially invalidated.

Case V - PDE5 Inhibitor Reexamination Case[5]

[Application No.] 201610205827.5

[Reexamination Requester]Strategic Science and Technology Co., Ltd.

[Reexamination Decision No.] 260637

[Post-filing Data]

Specification of Original Application: The specification explicitly discloses the technical solution of “using stabilized polymers, propylene glycol, and polyoxyethylene sorbitan surfactants to stabilize the composition,” and provides specific examples of the technical solution containing xanthan gum, propylene glycol, and polyoxyethylene sorbitan 20 in Examples 1-3. The specification also clearly discloses the effect of the composition containing stabilized polymers, propylene glycol, and polyoxyethylene sorbitan surfactants, namely, “as compared to compositions lacking one or more of the above substances, this composition unexpectedly provides temperature stability to the composition, such as at elevated temperatures like at least 40°C (at least about 104°F).”

Supplementary Data: Sample 1 in the post-filing data corresponds to the product containing the components requested for protection in the claims and in Example Table 1 of the present application. It aims to prove that the composition of the present application containing the mentioned components exhibits good temperature stability.

Conclusion: Accepted.

[Reexamination Decision]

The composition containing xanthan gum, propylene glycol, and polyoxyethylene sorbitan 20 simultaneously is the preferred and prepared solution in the examples of the present application. It clearly discloses that the composition containing all three components is superior in temperature stability compared to other compositions lacking one or more of these components, and specifically discloses the temperature range in which this excellent effect is observed. Those skilled in the art can confirm, based on the disclosure, that the specification's assertion of the composition “having temperature stability” is clear and directional, not merely a conjecture or speculation. It is a technical effect that the applicant had clearly focused on and actually achieved before the application date. 

Therefore, this effect is something that those skilled in the art can derive from the content disclosed in the patent application. Secondly, Sample 1 in the post-filing data corresponds to the product containing the components requested for protection in the claims and in Example Table 1 of the present application. The technical effect demonstrated by it is that the composition of the present invention containing stabilized polymers, propylene glycol, and polyoxyethylene sorbitan 20 exhibits superior temperature stability compared to compositions lacking one or more of the above substances. It can be seen that the post-filing data submitted by the requester is reinforcing evidence of the technical effect that could already be derived from the content disclosed in the present application, and it does not introduce content that was not completed before the application date.

Case VI - Rucaparib Invalidation Case[6]

[Patent No.] ZL201180009237.0

[Patentee] Pfizer Inc.

[Invalidation Requester] Nanjing Huaxun Intellectual Property Consulting Co., Ltd.

[Invalidation Decision No.] 49639

[Post-filing Data]

Specification of Original Application: The specification discloses that the camphorsulfonic acid salt form is physically stable compared to other salt forms of Rucaparib and is less prone to hydration. It belongs to a salt form suitable for solid dosage forms, especially the S-camphorsulfonic acid salt polymorphic form A.  It also points out that the prior art's phosphate salts are sensitive to hydration and are unsuitable for solid dosage forms. The examples of the specification specifically tests and characterizes multiple properties of the S-camphorsulfonic acid salt polymorphic form A, including non-hygroscopicity, thermal stability, and crystal stability (characterized by accelerated experiments at high temperature and high humidity).

Supplementary Data: It is indicated that the polymorphic forms of phosphate salts in the prior art have hygroscopicity and instability. An overview is provided that camphorsulfonic acid salts have the ideal combination of properties for solid dosage forms, especially Form A being the thermodynamically most stable form. Additionally, multiple properties of camphorsulfonic acid salts are specifically tested and characterized, including non-hygroscopicity, crystal stability (characterized by long-term experiments at two temperatures and humidities), chemical stability, as well as water solubility and dissolution rate.

Conclusion: Accepted.

[Invalidation Decision]

Regarding non-hygroscopicity, the present patent has already disclosed that Rucaparib camphorsulfonic acid salt is non-hygroscopic, and the non-hygroscopicity testing methods used in the present patent and the post-filing data are basically the same. The trends in moisture absorption of Rucaparib camphorsulfonic acid salt obtained from the present patent application documents are consistent, which is a technical effect that can be derived from the content disclosed in the present patent application.

Regarding crystal stability, although the testing methods for crystal stability used in the present patent are accelerated experiments under high-temperature and high-humidity conditions, and the testing methods for crystal stability used in the post-filing data are long-term experiments at two temperatures and humidities, these different testing methods are only different ways to demonstrate that the salt crystals of the present patent possess stability.  Therefore, the technical effect of crystal stability demonstrated by the post-filing data can also be derived from the content disclosed in the present patent application.

For chemical stability, the present patent application only concerns crystal stability and does not disclose its chemical stability. This crystal stability and the chemical stability disclosed in the post-filing data are two different properties. Therefore, the technical effect of this chemical stability is not disclosed in the content disclosed in the present patent application and is not a technical effect that can be derived from the content disclosed in the present patent application.

For water solubility and dissolution rate: The present patent did not focus on water solubility and dissolution rate during the research and did not make corresponding discloses.  The patentee interprets “water solubility and dissolution rate” as the property mentioned in the present patent of being “suitable for preparing solid dosage forms,” and the property of “suitable for preparing solid dosage forms” in this field covers many different characteristics.  The specification of the present patent only discloses that the property of “suitable for preparing solid dosage forms” includes crystal stability, non-hygroscopicity, controlled particle size, crystallinity, and crystal form, and this disclose cannot represent that the present patent also conducted research on other properties suitable for preparing solid dosage forms and completed the disclosure of their technical effects. Therefore, this property of water solubility and dissolution rate is not a technical effect that can be derived from the content disclosed in the present patent application.

In summary, the technical effects emphasized by the present patent and the post-filing data, which highlight that camphorsulfonic acid salts have better non-hygroscopicity and crystal stability relative to phosphate salts, can be considered for the final decision.

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