David Huang

In practice, when receiving a Notice of Reexamination from the Chinese patent office, the patent applicant usually would choose to further revise (normally narrow) the claims to increase the likelihood of persuading the reexamination panel.  As the general observation, it is difficult to persuade a panel to change its opinion by arguments only on this occasion.

In a recent case, after receiving the Notice of Reexamination, LexField proactively called the examiners for a more accurate understanding of the panel' s real opinion and presumption untold in the Notice, and then searched for and submitted evidence to prove that certain presumption by the panel is wrong, eventually managing to persuade the panel to reverse the lower rejection and then obtaining a patent for the client protecting a new pharmaceutical conjugate.

Subject application

The application seeks to protect a conjugate of mutant fibroblast growth factor 21 (FGF-21).  FGF-21 has long been considered to have the potential to treat diabetes, especially type II diabetes.  When entering the reexamination proceeding, claim 1 of the application protects a specific mutant FGF-21 peptide conjugate whose structure attaches the peptide sequence at an amino acid position near the C-terminus of the sequence to a glycosyl moiety, which is then attached to a linear PEG of 20 kDa (i.e. glycoPEGylation of the peptide sequence).   Meanwhile, the specification includes detailed experimental data showing that the subject conjugate can effectively reduce the level of glycosylated hemoglobin (HbA1c) in subject patients.

Examiners' opinion

From the lower substantive examiner to the reexamination panel, the examiners have held that the conjugate of the present application is obvious over the cited references.

The closest prior art R1 generally discusses glycoPEGylation of peptides.  Among the numerous peptides, R1 also tested FGF-21 of the same sequence (numbered B.41).  In comparison, differences between B.41 and claim 1 include: (1) differences in the glycosyl structure, (2) differences in PEG : B.41 uses branched PEG of 40kDa, while claim 1 uses linear PEG of 20kDa.  R1 does not address medical purpose or efficacy of the tested substances (including B.41), and in particular does not discuss or test whether B.41 has efficacy on diabetes.

In the Notice of Reexamination, the collegial panel held that: (1) besides B.41, R1 also taught the various glycosyl groups in the structure of claim 1, and (2) another reference R2 taught the use of 20kDa linear PEG-butyraldehyde to modify FGF-21, and the modified product retained the biological activity of the protein, and its thermal stability, anti-trypsin hydrolysis ability and in vivo half-life were significantly improved.  Therefore, on the basis of the above teachings of R1 and R2, those skilled in the art would be motivated to modify B.41 to reach the structure of claim 1.  As for the effect of  "lowering HbA1c level" of the present application, since HbA1c level has been the gold standard for diagnosis and treatment of diabetes, and R2 has taught that FGF-21 has the potential to treat diabetes, this effect could hardly be characterized as "unexpected". The panel finally held that claim 1 is not inventive.

Previously, the applicant had presented the following arguments: (1) R1 did not discuss the pharmacological efficacy of B.41 at all, but only generally discussed glycosylation of various peptides, and those skilled in the art could not determine how to modify B.41 or predict whether the modification would have efficacy similar to the present application, (2) the specification of the present application clearly states that glycoPEGylation at the C-terminus of the peptide sequence overcomes a long-held prejudice in the art, because it was traditionally believed that the C-terminus should be preserved for binding with β-Klotho protein to achieve its pharmacological efficacy.  The applicant also cited the failed FGF-21 conjugates with similar glycoPEGylated structures from Pfizer, Eli Lilly and Bristol-Myers Squibb as counter evidence to prove that the effect of the conjugate of the present application would be unexpected.

On the above arguments, the examiners gave these comments: (1) teachings of R1 and R2 would be sufficient to motivate those skilled in the art to modify B.41 to realize the present application, and since it was known that FGF-21 has the potential to treat diabetes, the effect of this application could be expected, (2) the effect of glycoPEGylation at the C-terminus or at the N-terminus could be easily determined through routine experiments.  As for the products of Pfizer, Eli Lilly and Bristol-Myers Squibb, the examiners held that their specific sequences or glycoPEGylation sites are different, and thus they have no reference value.

Communication with examiners and evidence

Since some of the comments in the Notice of Reexamination were vague and others indicated opportunities for the applicant to present counter evidence, LexField called the presiding examiner of the collegial panel several times in order to better understand the examiners' true opinion.

In a telephone conversation, the presiding examiner revealed that in the panelists' minds, whether a FGF-21 conjugate has efficacy mainly depends on the specific mutation while glycoPEGylation has only a minor effect, and this unwritten presumption actually is the root cause why the panel considered the conjugate of the present application obvious over B.41 of R1.  However, according to the previous communication with the inventor, LexField knew that this understanding is actually wrong.

LexField thus had in-depth discussions with the inventor and decided to introduce the following evidence:

(1) historical experimental data developed by the inventor, especially comparison data testing diabetes therapeutic potential of multiple FGF-21 mutants before and after glycoPEGylation, to show that the effect of glycoPEGylation on the therapeutic potential is actually more significant than the selection of mutants.

(2) analysis by the inventor to show that B.41 of R1 is likely inactive based on existing experimental data.

At the same time, LexField searched for literatures on the selection of the C- and N-terminus of the peptide sequence, and submitted a number of papers (including very new ones published after the priority date of this application) to prove that "the C-terminus of the sequence of the FGF-21 peptide should not be used for glycoPEGylation because it needs to be bound with the β-Klotho protein" was a longstanding understanding in the art, as further corroboration and reinforcement to existing statements in the specification of this application.

Based on further telephone communication with the presiding examiner and the final result, the above evidence played a decisive role.  The examiner must have paid more attention to the choice of parameters of glycoPEGylation, including the choice of C-terminal/N-terminal and the choice of PEG configuration and molecular weight.  The examiner even conducted his own search, and found and cited another reference occurring with references submitted by LexField, showing that "peptide sequences should not be glycoPEGylated near the C-terminus" was indeed a longstanding knowledge in the art.  In the end, the collegiate panel concluded that, in view of the above facts, those skilled in the art would be unable to determine whether B.41 of R1 was active, would not be motivated to modify it to realize the present invention, and thus the claimed conjugate would be non-obvious.  On top of this, the panel further recognized the experimental data in the specification of this application on controlling triglyceride and HbA1c levels, and held that the conjugate of claim 1 has achieved beneficial technical effects and thus made "notable progress" over the prior art, which completed the inventiveness analysis with a result favorable to the client.

Conclusion

Applicants and practitioners are often frustrated with examiners' stubbornness. This case highlights the need for effective communication to find out possible untold presumption examiners may be preoccupied with that are unwritten in the formal text of an office action.  The applicants can then try to search for evidence to rebut such assumptions.   From LexField's experience with this and other similar cases, when presented with convincing evidence and arguments based on the same, Chinese examiners can be persuaded.