The patent rights to the blockbuster patent for Smeaglutide were declared null and void.

semaglutide (semaglutide, formerly known as Somaglutide) is a long-acting GLP-1Receptor agonists (GLP-1RA），GLP-1RANot only has a significant hypoglycemic effect, the risk of hypoglycemia is small when used alone, but also has the effects of weight loss, blood pressure reduction, and improvement of blood lipid profile. It has become one of the best-selling hypoglycemic drugs in the world.

ForSmeaglutideThe heavyweight patent“CN101133082B(hereinafter referred to as "the patent in question"), the State Intellectual Property Office in2022Year9Month5DayMake No.57950Review decision on request for invalidation, declare all patent rights invalid;The legal basis for declaring all patent rights invalid is.Patent Law No.22Article3Section,The main points of the decision are"When a specific compound is claimed for protection, and the specification only records the specific screening method for screening the target compound with a certain excellent technical effect from the compound of the general formula, and does not disclose the experimental result data of any compound contained in the general formula in combination with the screening method, and it is difficult to confirm that the specific compound has the excellent technical effect according to the existing technology, the corresponding technical effect of the specific compound proved by the experimental data submitted by the applicant belongs to the technical effect that is difficult to obtain from the contents disclosed in the original application document".

For the patent rights of the patent involved, the claimant (Hangzhou Sino-US East China Pharmaceutical Co., Ltd.) requests to declare all the patent claims invalid.SubmissionIt'sThe first stage of the patent review involved.80658Review decision No.15a piece of evidence: Evidence1-1To evidence1-8, the evidence2-1To evidence2-3, the evidence3-1and evidence3-2, and the evidence4-1Evidence4-2.The patentee (Novo Nordisk) submitted a response to the above request for invalidation,16a counter-evidence(counter-evidence1To counter evidence16)and2a well-known evidence of common sense(known common sense evidence1and well-known common-sense evidence2）。

In response to the patent rights of the patent in question, the State Intellectual Property Office has2022Year04Month08Day No.55138The patent right shall be maintained on the basis of the amended claims submitted by the patentee.

The claims to remain valid prior to this request for invalidation are5Item:Claim1Protected is the compound "semaglutide".Claim2ProtectionInclude claims1compounds or their pharmaceutically acceptable salts and pharmaceutically acceptable excipients.Pharmaceutical composition;Claim3ProtectionClaim1Compounds for the preparation of the treatment or prevention of hyperglycemia,2type diabetes, impaired glucose tolerance,1type diabetes, hypertension,XSyndrome, dyslipidemia, inflammatory bowl syndrome, dyspepsia and gastric ulcer;Claim4ProtectionClaim1Preparation of compounds for the preparation of delay or prevention2drugs for the development of type 2 diabetes;Claim5ProtectionClaim1compounds for the preparation of reducedBeta-Apoptosis, increasedBeta-cell function andβ-cell mass and/or recoveryBeta-Glucose sensitivity of cells to drugs.

collegial group gives the above claim1-5The main comments of the decision, which should be null and void in its entirety, are as follows:

1.Claim1No creative comments.

(1) about the claims1Difference from the closest prior art

Claim1Technical solutions and evidence for protection2-1Example37Compared to the specific compounds disclosed, the difference is: claims.1The compound will be No.8The amino acid was replacedAib,Lys26The side chain modification group is[2-(2-[2-(2-[2-(2-[4-(17-carboxyl heptadecanoyl amino)-4(S)-Carboxybutyrylamino]ethoxy)ethoxy]Acetamide)ethoxy]ethoxy)acetyl]and the evidence2-1MediumGLPof the No.8The amino acid is not replaced, and the side chain group isγ-Glutamyl (Well--hexadecanoyl).

(2) Regarding the technical effects of the present invention and the technical problems actually solved by the invention

For the technical effect of the patent involved, first of all, the evidence2-1Publicly statedGLP-1Derivatives have the effect of treating insulin-dependent and non-insulin-dependent diabetes, andGLP-1Derivatives have moreGLP-1(7-37) Longer action curve. InvolvedPatentedThe description does not provide any specific experimental evidence of the effect of the protected compound, and it cannot be proved that the compound claimed in this patent can obtain more than evidence.2-1The technical effect of the above-mentioned compounds involved is longer. Therefore, the technical effect that can be achieved in the patent in question based on the above-mentioned distinguishing technical characteristics can be determined,and evidence2-1Medium embodiment37 Compared to the specific compounds disclosed in the claims.1Practical solutionsThe technical problem is to provide mutations with different side chains. GLP-1(7-37)Derivatives.

(3) Judgment on technical implications

(3.1) for the above distinctions, the collegial group argues that, first, the evidence3-1made publicGLP-1like peptide No.8Alanine can be replaceda-Aminoisobutyric acid (I.e.Aib), and No.26Lysine can be lipophilic substitution, table.IThe data indirectly indicate that8substitution of amino acids and26The lipophilic substitution of lysine can be prolonged.GLP-1the half-life, and the evidence3-1It also discloses the useXof the modifiedGLP-1(7-37) orGLP-1(7-36) can be evidence2-1The lipophilic substituents contained in. Secondly, the evidence2-1It is disclosed that the lipophilic substituent may be selected fromH00C(CH₂)16CO-of the content. Again, the evidence.4-1A linking group for better linking a reactive group to a therapeutic polypeptide is disclosedAEEA. Evidence4-1The reactive group in is equivalent to evidence2-1lipophilic groups in, and the evidence4-1It is mentioned that the reactive group is usually a carboxyl group, which is related to the evidence2-1The role of carboxyl substitution in is the same, and the connection is the same, are rightGLP-1The lysine side chain on the peptide chain is modified with an amide bond for the purpose of prolonging the action time of the parent peptide.

(3.2) Evidence2-1,3-1,4-1Both involve modificationGLP-1The purpose of modification involves extending.GLP-1Those skilled in the art can easily think of combining them based on the same purpose. InEvidence2-1,3-1,4-1On the basis of the above-mentioned contents of the disclosure, the skilled person in the art can easily think of appropriate adjustment evidence.2-1Medium embodiment37The length of the terminal lipophilic substituent on the parent peptide and its side chain groups on the disclosed compounds to prepare other analogous peptide derivatives. In the process of specific preparation, appropriate linking groups can be selected as needed to better connect the lipophilic substituent with the lysine side chain group, suchEvidence4-1disclosed linking groups, etc., and using evidence3-1Choice of ways of revelation8Peptides with mutations in amino acidsas the parent peptide. To sum up, the technical personnel in the field of evidence.2-1based on the combined evidence3-1and evidence4-1The teaching, can easily get involved in the claim.1The technical scheme, and the technical effect is also based on the general role of lipophilic substituents, amino acid substitution can be foreseen, so the claim.1is obvious, does not haveCreativity.

(4)Whether the technical effect proved by supplementary experimental data can be derived from the contents recorded in the original application documents.

(4.1)The collegial group held that:Combined with the records of the patent specification involved, it can be seen that the patentee did not emphasize and highlight that the duration of semaglutide in mice can reach the first set of experimental data (counter-evidence 1Counterevidence4-7Providedrelated activity assay experiments) mentioned in at least 48hours, the second set of experimental data can be reached in minipigs(counter-evidence 2Counterevidence8Counterevidence16-18ProvidedThe compound claimed in the present invention and the known compound Liralu.PeptideComparative experimental data on pharmacokinetics)referred to in the relevant evidence60-70Half-life of the hour. Therefore, the first and second sets of experimental data to prove the specific compound Smeglu.PeptideThe technical effect with a long action time cannot be derived from the contents recorded in the original application document, and the technical effect not disclosed in the application document and not obtained by the technical personnel in the art according to the contents recorded in the application document does not belong to the technical contribution made by the invention at the time of application.; The third set of experimental data (counter-evidence3,counter-evidence 9,10ProvidedContains LiraruPeptideandAib-LiraruPeptideComparison of pharmacokinetics) It is not to prove the technical effect of the present invention, but to proveTechnical person in this fieldstaff at that time can onlyGet reverse teaching"In Liraglutide's8position substitution does not have a longer-lasting effect”.

In addition, the patentee submitted a counter-evidence.11-13Mainly used to show that this patent meets the requirements of full disclosure., cannotThe inventive step of the present invention is proved.counter-evidence14,15It does not belong to the prior art itself, although it records the administration of liraglutide and selmeglutide, but based on the records of this patent, it is not possible to determine from many general compounds that selmeglutide can produce the clinical drug effect of once-a-week administration, which is difficult to derive from the original application documents.;ThereforeAlsoUnable to prove the inventionofCreativity. in addition,Submitted by the patenteeof2Known evidence of common senseIt is mainly used to illustrate that small rodents have a faster metabolic rate than humans, and rodents often seem to be sensitiveGLP-1compounds have a more radicalGLP-1Metabolism. It is difficult to confirm that the duration of selmeglutide in mice can reach at least according to the original instructions.48In the case of hours, it is also difficult to combine the contents of the well-known common sense evidence to further anticipate the experimental results of Smegaglutide in minipigs and humans and draw its creative conclusions based on the corresponding experimental results.

(4.2)CombinedPatent involvedAccording to the description,InvolvedThe patent specification relates to compounds of the general formula including a large number of specific compounds., and the specification only in the compound formulation example to claim the protection of the Smeglu peptide as an example of the composition can be used to explain the formulation method, that is, Smeglu peptide is still in essence need further experiments to be included from the general formula."A large number of tabular compounds" screened for "possible preferred compounds".Secondly, the patentee has not provided evidence that the general compound of this patent specification covers compounds other than selmeglutide that meet the duration of at least in mice.24The screening requirements such as hours, that is, although a variety of compounds are described in the specification, not each has the technical effect described in the present application, and those skilled in the art, without other evidence to support it, it is difficult to determine that selmegrlutide is a compound with an action time selected through experiments to meet the above requirements based on the general records in the specification.

2.Claim2-5No creative comments.

Claim2The pharmaceutical composition, claim.3-5the treatment or prevention of hyperglycemia,2type diabetes, impaired glucose tolerance,1type diabetes, hypertension,Xsyndrome, dyslipidemia, inflammatory bowel syndrome, dyspepsia and gastric ulcers, and reducedBeta-Apoptosis, increasedBeta-cell function andBeta-cell mass and/or recoveryBeta-The pharmaceutical use of glucose sensitivity of cells is based onGLP-1The hypoglycemic activity of the derivative or a derivative use having a certain correlation with the activity. Evidence2-1, Evidence3-1, Evidence4-1Both are disclosed.GLP-1The hypoglycemic activity of the derivatives can be used to prepare pharmaceutical compositions and treat diabetes, obesity and other corresponding diseases. As for the reductionBeta-Apoptosis or recoveryBeta-cell function, is evidence-based by those skilled in the art2-1For2The therapeutic effect of type 2 diabetes can be reasonably expected. Therefore in the claims1The compound is not inventive, the claim.2The pharmaceutical composition, claim.3-5The pharmaceutical use is also not inventive.

For other details of the invalid case, please consult.Section57950Invalidation Request Review Decision.