Chinese Patent No. 99805836.X
`Judgement
`
`1
`
`Your Ref: P1241R1'CN
`Our Ref: LRL80822
`
`Beijing High Court
`
`Administrative Judgment
`
`(2010) High Court - Administrative - final - no. 1295
`
`Appellor (the plaintiff of the first instance)
`
`Genentech Inc.
`
`Address: 1 DNA Way, South San Francisco, CA, USA.
`
`legal representative
`
`Ms. Diane Marschang
`
`senior attorney
`
`authorized representative
`
`Xinqin Feng
`
`Attorney
`
`Liu, Shen & Associates
`
`Dan Min
`
`patent agent,
`
`Liu, Shen & Associates
`
`Appellee (the defendant of the first instance)
`
`Patent
`
`Board
`
`, Reexamination Address: Yingu Plaza, 9 North 4th Ring West Road, Haidian
`
`District, Beijing, P.R.C.
`
`legal representative
`
`Maoyu Zhang
`
`vice director
`
`authorized representative
`
`Yi Feng
`
`Qian Zhu
`
`examiner
`
`examiner
`
`Appellee (the third party of the first instance)
`
`Caihui Lee
`
`address:
`
`room 201—202, 338 Xietu East Road, Huangpu
`
`District, Shanghai, P.R.C.
`
`authorized representative
`
`Renmin Huang
`
`patent agent
`
`Lecome
`
`Intellectural Property
`
`Agent Ltd.
`
`The appellor, Genentech Inc., was not satisfied with the Administrative Judgment, (2009)
`No.
`1 Intermediate Court
`- Administrative - first
`- no. 661, made by Beijing No.
`1
`
`Intermediate Court on the validation decision issued by the Patent Reexamination Board
`(“PRB”), and instituted this appeal before the present court. The present court accepted
`the appeal, set up a panel and held a court hearing. Ms. Diane Marschang, the legal
`representative of Genentech Inc.; Ms. Xinqin Feng and Dan Min,
`the authorized
`
`1
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`Chinese Patent No. 99805836.X
`Judgement
`
`Your Ref: P1241R1 CN
`Our Ref: LRL80822
`
`representatives of Genentech 1110.; Ms. Yi Feng and Qian Zhu,
`representative of PRB; Ms. Caihui Lee; and, Ms. Renmin Huang,
`
`the authorized
`the authorized
`
`representative of Ms. Lee, attended the hearing. The present case is now closed.
`
`PRB issued Validation Decision No. 12385 (“Decision 12385”) on October 21, 2008,
`
`declaring that all the claims of the patent No. 99805836.X (“the present patent”) are
`
`invalid. Genentech Inc. sued Decision 12385 before the Beijing No.
`
`1 Intermediate
`
`Court of China (“the first court”).
`
`The first court finds the following facts. Claim 1 of the present patent differs from the
`composition of D1 in that: D1 does not recite the technical feature that the amount of the
`
`acidic variant(s) is less than 25% in said composition. However, those skilled in the art
`can see from the disclosure of D1 that the cation exchange chromatography of D1 has
`
`measured the content percentage of the native protein and the degraded protein. The
`content of the degraded protein is in a range of 18% - 25% (corresponds to 0 — 15 days).
`The major degradation route for HER2 antibody was deamidation. It is recited in the
`
`present patent that an acidic variant of an anti—HER2 antibody is a variant formed by
`
`deamidation and is more acidic than the initial polypeptide. Thus, an acidic variant
`belongs to a degraded protein.
`It can then be deduced that the amount of acidic variant(s)
`in the composition of D1 is definitely less than the total amount of the degraded proteins
`and thus definitely less than 25%. Based on the composition of anti—HER2 antibody
`disclosed in D1,
`those skilled in the art can determine, through logical analysis and
`
`reasonable deduction, that, the amount of acidic variants in the composition of D1 is less
`
`than 25%. Therefore, Claim 1 of the present patent is obvious to those skilled in the art,
`
`and thus does not possess inventiveness over D1.
`
`From Dl, the brief description of Figures 5-8 and the steps of measuring rhuMAb HER2
`formulation in Example 1,
`it
`is seen that the % native protein in Figures 5-8 is the
`percentage for the non-degraded proteins, and it does not mean that the native protein
`
`fraction includes degraded proteins such as unpurified and un-separated acidic variants, as
`alleged by Genentech. Genentech failed to prove that such acidic variants are in the
`native protein fraction rather than in the remaining 18% non-native fraction. Therefore,
`
`the first court did not agree with Genentech’s allegation.
`
`The ion exchange chromatography for measurement and purification of a HER2 antibody
`composition certainly involves different conditions.
`Those skilled in the art can
`determine and modify the conditions with conventional means. Merely based on the
`different ion exchange chromatographic conditions, there is no reasonable ground to deny
`the fact that the amount of acidic variants in the composition measured in Figures 5-8 of
`D1 is less than 25%. The counter evidences 1 and 2 submitted by Genentech can not
`
`directly or indirectly prove that the amount of the acidic variant(s) in a HER2 antibody
`, composition measured in D1 can not be less than 25%. Moreover, Claim 1 does not
`
`define the composition by a process.
`
`In other words, Claim 1
`
`is directed to a
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`Chinese Patent No. 99805836.X
`Judgement
`
`Your Ref: P1241R1 CN
`Our Ref: LRL80822
`
`composition that can be prepared by any process. Genentech failed to provide sufficient
`reasons and evidences in the responses and oral hearing to prove that, the amount of acidic
`variant(s)‘ in a HER2 antibody composition is impossible to be less than 25% under the
`chromatography of D1 or any other slightly modified condition. Thus, Genentech’s
`argument that, due to difficulty in protein purification, the composition of Claim 1 can be
`obtained by none of the prior art processes but only the process of the present patent, is
`
`not convincing.
`
`The dependent claims 2 and 3 further define that the composition of Claim 1 further
`
`comprises a pharrnaceutically acceptable carrier and that said anti-HER2 antibody is
`humMAb4D5—8, respectively. The above additional technical features are disclosed in
`D1. Thus, when Claim 1 does not possess inventiveness, Claims 2 and 3 do not possess
`
`inventiveness over D1, either.
`
`In conclusion, Decision 12385 recognizes the exact facts and applies the appropriate laws
`
`and rules. According to the provision of Article 54, Item (1) of ADMINISTRATIVE
`PROCEDURE LAW OF THE PEOPLE'S REPUBLIC OF CHINA, a judgnent is made to
`sustain Decision 12385.
`
`Genentech was not satisfied with the judgment made by the first court and instituted an
`appeal.
`Genentech alleged that:
`1.
`the first court seriously misunderstood the
`explanation of the acidic variant provided by the appellor, and improperly deemed that the
`appellor admitted that the composition of D1 comprised the acidic variants.
`2. The first
`court and PRB both ignored an important reason provided by the appellor in the argument
`
`regarding “D1 does not disclose or imply the claims of the present patent”: D1 does not
`
`disclose the presence of an acidic variant, while it is defined in the claims of the present
`patent that the composition comprises acidic variants (see Supplemental submitted by the
`appellor to the first court on November 11, 2009, especially pages 2 and 3).
`3. The first
`8 court and PRB improperly deemed that (1) the fraction other than the 82% native (not
`degraded) proteins in D1 is definitely “degraded protein”, and that (2) those skilled in the
`art can reach the conclusion without additional information.
`In fact,
`it is completely
`
`the remainder of the composition in addition to the 82% native
`unclear what
`(non—degraded) portion was.
`4. The first court and PRB improperly deemed that the
`
`composition of Claim 1 of the present patent could be obtained by the process of D1 or
`another slightly revised process.
`5. The first court and PRB improperly required the
`appellor rather than PRB and Caihui Lee to prove what the portion (the portion of 18%) in
`addition to the “native” (non-degraded) portion was. Based on the above reasons,
`Genentech deemed that the judgment of the first court was made on facts recognized
`improperly and according to improper laws. Therefore, Genentech requested the higher
`court to repeal the judgment made by the first court and repeal Decision 123 85 issued by
`PRB.
`‘
`
`PRB insisted on Decision 12385. PRB deemed that the judgment made by the first court
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`Chinese Patent No. 99805836.X
`Judgement
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`7 Your Ref: P1241Rl CN
`Our Ref: LRL80822
`
`was made based on facts recognized properly and according to proper laws, and the
`procedure of examination and judgment was legal. PRB also deemed that the appeal of
`
`PRB requested the higher court to reject the
`Genentech lacks factual and legal basis.
`appeal of Genentech and sustain the judgment made by the fist instance.
`
`Caihui Lee agreed with PRB.
`
`During the procedures of the first
`
`instance of the present case, PRB submitted the
`
`following main evidences: 1. a copy of the PCT international application publication No.
`WO 97/04801 A1 published on February 13, 1997, 46 pages in total (i.e., the evidence D1
`
`in Decision 12385); 2. a copy of the specification of the present patent.
`
`Genentech submitted the following main evidences to the first court: 1. a copy of the PCT
`
`international application publication No. WO 97/04801 A1 published on February 13,
`1997, 46 pages in total (i.e., the evidence D1 in Decision 12385); 2. a copy of the
`specification of the present patent; 3. a copy of Jiacheng Hua, et al., “Practical Chemical
`Technology on Proteins”, published in Chinese language, Shanghai Scientific & Technical
`Publishers, cover page, pages 1-3, 15 and 16, all together 6 pages (i.e.,
`the counter
`evidence 1
`in Decision 12385); 4. a copy of Li’an Guo, “Theory and Technology on
`Purification of Proteins by HPLC”, published in Chinese language, Shanxi Scientific &
`Technical Publishers, cover page, pages 1, 2, 4, 78, 79 and 387—394, all together 12 pages
`
`(i.e., the counter evidence 2 in Decision 123 85).
`
`Caihui Lee did not submit any evidence to the first court.
`
`After examination,
`
`the first court deemed that, all evidences submitted by PRB and
`
`Genentech were related with the legality examination of Decision 12385 of the present
`case, and complied with the formal requirement for legality and authenticity, and thus
`
`were acceptable.
`
`The above evidences were all transferred to the present court together with the file.
`During the procedures of the second instance, no new evidence was submitted by either
`party. After court hearing and investigation, the present court finds that the opinion of
`the first court is correct and thus recognizes the following facts of the present case.
`
`The present case relates to a patent entitled “PROTEIN PURIFICATION BY ION
`EXCHANGE CHROMATOGRAPHY” issued on June 21, 2006.
`For the present patent,
`
`the application number is 99805836.X, the filing date is May 3, 1999, and the priority date
`
`is May 6, 1998. The patentee is Genentech. The granted claims of the present patent
`' are as follows:
`
`1. A composition comprising a mixture of anti-HER2 antibody and one or more acidic
`variants thereof, wherein the amount of the acidic variant(s) is less than 25%.
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`Chinese Patent No. 99805836.X
`Judgement
`
`Your Ref: P1241R1 CN
`Our Ref: LRL80822
`
`2. The composition of claim 1 further comprising a pharmaceutically acceptable carrier.
`3. The composition of claim 1 wherein the anti-HER2 antibody is humMAb4D5—8.
`
`Caihui Lee submitted a Request for Invalidation against the present patent on March 25,
`
`2008 to PRB, together with the following evidences: 1. D1, acopy of a PCT international
`
`application publication No. WO 97/04801 A1 published on February 13, 1997, 46 pages
`
`in total; 2. D2, a copy of a PCT international application publication No. WO 96/33208
`
`Al published on October 24, 1996, 39 pages in total; 3. D3, a copy of Fusheng Han,
`“Chromatofocusing - a novel method for isolating protein”, Physiological Science, 1982,
`
`2(9):13—14, published in Chinese language; 4. D4, a copy of Raojun Guo et a1.,
`“Immobilized pH Gradient Isoelectrofocusing,
`the electrophoresis technique with the
`highest
`resolution nowadays, 1994, 21(2):l43-146, published in Chinese language.
`Meanwhile, Caihui Lee submitted the Chinese translation of D1 (47 pages in total) (i.e. a
`
`copy of the granted Chinese patent No. 961958308, which is announced on June 2, 2004),
`
`and some parts of D2 (4 pages in total).
`
`In the Request for Invalidation, Caihui Lee alleged that, (1) D1 discloses a formulation of
`a composition comprising the anti~HER2 antibody of Claim 1 of the present patent (see
`Example 1 on Pages 18-27 of the English description of D1). The protein in said
`formulation is essentially pure (i.e. a composition comprising about 90%, 95% and 99%
`by weight of the protein) and homogeneous (i.e. free of contaminating proteins etc.) (see
`Lines 5-9, Page 7 of the English description of D1).
`In the liquid state, rhuMAb HER2
`was observed to degrade by deamidation (30Asn of light chain) and isoaspartate formation
`via a cyclic imide intermediate, succinimide (102Asp of heavy chain). There is a
`relatively greater deamidation in protein formulations (see lines 13—15, page 19 of the
`English description of D1).
`Therefore, D1 discloses a composition comprising the
`anti—HER2 antibody and one or more acidic variants thereof. Moreover, the conditions of
`cation exchange chromatography on rhuMAb HER2 deamidation and succinimide
`formation in D1 (see Pages 25-26 of the English description of D1) are identical with the
`chromatographic condition for determining rhuMAb HER2 in the present patent.
`Meanwhile, Figures 5-8 in D1 disclose the result of the assays (see lines 20—38, page 4 of
`the English description of D1).
`It is seen from the figures that the content of the native
`(non-degraded) protein was gradually decreased from 82% along with the storage of the
`rhuMAb HER2 formulation, but the content of the native protein remained no less than
`
`In other words, the content of degraded proteins in the formulation is less than
`75%.
`25%. The aforesaid disclosure suggests that, the amount of the acidic variant(s) in the
`composition as disclosed in D1 is less than 25%. Therefore, all the technical features of
`Claim 1 of the present patent are disclosed by D1, and Claim 1 does not comply with the
`provision on novelty as required by Article 22, paragraph 2 of the Chinese Patent Law.
`The additional technical features of the dependent claims 2 and 3 are also disclosed in D1,
`and thus Claims 2 and 3 do not possess novelty, either.
`(2) Claims 1-3 do not possess
`inventiveness over D2 in combination with D3 or D4. DZ discloses an anti-HER2
`
`antibody and the method for the purification of antibody proteins. DB and D4 disclose
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`Chinese Patent No. 99805836.X
`
`Judgement Our Ref: LRL80822
`
`the _
`for
`isoelectric focusing electrophoresis
`the methods of chromatofocusing or
`purification. of proteins, respectively. Using the methods disclosed by D2 or D3 or D4, it
`is possible to isolate the acidic variants in the antibody, so as to obtain the antibody
`
`composition of Claim 1. Therefore, Claim 1 does not comply with the provision of
`
`Article 22, paragraph 3 of the Chinese Patent Law. The additional technical features of
`
`the dependent claims 2 and 3 are also disclosed in D2, and thus Claims 2 and 3 do not
`
`possess inventiveness, either.
`
`After a formality examination, l’R‘B accepted said request, and issued the Notification of
`
`Acceptance ot‘the Request. for itwalidation to Cienenteeh and Caihui Lee on April 1 l, 2008,
`and transferred 2: copy of the Request for invalidation and the attachments thereof to
`Genentech, requiring Genentech to respond within the specified time limit.
`
`On April 25, 2008, Caihui Lee submitted the supplementary observations. Caihui Lee
`alleged that, (1) Claims 1-3 do not possess inventiveness over D1. D1 discloses that in
`the liquid state, rhuMAb HER2 was observed to degrade by deamidation (30Asn of light
`chain) and isoaspartate formation via a cyclic imide intermediate, succinimide (102Asp of
`heavy chain).
`There is
`a relatively greater amount of deamidation in protein
`formulations. Meanwhile, those skilled in the art understand that: the conditions of the
`cation exchange chromatography in D1 can separate the native protein from the degraded
`proteins, if a single elution peak from the cation exchange chromatography is collected,
`the native protein of a high purity (more than 25%) will definitely be obtained.
`Therefore, those skilled in the art can obtain the technical solution of Claim 1 of the
`
`present patent without creative work on the basis of D1 in combination with the common
`knowledge, and Claim 1 does not possess inventiveness.
`The additional
`technical
`features of the dependent claims 2 and 3 are also disclosed in D1, and thus Claims 2 and 3
`
`(2) Claims 1-3 do not possess inventiveness over
`do not possess inventiveness, either.
`the combination of D1 and D2. D2 discloses the method for preparation and purification
`
`of a rhuMab 4D5-8 HER2 antibody.
`
`«The technical solutions of Claims 1—3 of the present
`
`{3).Claims l-3 do not possess
`patent are obvious in light. of DB in combination with Dl.
`inventiveness over 91 and D2 in combination with D3 or D4.
`133 and D4 disclose the
`
`methods of ohrmnatofocusing or isoelectrie focusing electrophoresis for the purification of
`proteins, respectively. Those skilled in the art can easily obtain. the technical solutions of
`Claims l~~3 of the present patent by applying the technical means ofD3 or D4 on the basis
`of I): in combination. with D 1.
`
`In response to the Request for invalidation. submitted by Caihui ice on March .335, 2008,
`Genentech submitted the observations on Wiley 126, 2008. Genenteeh alleged that, ( 1) D1
`neither descrihes a composition of the present patent, nor discloses the technical feature of
`“amount of the acidic variant(s) is less than about 25%”, nor provides a description of how
`to prepare such a composition. Hence, Claims 1-3 of the present patent do possess
`novelty over D1.
`(2) D2 merely provides a method to remove an antibody fragment
`failing to correctly associate through disulfide bonding, which is diffierent from the
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`Chinese Patent No. 99805836.X
`Judgement
`
`,
`
`Your Ref: P1241R1 CN
`Our Ref: LRL80822
`
`technical problem of decreasing the amount of the acidic variant(s) in the composition to
`
`be solved in the present patent. D3 and D4 do not disclose that said method can reduce
`the content of the acidic variants in the composition. Thus, said antibody composition of
`Claim 1
`in the present patent does possess inventiveness over D2 alone, or D2 in
`combination with D3 or D4.
`In addition, Genentech questions the authenticity of D3 and
`D4.
`
`PRB transferred a copy of the Observations and the attachments submitted by Caihui Lee
`on April 25, 2008 to Genentech on June 20, 2008. On July 21, 2008, PRB issued the
`
`Notification of Oral Hearings of the Request for Invalidation to the two parties, informing
`
`that an oral hearing with regard to the Request for Invalidation of the present patent would
`
`be held on August 27, 2008. Additionally, PRB transferred a copy of the Observations
`submitted by Genentechon May 26, 2008 to Caihui Lee.
`
`In response to the Observations submitted by Caihui Lee on April 25, 2008, Genentech
`submitted the Observations on August 5, 2008. Genentech alleged that,
`(1) The
`conditions of cation exchange chromatography for determining the protein in D1 is totally
`different from the conditions of cation exchange chromatography for separating and
`
`collecting a composition comprising less than 25% acidic variants used in the present
`patent.
`It is not possible to obtain an anti-HER2 antibody composition comprising less .
`than 25% acidic variants of Claim 1 of the present patent, using the cation exchange
`chromatography in D1,
`simply by collecting the single
`elution peak of
`said
`chromatography.
`/ (2) On page 19, lines 25-27, D1 explains that the “major degradation
`route for this protein [rhuMAb HERZ] upon lyophilization was aggregation, and therefore
`the protein stability was assessed by non-denaturing size exclusion chromatography to
`measure the recovery of intact native protein.” D1 emphasizes a non-degraded protein
`that is non-aggregated protein rather than a composition without acidic variants.
`(3) The
`Figures 5-8 of D1 neither determines whether the percentage of the protein other than
`native protein represents acidic variants or not, nor teaches how to reduce the amount of
`acidic variants to less than 25% by ion exchange chromatography with specific conditiOns.
`Therefore, from the disclosure of D1, those skilled in the art can not obtain the technical
`
`inspirations of the composition of the present patent and how to prepare the composition.
`Claims 1-3 do possess inventiveness over D1.
`In addition, the technical solutions of
`Claims 1—3 in the present patent do possess inventiveness over D1 in combination with D2,
`or over D1 in combination with D2 and D3, or over D1 in combination with D2 and D4.
`
`PRB transferred the copies of the response submitted by Genentech on August 5, 2008 to
`
`Caihui Lee on August 19, 2008.
`
`‘
`
`the oral hearing was held as scheduled. Caihui Lee and her
`On August 27, 2008,
`authorized representative and the authorized representatives of Genentech were present in
`the oral hearing.
`PRB investigated the reasons and relevant facts for invalidation with
`regard to the present case one by one. The parties concerned sufficiently stated their
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`Judgement Our Ref: LRL80822
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`respective opinions. The facts determined by the investigation in the oral hearing were
`as follows: (1) The two parties did not object the identity and qualification of the stafi' of
`the opposing party, and did not request evasion of any member in the Panel.
`(2) Caihui
`Lee gave up D2 and the reason that Claims 1-3 are not inventive over D2 in the oral
`hearing.
`(3) Caihui Lee clarified the grounds and scope for invalidation in the oral
`
`hearing as follows: Claims 1—3 of the present patent do not possess novelty over D1;
`Claims 1-3 of the present patent do not possess inventiveness over D1 alone or in
`combination with D3 or D4.
`(4) Caihui Lee presented the copies of D3 and D4 stamped
`with the seal of information service department, Shanghai Technology and Science
`Intelligence Research Institutes, Shanghai Library.
`Genentech did not object
`the
`authenticity, legality, relevance and public availability of D3 and D4.
`(5) Genentech did
`not object the authenticity,
`legality, relevance and public availability of D1 and the
`accuracy of the translations thereof.
`(6) Genentech submitted the counter evidence 1 and
`the counter evidence 2 and the copies thereof as common knowledge evidence during the
`oral hearing. Caihui Lee did not object to the authenticity, legality, relevance and public
`
`availability of the counter evidence 1 and the counter evidence 2.
`
`Genentech submitted the following counter evidences during the oral hearing: the counter
`evidence 1, a copy of Jiacheng Hua, et a1., “Practical Chemical Technology on Proteins”,
`Shanghai Scientific & Technical .Publishers, cover page, pages 1-3, 15 and 16, 6 pages in
`total, published in Chinese language; the counter evidence 2, Li’an Guo, “Theory and
`Technology on Purification of Proteins by HPLC”, Shanxi Scientific & Technical
`Publishers, cover page, pages 1, 2, 4, 78, 79 and 387-394, 12 pages in total, published in
`
`Chinese language.
`
`Genentech and Caihui Lee submitted written statements showing the comments presented
`
`at the oral hearing, on September 1 and September 3, 2008, respectively.
`
`Based on the above procedures, PRB alleged that,
`
`1. With regard to the text for examination
`
`Decision 12385 was based on the text of the present patent that was granted and
`announced.
`
`2. With regard to the grounds and evidence for invalidation
`
`‘ Caihui Lee gave up D2 and the relevant reasons in court. Thus, no comment on this
`evidence and the relevant reasons was provided. D1 is a patent, and D3 and D4 are
`published journals. Caihui Lee presented the copies of D3 and D4 stamped with the seal
`of information service department, Shanghai Technology and Science Intelligence
`Research Institutes, Shanghai Library. Genentech did not object the authenticity, legality,
`relevance and public availability of D1, D3 and D4 and the accuracy of the translation of
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`Chinese Patent No, 99805836.X
`Judgement
`
`Your Ref: P1241Rl CN
`Our Ref: LRL80822
`
`,
`
`D1. All these three evidences were published before the date of filing of the present
`patent. Hence, D1, D3 and D4 can be regarded as the prior art to comment on novelty
`and inventiveness of the present patent. Caihui Lee did not object the authenticity,
`
`legality, relevance and public availability of the counter evidence 1 and the counter
`evidence 2 submitted by Genentech as common knowledge. Thus, the counter evidence
`
`1 and the counter evidence 2 were accepted.
`
`Based on the statements of Caihui Lee during the oral hearing, grounds for invalidation
`were that: Claims 1—3 are do no possess novelty over D1 and thus do not comply with the
`provision of Article 22, paragraph 2 of the Chinese Patent Law; Claims 1—3 do not possess
`inventiveness over D1 alone or in combination with D3 or D4, and thus do not comply
`
`with the provision of Article 22, paragraph 3 of the Chinese Patent Law.
`
`3. With regard to Article 22, paragraph 3 of the Chinese Patent Law
`
`According to Article 22, paragraph 3 of the Chinese Patent Law, inventiveness means that,
`as compared with the technology existed before the filing date,
`the invention has
`prominent substantive features and represents a notable progress and that the utility model
`
`has substantive features and represents progress.
`
`When determining whether an invention is inventive or not, the claimed technical solution
`shall be compared with the closest prior art so as to determine the distinguishing features
`of the claimed invention.
`If the technical solution with the distinguishing features can be
`
`figured out by those skilled in the art through logical analysis or reasonable inference
`
`based on the closest prior art, said technical solution is obvious and does not possess
`inventiveness.
`
`is directed to a composition comprising a mixture of
`Claim 1 of the present patent
`anti-HER2 antibody and one or more acidic variants thereof, wherein the amount of the
`acidic variant(s) is less than 25%.
`D1 discloses a formulation of a composition
`comprising a HER2 antibody, wherein the HER2 antibody protein is essentially pure (i.e. a
`composition comprising about 90%, 95% and 99% by weight of the protein) and
`homogeneous (i.e. free of contaminating proteins etc.) (see Lines 5-9, Page 7 of the
`English description of D1).
`Slightly greater deamidation was observed in said HER2
`antibody protein formulation. The rhuMAb HER2 was observed to degrade in the
`aqueous solution mainly by deamidation (30Asn of light chain) or isoaspartate formation
`via a cyclic imide intermediate, succinimide (102Asp of heavy chain) (see lines 13-15,
`page 19, lines 14-16, pages 26 of the English description of D1). The amount of native
`protein in the rhuMAb HER2 formation upon deamidation or succinimide formation was
`measured by cation exchange chromatography (see lines 13-20, page 26 of the English
`description of D1). Meanwhile, Figures 5-8 in D1 disclose the result of the assays (see
`lines 20-3 8, page 4 of the English description of D1).
`It is seen from the figures that the
`content of the native (non—degraded) protein was gradually decreased from 82% along
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`Pfizer Ex. 1029
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`Page 9 of 14
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`Pfizer Ex. 1029
`Page 9 of 14
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`

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`Your Ref: P 1241Rl CN
`Chinese Patent No. 99805836.X
`
`Judgement Our Ref: LRL80822
`
`with the storage of the rhuMAb HER2 formulation, but the content of the native protein
`remained no less than 75%.
`In other words, the content of degraded proteins was less
`than 25%.
`
`Therefore, D1 discloses a composition comprising an anti—HER2 antibody and degraded
`variants thereof with an amount less than 25%. The technical solution of Claim 1 of the
`
`present patent differs from the composition of D1 in that: Dl does not recite the technical
`feature that the amount of the acidic variant(s) is less than 25% in said composition.
`However,
`those skilled in the art can see from the disclosure of D1 that the cation
`
`exchange chromatography of D1 has measured the content percentage of the native protein
`and the degraded protein. The content of the degraded protein is in a range of 18% -
`25% (the corresponding time point is in a range of 0 ; 15 days).
`Since the major
`degradation route for HER2 antibody was deamidation, the acidic variants of anti-HER2
`antibody in the present patent are a variant of the HER2 antibody polypeptide formed by
`deamidation, which is more acidic than the initial polypeptide (see lines 19-33, page 5 of
`the English description of the present patent). Thus, said acidic variants are degraded
`protein. Thereby,
`it can be deduced that the amount of the acidic variant(s) in the
`composition formulation of a HER2 antibody protein measured in D1 is definitely less
`than the total amount of the degraded protein and thus definitely less than 25%. Thus,
`based of the anti-HER2 antibody composition disclosed in D1, those skilled in the art can
`determine that the amount of the acidic variants in the HER2 antibody protein composition
`
`disclosed in D1 is less than 25% through logical analysis and reasonable deduction.
`Therefore, the technical solution of Claim 1 of the present patent is obviOus to those
`skilled in the art, and does not possess inventiveness over D1 and thus does not comply
`with the provision of Article 22, paragraph 3 of the Chinese Patent Law.
`
`Genentech admitted during the oral hearing that Dl discloses a composition comprising
`the anti—HER2 antibody and one or more acidic variants thereof, but still alleged that: l)
`The result of the assays disclosed in Figures 5-8 of D1 can not prove that the remaining
`18% component of the composition is acidic variants. Although the native protein ,
`percentage is indicated to be 82%, said native protein component contains unpurified and
`unseparated acidic variants. Thus, the Figures 5-8 of D1 neither determines whether the
`percentage of the protein other than the native protein represents the acidic variant, nor
`teaches how to reduce the amount of acidic variants to less than 25% by the ion exchange
`
`'2) The condition of cation exchange
`chromatography with specific conditions.
`chromatography for determining the protein as disclosed in D1 is totally different from the
`condition of the cation exchange chromatography for separating and collecting a
`composition comprising less than 25% acidic variants as used in the present patent. That
`is to say, it is not possible to obtain a composition of the anti-HER2 antibody and its acidic
`variants comprising less than 25% acidic variants of Claim 1 of the present patent, using
`the cation exchange chromatography in D1, simply by collecting the single elution peak of
`said chromatography.
`3) On page 19, ’ lines 25—27, Dl explains that
`the “major
`degradation route for this proteinIrhuMAb HER2] upon lyophilization was aggregation,
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`Page 10 of 14
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`Pfizer Ex. 1029
`Page 10 of 14
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`

`

`Your Ref: P 124lRl CN
`Chinese Patent No. 99805836.X
`
`Judgement Our Ref: LRL80822
`
`and therefore the protein stability was assessed by non-denaturing size exclusion
`chromatography to measure the recovery of intact native protein.” D1 emphasizes a
`
`non-degraded protein that is not the aggregated protein instead of a composition without
`
`the result of the assays disclosed in D1 mainly shows the
`Thus,
`acidic variants.
`degradation of the protein caused by aggregation” before or after the reconstruction of
`formulation, which has no relation to the degradation of the acidic variants.
`In sum, D1
`neither discloses the composition of the present patent, nor teaches hOW to prepare the
`composition.
`From the disclosure of D1, those skilled in the art can not obtain the
`
`technical inspiration of the composition of the present patent and of how to prepare the
`
`composition. Meanwhile, Genentech submitted the counter evidence 1 and the counter
`
`evidence 2 to demonstrate that in general, there is difficulty of purification with respect of
`an ordinary protein.
`It is not possible to obtain a composition of comprising a mixture of
`anti—HER2 antibody and acidic variants thereof, wherein the amount of the acidic variant(s)
`
`is less than 25%